Primary combination therapy of early Parkinson's disease. A long-term comparison between the combined regimen bromocriptine/levodopa and levodopa monotherapy--first interim report.

The aim of this multicenter randomized prospective study in patients with early Parkinson's disease is to differentiate over a 4-year period between levodopa/benserazide monotherapy and the corresponding combination with bromocriptine by the assessment of motorial side effects, therapeutical benefit and fine motorial skills. Although there is circumstantial evidence, that partial substitution of levodopa by bromocriptine carries benefit in preventing late levodopa-specific side effects and delaying the declining therapeutical benefit, so far no knowledge has been available how levodopa and the corresponding combination with bromocriptine would compare on a long-term basis. Such study appears all the more important since there are experimental findings consistent with a neurotoxic effect of levodopa on the one hand and some 'protective' impact of bromocriptine on the other. As to the practical procedure of the comparison, all patients were first treated with a levodopa monotherapy for 3 months. This was a platform for the consecutive randomized splitting of the patients into two groups receiving either continuing levodopa therapy or combination therapy, based upon at least 40 +/- 10% substitution of levodopa by bromocriptine. The investigation methods included, besides the usual clinical rating scales (Webster, Zung, Hoehn and Yahr), an apparative test series, the so-called 'MLS', which allowed a sensitive and reliable assessment of fine motorial skills. The results of the first 3 months of treatment with levodopa monotherapy before the consecutive splitting into the two treatment regimens demonstrate that the randomization was successful and that there were no significant differences, that potentially might interfere with the drug-specific evaluation afterwards. The results of the substitution phase show that combined treatment permitted a mean reduction of the levodopa dosage by 40%, without deterioration of therapeutic response. In addition, feasibility of the overall approach based upon a sophisticated interplay between the practising neurologists (101) and the centers (27) was demonstrated.


An interim report of the effect of selegiline (L-deprenyl) on the progression of disability in early Parkinson's disease. The Parkinson Study Group.

The pathogenesis of Parkinson's disease (PD) has been linked to oxidative-mediated events including increased monoamine oxidase (MAO) and free-radical generation. We are investigating the ability of the MAO inhibitor, selegiline (deprenyl), and of the free-radical scavenger, tocopherol, to delay the onset of disability requiring levodopa therapy (primary end point) in patients with early PD. Eight hundred patients with early, untreated PD were enrolled in the multi-center placebo-controlled, double-blind clinical trial 'Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP)'. Subjects were assigned by 2 x 2 factorial design to receive selegiline (10 mg/day), tocopherol (2,000 IU/day), a combination of both drugs, or placebo, and followed to determine if and when disability occurred requiring levodopa therapy. After 12 +/- 5 months of observation, independent monitoring prompted a preliminary analysis indicating that selegiline 10 mg/day significantly extended the time to the primary end point. Selegiline therapy, alone or in combination with tocopherol, resulted in a 57% reduction in the rate of developing disability requiring levodopa therapy (p < 10(-10)) and a 50% reduction in the rate of loss of full-time employment (p = 0.01). Deterioration of motor and mental features was significantly less in selegiline-treated subjects. Adverse effects were minor and infrequent. We conclude from these preliminary results that selegiline (10 mg/day) delays the onset of disability associated with early, otherwise untreated PD. It remains unclear whether these benefits derive from mechanisms that are symptomatic (dopaminergic), protective (anti-neurotoxic), or both. The DATATOP study is ongoing to examine the long-term effects of selegiline and the independent and interactive effects of tocopherol.


Nation-wide collaborative study on the long-term effects of bromocriptine in the treatment of parkinsonian patients. Final report.

Final results of the 5-year multicentric collaborative study on the long-term effects of bromocriptine in the patients with Parkinson's disease are reported. This prospective study started in May 1985 in order to see whether the early combination therapy with bromocriptine and levodopa is really superior to the levodopa monotherapy with regard to the late side effects of levodopa in the treatment of parkinsonian patients. Another project of the study was to see the therapeutic efficacy of bromocriptine monotherapy without concomitant use of levodopa. For these purposes, a total of 702 patients with Parkinson's disease were enrolled into three groups: Group 1 (n = 286) with bromocriptine monotherapy, Group 2A (n = 216) with early combination of bromocriptine and levodopa, and Group 2B (n = 200) with levodopa alone. At the end of the 5-year study, 48 patients in Group 1 (16.8%) were still continuing bromocriptine monotherapy with satisfactorily good therapeutic effects. About half (49.1%) of the Group 2A patients remained on the combined therapy, and the comparable number of the Group 2B patients (46.0%) were also kept on the initial mode of therapy, while 13.5% of the latter group with levodopa monotherapy needed bromocriptine to be added in order to assure the good therapeutic effects. Moreover, significant differences were seen between group 2A and Group 2B with regard to the incidence of wearing-off phenomenon and dyskinesias. Disappearance rate of dyskinesias which were present at the time of enrollment was significantly higher in Group 2A than in Group 2B. No significant difference was noted as to the incidence of untoward symptoms and the death rate among all three therapeutic groups. These results support the view that the early combination of bromocriptine with levodopa is superior to levodopa alone in the treatment of Parkinson's disease.


Pharmacokinetics and metabolism of [3H]-pipethiaden in healthy volunteers.

Six healthy volunteers participated in a single-dose study of pharmacokinetics and metabolism of oral administration of [3H]-pipethiaden (1 mg). Plasma levels of total radioactivity, urinary excretion and metabolism were analyzed by liquid scintillation counting and radio-TLC. The mean peak plasma concentration of radioactive metabolites was 4.9 ng eq/ml, and the mean elimination half life was 11.5 h. 34% of radioactivity was recovered in 4 days in urine, with only 0.4% present as unchanged drug. Pipethiaden was extensively metabolized by S-oxidation, N-demethylation, and N-oxidation.


Sixty minutes normothermic ischemia in rat liver: the declining tissue concentration of hypoxanthine during reperfusion is not a washout phenomenon.

A rat liver normothermic ischemia-reperfusion model was used to investigate whether hypoxanthine (HXA) that accumulated during ischemia was washed out in hepatic veins during reperfusion. Ischemia was induced in median and left lobes by clamping of the proper hepatic artery and portal branches. The effect of allopurinol (ALL) on metabolism of ATP and HXA was studied before, during and after a 60-min normothermic ischemic insult. Liver cell concentration of HXA in the group treated with ALL increased during ischemia and decreased rapidly during the first 10-min reperfusion. Recovery of ATP increased gradually during the 10-min reperfusion period and was significantly higher in the group treated by ALL compared to that of controls. Liver venous blood concentration of HXA in the ALL-treated group was 10-to 40-fold lower than that in liver tissue. The rapidly decreasing concentration of HXA in liver tissue during reperfusion and a minimal washout may indicate that HXA was used for resynthesis of ATP during reperfusion.


Decrease in regeneration capacity of rat liver after external biliary drainage.

In order to discover the effect of external biliary drainage on liver regeneration, we have produced a model system carrying cannula in the common bile duct of rat liver and examined the regeneration capacity of liver after partial hepatectomy under various conditions. Previously we have shown that hepatic cells proliferate by obstructive jaundice alone without partial hepatectomy [Terasaki et al; Jpn J Cancer Res 1991;82:170-175]. In the present study, we showed that DNA polymerase-alpha was induced by partial hepatectomy of rats suffering from obstructive jaundice and the induced level was similar to that of the normal regenerating liver. The level of DNA polymerase-alpha activity corresponded well to the liver regeneration capacity estimated by mitotic index. Contrary to our expectation, external biliary drainage for obstructive jaundice markedly suppressed the regeneration capacity of the remaining liver which was estimated by DNA polymerase-alpha activity, mitotic index and [3H]thymidine incorporation. The suppression may be due to the external biliary drainage itself because the liver regeneration of normal rats without jaundice was also suppressed by the biliary drainage. These results suggest that the external biliary drainage seriously suppresses the regeneration capacity of liver at least at the early stage of obstructive jaundice.


Mass spectrometric identification of urinary and plasma metabolites of 2-(6'-carboxyhexyl)-3-n-hexylcyclohexylamine, a new antiaggregating agent.

The compound IBI-P-05006, 2-(6'-carboxyhexyl)-3-n-hexylcyclohexylamine, is an antiaggregating agent under development. IBI-P-05006 is an in vitro inhibitor of platelet aggregation. The biotransformation of this compound has been studied in the dog and rat. We present here a study on the metabolites of IBI-P-05006 found in dog and rat urine, and in dog plasma. Analyses were done by gas chromatography-mass spectrometry. In dog urine 15 metabolites were identified. Some of them were also found in dog plasma and in rat urine. The unmetabolized drug was found only in plasma. 10 different hydroxylated metabolites were characterized. The hydroxyl groups were introduced in the hexyl chain in positions omega-4, omega-3, omega-2, omega-1 and omega.


A standardized surgical technique to obtain a stable and reproducible chronic renal failure model in dogs.

The remnant kidney, a model of chronic renal failure in animals, can be obtained by two techniques: either surgical removal of tissue of one kidney, combined with contralateral nephrectomy or inducing necrosis of kidney tissue by ligation of branches of the renal artery of one kidney combined with contralateral nephrectomy. In the literature, most reports concern the ligation technique. The technique is safe and simple but the results in dogs are unpredictable. In this paper, both techniques were compared. We could demonstrate that the unpredictable result of the ligation technique is due to the formation of collateral vessels bypassing the ligated branches and to the inconstant ramification pattern of the renal artery. In this study, a standardized technique consisting of the resection of 16-18 g of tissue of one beagle kidney and removal of the other one is described. This method results in a stable chronic renal failure until the dogs are sacrificed at 9-12 months.


Variations of magnesium, iron, copper and zinc during the colonic wound healing process: experimental study on rabbits.

The role of trace elements in the wound-healing process is still controversial. Their variations within a normal colonic wound healing have never been studied. An experimental study on rabbits was designed to study magnesium, iron, copper and zinc variations in blood, normal colonic walls and colonic anastomoses on each of the first 7 postoperative days. No major variations of Mg could be observed. Fe decreased in blood as well as in colonic walls and anastomoses. Cu increased in blood, whereas it decreased in colonic walls and anastomoses. Zn decreased in blood, whereas it increased in colonic walls without significant changes in anastomoses. The role of Fe seemed to be rather difficult to understand. Plasma mobilization seems to explain the local use of Zn, while early tissue release with further return in blood occurred for Cu. The importance of a well-balanced nutritional status is underlined to prevent and correct the variations of trace elements in the postoperative course.


Whole pancreatic blood flow and islet blood flow in hypovolemic hypotension in rats.

The blood volume of adult, male rats was reduced with 5 ml (approximately 30% of the total blood volume) by bleeding, which reduced the mean arterial blood pressure (MAP) to 50 mm Hg. This hemorrhagic hypotension caused an increase in both serum glucose and serum insulin concentrations when compared with either normotensive control animals or with rats infused with nitroprusside to obtain an MAP similar to that of the bled animals. The blood perfusion of the whole pancreas was reduced in both groups of hypotensive animals but more markedly in those with hemorrhagic hypotension. The islet blood flow was reduced only in the bled animals. The percentage fraction of blood diverted through the islet organ was markedly increased in bled rats compared to the control animals, whilst this increase was less pronounced in the nitroprusside-infused rats. The vascular conductance in the nitroprusside-treated rats was unchanged for the whole gland, but increased for the islets. Both these values in bled animals were decreased. It is concluded that the blood flow regulation differs between the endocrine and exocrine parts of the pancreas in hypovolemic hypotension.


Effect of activated protein C on impaired fibrinolysis in rats with obstructive jaundice.

We studied the effect of activated protein C (APC) on impaired fibrinolysis using a rat model in which disseminated intravascular coagulation (DIC) is induced by the intravenous injection of endotoxin in rats with obstructive jaundice. An intravenous injection of endotoxin in rats with obstructive jaundice resulted in pulmonary hemorrhages and a marked increase in the plasma levels of tissue-type plasminogen activator (t-PA) antigen and plasminogen activator inhibitor activity. Prophylaxis with APC before the injection of endotoxin resulted in a decrease of the number of lung hemorrhages and an accelerated release of t-PA antigen. Thus, DIC in obstructive jaundice may be due to impairment of fibrinolysis and an increased susceptibility of endothelial cells to endotoxin. APC may be effective as a treatment for patients with obstructive jaundice associated with DIC.


An electrohydrothermosation system for application in endolaryngeal and enoral surgery: a technical report.

The use of medical lasers or high-frequency (HF) devices ('electrocautery') allows the dissection of tissue by an application of heat. The main advantage of such techniques is the reduction of intra-operative bleeding. On the other hand, carbonization and coagulation lead to difficulties in the histological investigation of the resected specimen. Electrohydrothermosation (EHT) systems are irrigation-supported HF devices. The cutting or coagulation electrodes are continuously rinsed with distilled water in order to minimize thermal interactions with the tissue. We developed an EHT system for endoscopic head and neck surgery. The system was used to remove defined specimens from pig larynges and tongues experimentally. We compared the results with those obtained by a surgical CO2 laser and found that carbonization and overall tissue damage were less severe with EHT than with laser surgery. This leads to the conclusion that EHT is an improvement of conventional HF surgery and may be an alternative to laser surgery in the head and neck.


The role of the gastrointestinal microflora in postsurgical adhesion formation--a study in germfree rats.

The elucidation of the pathogenesis of postsurgical adhesion formation is still lacking. In this study experimental adhesion formation was studied in germfree (i.e. void of bacteria) and conventional rats (intestinal flora comprising over 400 species) using a caecal crush model. The germfree rats responded significantly weaker to the same stimuli, forming adhesions in only 20% of the cases as compared to the conventional rats 87.5% (p = 0.0076). The findings indicate that the bowel flora is of importance but not essential for postsurgical adhesion formation in rats.


Tumor collagenase-stimulating factor and tumor autocrine motility factor as tumor markers in bladder cancer--an update.

We have studied the role of combined measurements of tumor collagenase-stimulating factor (TCSF) and tumor autocrine motility factor (TAMF) in 83 first morning voids and 24-hour specimens in patients with bladder and renal cancer and control subjects. TCSF and TAMF were measured by immunoabsorption assay and motility test utilizing modified Boyden chamber. The mean concentrations of urinary TCSF and TAMF from cancer patients (n = 32) were 4- to 5-fold higher than those from benign conditions (n = 70). We compared TCSF and TAMF utilizing motility test in first morning voids (n = 18) and 24-hour urinary samples (n = 19). TCSF and TAMF were almost identical in terms of eluted proteins from morning voids and 24-hour urine samples. Invasive bladder cancer (n = 12) showed a significantly higher correlation (r = 0.9 and p = 0.0001) between motility response and urinary concentration of TCSF and TAMF. We have also localized these two glycoproteins in cell membranes and cytoplasms of cancer cell.


Tissue polypeptide antigen for monitoring of advanced bladder cancer after MVEC chemotherapy.

58 patients with advanced bladder cancer were treated with MVEC chemotherapy (methotrexate, vinblastine, epirubicin and cisplatinum). 22 patients suffered from locally advanced disease (pT3-4 M0 N0), in 20 patients regional lymph node metastases were found (pT3-4 N1-3 M0). In 16 patients distant metastases were noted (pT1-4 N0-1 M1). In 89% transitional cell and in 11% squamous cell cancer or anaplastic carcinoma was seen. Complete response was noted in 45%, partial response in 23% and no response in 32%. Tissue polypeptide antigen (TPA) was registered before each course of chemotherapy and 3 months after the last application. The sensitivity for (pT3-4 N0 M0) tumors was 90.9%, for (pT3-4 N1-3 M0) 100% and for tumors with distant metastases 100% also, overall 96.6%. No statistically significant different values between each tumor group were found. In 85.7% a concordant reaction of TPA values and clinical status was notable. In conclusion, TPA has been proven as a valuable and a reliable marker for monitoring therapeutic efficacy of chemotherapy for advanced bladder cancer.


Bladder wash cytology and flow cytometry for the diagnosis of transitional cell carcinoma of the urinary bladder.

The role of bladder wash (BW) cytology and flow cytometry in the diagnosis of low-grade transitional cell carcinoma (TCC) of the bladder is yet to be demonstrated. We have studied a series of BW specimens by both conventional cytology and flow cytometry: there were 16 BW from patients with histologically proven TCC and 14 BW from patients with clinical suspicion of tumor or under follow-up for previous TCC in which no evidence of tumor was found by cystoscopy and multiple biopsies. As control group, 21 BW were studied from patients undergoing cystoscopy for causes other than TCC. In conclusion, the conventional cytologic study of BW specimens was highly sensitive for grade II-III TCC, but missed most grade I TCC; flow cytometric analysis did not improve significantly the detection rate in low-grade TCC.


Prognostic role of flow cytometry in superficial bladder cancer.

Prognostic factors in superficial transitional cell carcinoma of the bladder were assessed with histopathological and flow cytometry analysis in a series of 61 patients operated transurethrally between 1988 and 1990. In particular, we evaluated the usefulness of flow cytometry in order to identify patients who require a more accurate clinical follow-up or a more aggressive therapy. A multivariate analysis was done in 61 cases, considering patient age and sex, stage, grade and number of lesions (unifocal or multifocal), post-TUR therapy (therapy or not), and DNA ploidy (diploid/aneuploid). DNA pattern and number of recurrences were determinant for selecting risk cases for progression.


Prediction of recurrence and progression in primary superficial bladder cancer with DNA flow cytometry.

Intravesical chemotherapy has been well established as an effective therapy for recurrent superficial bladder tumors. We investigated the role of flow cytometry as a predictor of tumor recurrence/progression after intravesical chemotherapy. Flow cytometric analysis of nuclear DNA ploidy pattern was performed on 'cold cup' biopsy samples of 52 patients with primary superficial bladder cancer. Cell suspensions, retrieved after mechanical fragmentation, were stained with propidium iodide and examined on FACScan flow cytometer. Clinical follow-up ranged from 3 to 57 months with a median of 20 months. Of the 52 patients, 24 aneuploid and 28 diploid tumors were observed. The degree of ploidy in relation to histological grade showed an increasing frequency of aneuploid pattern in grades 2 and 3 but with no statistical significance. 17.8% of diploid tumors versus 54.1% of aneuploid tumors recurred (p less than 0.05). 12.5% of the aneuploid tumors progressed. No progression among diploid tumors was observed. Of the 52 patients examined, 35 (16 aneuploid and 19 diploid) were treated, after TUR, with intravesical prophylactic therapy. Epirubicin in 24, mitomycin C in 4 and recombinant interferon alpha 2a in 7 were used. 50% of aneuploid tumors versus 10.5% of diploid tumors recurred (p less than 0.05). Strong predictors of response to intravesical prophylaxis of recurrence were G1 grade and diploid DNA content.


Biological and clinical implication of cellular DNA content in renal cell carcinomas.

DNA flow cytometric analysis (FCM) was performed on surgical bioptic samples taken from 82 renal cell carcinomas. FCM has evidenced that 35% (29/82) of renal carcinomas resulted diploid, 65% (53/82) aneuploid and of the latter 22% (12/53) multiclonal. Our results do not indicate any relationship among cytometric ploidy, Fuhrman grading, Robson and pTNM staging. A possible interesting increase of aneuploidy frequency was observed between the NMV (66%) subgroup and the no zero NMV (90%) subgroup, while in diploid patients these values were 40% and 10%, respectively. Follow-up data evidence a significant difference in survival pattern of patients between diploid and aneuploid groups. In conclusion, our results show that cytometric ploidy is a potential important prognostic parameter in survival term.


The prognostic significance of DNA ploidy pattern in transitional cell cancer of the renal pelvis and ureter: continuing follow-up.

Among 190 patients operated on for transitional cell cancer of the renal pelvis and/or ureter from 1976 to 1990, 95 had their tumor studied by flow cytometry. Of these, the prognostic significance of the DNA ploidy pattern with respect to the standard pathologic features was assessed in a retrospective analysis, where survival information were updated to October 1991 and the mean follow-up of patients exceeded 5.5 years (longest follow-up: 15.5 years). Five and ten-year survival probabilities for the whole group were, respectively, 65.5 and 51%. Patients with a diploid tumor had significantly better survival rates than patients with tetraploid/aneuploid cancer (p less than 0.00001). The impact of the DNA ploidy on survival was confirmed by a multivariate analysis of prognostic factors, where only tumor grade (p less than 0.0001), tumor stage (p less than 0.0001), number of neoplastic foci (p = 0.022) and nuclear DNA pattern (p less than 0.068) had a significant influence on survival. In the group of patients with low-stage (pTa-pT1) and low-grade (G1-G2) transitional cell cancer of the upper urinary tract, the DNA analysis was unable to identify any subset of patients at higher risk for disease progression.


Morphometric and immunohistochemical characterization of bladder carcinoma in situ and its preneoplastic lesions.

We performed a morphometric and immunohistochemical study of 26 bladder carcinoma in situ (Cis) specimens, compared with normal urothelium and urothelial preneoplastic lesions. The following morphometric parameters were evaluated: nuclear area, nuclear perimeter and maximum nuclear diameter. For the immunohistochemical study we used five lectins, antibodies against four epithelial differentiation antigens, and antibodies against blood group isoantigens. A progressive increase in nuclear size from normal urothelium to dysplastic urothelium and Cis was detected. Nuclear size values in Cis and in high-grade, high-stage bladder carcinomas were similar. The most relevant immunohistochemical results were obtained with CEA, CK, UEA-1 and ABH isoantigens, which show significant immunoreactivity changes in preneoplastic urothelium and Cis when compared with normal urothelium. We conclude that bladder Cis behaves morphometrically and immunohistochemically as an invasive bladder carcinoma, and we emphasize the usefulness of these techniques for detecting flat dysplastic and neoplastic lesions in random bladder biopsies.


Erythrocyte sedimentation rates in patients with renal cell carcinoma.

The importance of erythrocyte sedimentation rate (ESR) in patients with renal cell carcinomas (RCCa) is still controversial. ESR levels increased in over half of these patients. In this study, ESR levels of 19 patients with RCCa were investigated (85.368 +/- 5.914). In 11 patients in whom carcinomas were only localized in the kidney, the ESR levels were detected as 78.182 +/- 8.686. In 8 patients who had metastasis, the ESR levels were found as 95.250 +/- 6.427. ESR levels were also estimated in 15 healthy adult persons as control group (18.133 +/- 2.180). Mean ESR values were significantly higher in the tumor group than in the control group (p less than 0.01). There was no statistical difference of the ESR levels between the patients who had local RCCa and advanced RCCa (p greater than 0.05, NS). The removal of the tumoral mass caused the ESR levels to diminish. In conclusion, the ESR levels were not a good criteria in patients with RCCa for evaluating either prognosis or metastasis.


DNA markers in diagnosis of adult dominant polycystic kidney disease.

We report the results of a biological and molecular study carried out on 11 Italian families, with a total of 111 individuals in which adult dominant polycystic kidney disease segregates. A restriction fragment length polymorphism analysis was performed. Two families have shown a genetic heterogeneity even if not phenotypically different from the other ones: they resulted unlinked to 16p markers. A prenatal diagnosis has been performed in a family of the linked type.


Identification of new prostate cancer progression markers by differential hybridization analysis.

In studies on the onset and progression of cancer, molecular biology has proven to be very useful. Reasoning that tumorigenesis can be considered as a multistep process in which a normal cell gradually escapes from its delicately regulated growth pattern, one might describe this process in terms of gene expression. The group of genes that are good candidates for such studies are the proto-oncogenes. Recent progress in oncogene research, however, has made us believe that the group of oncogenes is much greater than the 50 so far characterized, since all growth factor-, growth factor receptor-, signal transducer- and transcription-regulating genes have a potency to become oncogenic. Alternatively, recessive genes, such as tumor suppressor genes, might be equally relevant to the onset and progression of cancer. Therefore, new approaches in molecular studies on the genesis and progression of malignancies are urgently needed. One of these methods is the so-called differential or subtraction hybridization analysis. Particularly, the rationale of differential hybridization and the first applications to prostate cancer research are discussed in this paper.


Nucleolar organizer regions: preliminary results of the clinical use of a new marker for prostatic carcinoma (40 cases).

It is a widely diffused opinion that moving backwards in time the moment of the diagnosis of cancer of prostate, so that the tumor is detected earlier than normal, means that the treatment would be more effective than the one adopted in the usual times of diagnosis. For this reason the earlier diagnosis of prostate cancer has become more and more a compulsory target of the modern urologist, at a time of booming of the third age, of increased lifetime expectancy, of significant elevation of prostate cancer rate and of the persistent uncertainty of the efficacy of available treatments. Theoretically the mortality rate of prostate cancer can be reduced by the prevention programs and by the improvements of treatment methods, but the 'earlier' diagnosis is certainly an easier and less expensive strategy to achieve the same objective. The authors have evaluated the argyrophilic-nucleolar organizer region (Ag-NOR) proteins on 40 cases of adenocarcinoma of prostate collected through a multicentric program in France and in Italy. The Ag-NOR have been stained with silver technique set up by Ploton and Derenzini while the quantitative index has been evaluated by a semiautomatic system partially commercially available, partially modified by the authors. The conclusions: (a) the Ag-NOR index is a simple and reproducible method; (b) the Ag-NOR staging system corresponds to Gleason's grading; (c) the Ag-NOR elevation is a reliable marker of increased cell proliferation and is detectable much earlier than the morphologic changes of Gleason's classification.


The prognostic value of DNA content in patients with prostatic carcinoma.

In 80 patients with pathologically proven prostatic cancer, DNA content was correlated to grade, stage and survival. The survival curve and duration of response to therapy in these patients was examined. At the end of follow-up the cumulative survival curve in the aneuploid patients was 0.40, according to the Kaplan-Meier method, while in the diploid population it was 0.65. Differences between the two groups, aneuploid and diploid, were observed within the various histological subgroups: survival in the G2 population was 0.57 for the diploid and 0.30 for the aneuploid whereas in the G3 patients it was respectively 0.69 for the diploid and 0.05 for the aneuploid patients.


Reappraisal of radical perineal prostatectomy.

Radical prostatectomy is frequently the treatment of choice for localized adenocarcinoma of the prostate. The procedure can be accomplished through either a perineal or a retropubic approach; both have their advantages and disadvantages. Recently, concerns over transmission of blood-borne viruses during transfusions and the advent of laparoscopic pelvic lymphadenectomy have resulted in a rejuvenation of interest in perineal prostatectomy. Herein, we discuss the history of perineal prostatectomy, the technique and its advantages and disadvantages.


Results of a questionnaire among Dutch urologists and general practitioners concerning diagnostics and treatment of patients with prostatitis syndromes.

By means of a questionnaire, all Dutch urologists (n = 250, 136 responded) and regional general practitioners (GPs; n = 400, 176 responded) were contacted concerning current diagnostics and treatment modalities applied in patients with prostatitis syndromes. The patients seen by urologists seem to be younger (30-40 years) and they mostly complain of pain in the perineum, penis or scrotum, while GPs see older patients (> 40 years) mainly presenting with micturition complaints. Urologists think nonbacterial causes (40%) most important, while GPs mention bacterial infections (63%) as the most important cause. The first choice of therapy is antibiotics, mostly co-trimoxazole Sulfatrim for 3 weeks, but patients seen by urologists are more resistant to this therapy. If not successful, urologists frequently prescribe a second course with antibiotics. However, many urologists think psychosomatic causes are an important factor in the etiology of prostatitis.


Surgical repair versus medical treatment of varicocele in the rat: pharmacological manipulation of the varicocelized testicle.

Human chorionic gonadotropin, kallikrein, indomethacin, and hydralazine were administered to different groups of varicocelized rats, while surgical repair of the varicocele was performed in another group of rats. The effects of conservative and surgical treatment on epididymal sperm content and motility, the weights of the testes, epididymis, and male accessory genital glands, and fertility were compared between each group and a sham-treated group of rats. Surgical repair significantly improved all the evaluated parameters and all the conservative regimens, except hydralazine, resulted in a significant improvement in most parameters. Our results indicate that stimulation of the Leydig or/and Sertoli cells of a varicocelized testicle can counteract some of the detrimental consequences of the varicocele itself.


Epididymitis in children and adolescents on clean intermittent catheterisation.

The records of 119 children and adolescents on clean intermittent catheterisation (CIC) were reviewed to assess the incidence and predisposing factors, if any, of epididymo-orchitis. CIC had been performed for a total of 448 patient years with a mean of 4.5 years (range 3 months to 19 years). Of the evaluable 99 patients, 10 suffered attacks of epididymo-orchitis after commencing CIC. There was an equal incidence on both sides. Three patients had recurrent attacks. Epididymitis occurred at the rate of 1 episode for 10 patient years. Those who had neuropathic bladders and more than 2 symptomatic urinary tract infections annually had a higher incidence. Prophylactic antibiotics did not reduce the incidence but long-term specific antibiotic therapy may prevent further attacks. Vasectomy and orchidectomy had to be done in 2 patients for recurrent attacks and intractable sepsis.


Modified meatal advancement and glanduloplasty with complete foreskin reconstruction.

We report 28 boys who underwent repair of a distal hypospadias with a combination of a modified meatal advancement and glanduloplasty and reconstruction of the foreskin. An excellent result was achieved in 24 patients. In 4 boys, preputial reconstruction failed. Only one group of parents demanded further surgery. Improved cosmetic results with avoidance of serious complications make this operation ideal for treating distal hypospadias in countries where the circumcised penis is an exception.


In vitro lithotripsy with the Alexandrite laser.

The Alexandrite laser system has proven to be an effective and safe method of ureteral lithotripsy. Some authors have recently reported the risk of interspersion of fiber splinters into tissue during lithotripsy, when short pulses and high power densities are employed. In vitro lithotripsy on renal calculi artificially placed in human ureters was realized under the parameters of a manufactured model (Alexantriptor, HMT). We have observed neither interspersion of fragments nor ureteral damage. These in vitro experiments and our clinical experience confirm that Alexandrite laser lithotripsy is reliable and safe.


Effect of high-energy shock wave frequency on viability of malignant cell lines in vitro.

In this study, the effects of high-energy shock wave (HESW) frequency on the viability of three different malignant cell lines were evaluated using a piezo-electric generator. The cell lines studied were AR42-J, VX-2 and HeLa. These cells were targeted both in free suspension and immobilised in gelatine beads. All cell lines in free suspension were acutely sensitive to HESW over a range of frequencies. When cells were immobilised in gelatine, however, the effect on cell viability was not as pronounced. However, at frequencies of 80- and 160-Hz kill rates approaching 80 and 90%, respectively, were observed. Cell proliferation following HESW treatment was not adversely affected. This study demonstrates that single cell suspensions are not appropriate for assessing the in vitro cellular effects of HESW. However, even when cells were immobilised in gelatine, high-frequency HESW produced substantial kill rates. The effects of high-frequency HESW merit further evaluation particularly using in vivo tumour.


Experimental model for ureteral autotransplantation in the rat.

The development of an experimental model for ureteral autotransplantation without kidney transplantation, in an attempt to confirm viability of the ureter after denervation and total ischemia, is reported. Stages of the study and the experimental microsurgical technique used are discussed. Experiments were carried out in 30 Sprague-Dawley rats distributed in two experimental stages. The absence of histologic lesions was demonstrated by exeresis of the autotransplantated ureter and latter pathological study. Size, colour, renal consistency, ureteral peristalsis and the macroscopic appearance of the surgical piece were recorded. Histological examination confirmed macro- and microscopic normality of the autotransplanted ureteral segment.


Implantation metastasis after a suprapubic catheter in a case of bladder cancer.

We report about a patient who was treated with a percutaneous suprapubic cystostomy in order to relieve repeated urinary retention. Two hours later a bladder tumor was found and the suprapubic catheter was removed. After transurethral resection of the bladder tumor the histological specimen showed a pT3 G3 squamous cell carcinoma. Because of the age and reduced performance status of the patient a radical cystectomy was contraindicated. In a second approach we performed again a transurethral resection of the bladder tumor simultaneously with a resection of the prostate. Eight weeks later the patient was admitted to our hospital because of reduced performance status and gross haematuria. We found a widespread bladder tumor with an implantation metastasis in the abdominal wall at the site where the suprapubic catheter was placed and multiple lung metastases. The patient died within one week after admission. The literature is reviewed and therapeutic strategies are discussed.


Determinants of coronary effects of atrial natriuretic factor in dogs.

The direct vascular action of atrial natriuretic factor (ANF) is unclear. In coronary vasculature, vasodilation has been reported as well as vasoconstriction. Doses of ANF, baseline plasma ANF levels and interference with the renin-angiotensin system might account for the controversy. We tried to further analyse determinants of the effect of ANF on coronary blood flow in anaesthetized dogs. The chest was opened and the left anterior descending coronary artery cannulated and perfused at constant normal (= 76 +/- 5 mmHg, n = 10) or reduced (= 37 +/- 3 mmHg, n = 10) pressure from the femoral arteries. At normal coronary perfusion pressure, ANF (1 ng kg-1 i.c.) reduced coronary flow from 30.7 +/- 4.2 to 26.9 +/- 4.0 ml min-1 (P less than 0.05). This effect was no longer significant at reduced coronary perfusion pressure (4.9 +/- 0.8 vs. 4.6 +/- 0.7 ml min-1). ANF (1 ng kg-1 i.c.) reduced coronary blood flow in correlation with baseline plasma ANF levels (r = 0.77, P less than 0.001). However the large variability of the constrictor effect of ANF in the rather small range of baseline plasma ANF, weakens the importance of this result and suggests other additional determinants. ANF (100 ng kg-1 i.c.) significantly increased coronary blood flow by 16-23% (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Culturally sensitive instructional practices for African-American learners with disabilities.

This article discusses the cultural and educational needs of African-American learners with disabilities. Six theoretical assumptions establish some basic suppositions about culturally and linguistically diverse learners and effective instructional practices. A review of the literature describes African-American cultural practices, interests, and cognitive styles; highlights the attitudes, perceptions, and instructional practices of effective teachers of African-American students; and includes patterns of teacher-student and peer-group interactions that promote high academic achievement among African-American learners. Recommendations include organizing teaching, learning, and performance in ways that are compatible with the social structure of African-American students with disabilities.


Reappraisal of the role of insulin on sodium handling by the kidney: f1fect of intrarenal insulin infusion in the dog.

Since several studies suggest that increased insulin levels may induce antinatriuresis, the present work was undertaken to determine whether a physiological increase in insulin levels in blood perfusing the kidney may exert direct effect on kidney function, and more specifically on sodium reabsorption. To this end, insulin was infused directly into one renal artery of 10 anaesthetized dogs at the rate of 4 mU min-1 for a period of 90 min. The contralateral kidney was infused with saline alone, to provide reference values. Insulin level in the renal vein of the insulin-infused kidney went up from 1.4 +/- 0.9 before to 30.6 +/- 7.1 microU ml-1 after 90 min of insulin perfusion. There was no significant effect on renal plasma flow, glomerular filtration rate and renal uptake of substrates or oxygen between ipsi- and contralateral kidney. The fractional excretion of sodium was likewise unaffected, since it averaged at the end of insulin infusion 0.41 +/- 0.11% vs. 0.50 +/- 0.14% for the contralateral saline infused kidney. Even if one may assume that the baseline low insulin concentrations promote tubular sodium reabsorption, the results of the present study suggest that a moderate hyperinsulinaemia is without any additional effect on renal sodium handling.


Normal lipoprotein(a) concentrations and apolipoprotein(a) isoforms in patients with insulin-dependent diabetes mellitus.

Lipoprotein(a) [Lp(a)] is an LDL particle in which apoliporotein B-100 is attached to a large plasminogen-like protein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined phenotypes differing in molecular weight, to which Lp(a) concentrations in plasma are inversely correlated, and plasma Lp(a) concentrations above 20-30 mg dl-1 are an independant risk factor for ischaemic heart disease (IHD). To investigate whether Lp(a) could be important for the high cardiovascular mortality rate in patients with insulin dependent diabetes mellitus (IDDM), we determined Lp(a) concentrations and phenotypes in a group of 108 men (median age 32 years) with IDDM without nephropathy. A group of 40-year-old men (n = 466) served as controls. The median Lp(a) concentration was 7.4 mg dl-1 [95% CI 4.9 to 11.7] in the diabetic patients and 6.3 mg dl-1 [95% CI 5.2 to 7.0] in controls. The Lp(a) concentration exceeded 30 mg dl-1 in 22% of IDDM patients and in 20% of controls (P = 0.13). Moreover, the distribution of apo(a) phenotypes did not differ between patients and control. Lp(a) levels and apo(a) phenotypes are thus apparently the same in IDDM patients without nephropathy and controls. These findings do not exclude the possibility that Lp(a) may be increased in patients with nephropathy in whom coronary artery disease frequently co-exist or that Lp(a) in a given concentration is more atherogenic in IDDM patients than in persons without IDDM.


Bone mass and biochemical parameters of bone metabolism in men with spinal osteoporosis.

With advancing age both sexes have an increased incidence of osteoporotic fractures, although fractures are more common in women than in men. Whereas in women several potential risk factors have been identified, less is known about osteoporosis in men. A total of 27 Austrian men (mean age: 65 +/- 2 years) with atraumatic spine fractures were studied. In all patients, medical history gave no evidence of disease or medications causing osteoporosis. Peripheral bone mass was determined by single-photonabsorptiometry on the distal non-dominant forearm; lumbal bone density was measured by quantitative computed tomography. Serum levels of calcium, phosphate, alkaline phosphatase, osteocalcin, testosterone, estrogen, parathyroid hormone and 25-hydroxy-vitamin D as well as 2-h-urinary-OH proline and calcium excretion were measured. All data were compared with those of an age and sex matched control group consisting of 19 healthy males. A significant difference in mean peripheral and axial bone mass (SPA: P less than 0.004; QCT: P less than 0.0001) was observed between osteoporotic men and controls. When compared to controls, serum levels of alkaline phosphatase (P less than 0.012), urinary OH proline (P less than 0.05) and urinary calcium excretion (P less than 0.003) were significantly higher in the osteoporotic males. Additionally, there was a significant positive correlation between serum alkaline phosphatase and urinary OH proline excretion (r = 0.32; P less than 0.04) in the osteoporotics. All other biochemical parameters showed no significant differences. Our results may lead to the assumption that osteopenia in men is related to increased bone turnover.


Nutritional behaviour and quality of life during oncological polychemotherapy: results of a prospective study on the efficacy of oral nutrition therapy in patients with acute leukaemia.

A total of 29 patients with acute leukaemia were prospectively randomized before starting cytostatic treatment to be nourished either with intensified oral nutrition (intervention group) or ad libitum nutritional intake during the whole tumour therapy (median 22 weeks). All received menus of free choice (daily offer of 1.0-2.0 g protein, 30-50 kcal kg-1 body weight (BW)). Beyond this, intervention patients received nutrition education, daily visits by the dietician and record of food intake, as well as a weekly assessment of subjective well-being (linear analogue self assessment 'LASA'). From the LASA items, the factors: 'malaise', 'psychological distress', 'therapy side-effects' were extracted by principal component analysis, and correlated to nutrient intake and nutritional status. At the end of antineoplastic induction therapy, after continuous hospitalization of 10 weeks (median), 31.3% of the controls had regained their initial nutritional status, and 68.8% of the intervention group. Mean daily energy intake was 23.2 kcal kg-1 BW during weeks with weight loss (constant weight: 30.9, weight gain: 39.3 kcal kg-1 BW). Nutritional behaviour correlated with subjective well-being, low intake with complaints of tumour treatment side effects and weight loss with malaise.


A comparison of octreotide delivered by continuous subcutaneous infusion with intermittent injection in the treatment of acromegaly.

This study was undertaken to evaluate GH, IGF1 and drug levels during incremental continuous subcutaneous infusion of octreotide and compare these parameters following long-term treatment of 300 micrograms 24 h-1 by intermittent injection in a group of acromegalic patients. Ten patients were treated by continuous subcutaneous infusion in increasing dose from 200 micrograms 24 h-1 to 1600 micrograms 24 h-1; this resulted in consistent 24-h growth hormone suppression (less than 5.0 mU l-1), and normalisation of IGF1; the optimum dose was 400 micrograms 24 h-1, the maximum dose was tolerated without any untoward effects. There was no deterioration in carbohydrate tolerance despite a marked decrease in fasting and stimulated insulin levels. After 1 year of maintenance treatment, 300 micrograms 24 h-1 by intermittent injection, patients were re-evaluated; GH levels were not so consistently suppressed over the 24-h period and carbohydrate tolerance had deteriorated. A sub-group of patients with sub-optimal GH suppression on this regimen were identified and reassessed after 6 weeks treatment with an increased dose, 600 micrograms 24 h-1 by intermittent injection; both mean GH suppression and carbohydrate tolerance improved. The dose of drug and method of administration is best adjusted for each patient to achieve optimum GH suppression, thereby minimise compensatory hyperinsuliaemia and hopefully reduce morbidity and mortality. Alterations in pituitary tumour size and acquisition of gallstones during treatment have been observed which substantiate the need to re-evaluate these parameters on routine follow-up of acromegalic patients on long-term octreotide.


The use of selected theatre rehearsal technique activities with African-American adolescents labeled "behavior disordered".

The extensive literature on the overrepresentation of adolescent African-American male learners in classes for students identified as behavior disordered has essentially not addressed the problems caused by teacher reactions to adolescent conversational language use, the qualitative differences in language choices, or the impact of the conversational choices of adolescents on their educational treatment. This article explores how the dramaturgical perspective of selected Theatre Rehearsal Technique (TRT) activities can be used as learning experiences in communication with this student population. If these students gain quantifiable success in their social communication interactions, reassessment of their special education placement might facilitate their entrance into less restrictive educational environments.


Renal reserve filtration capacity in growth hormone deficient subjects.

In normal subjects, the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) acutely increase in response to infusion of amino acids and to low doses of dopamine. It is uncertain whether circulatory growth hormone (GH) is a permissive factor for these stimulatory effects. GFR and ERPF (constant infusion technique using 125I-iothalamate and 131I-hippuran, respectively) were measured before and during the infusion of dopamine and amino acids in 8 GH deficient subjects. The clearance study was repeated during concomitant administration of octreotide to investigate whether this somatostatin analogue would modify the amino acid and dopamine-induced renal haemodynamic changes. Dopamine increased baseline GFR from 89 +/- 3 (mean +/- SEM, n = 8) to 102 +/- 4 ml min-1 1.73 m-2 and ERPF from 352 +/- 19 to 476 +/- 26 ml min-1 1.73 m-2, P less than 0.001 for both. During amino acid infusion GFR and ERPF increased to 108 +/- 3 and 415 +/- 23 ml min-1 1.73 m-2, respectively, P less than 0.001 for both. Octreotide did not significantly decrease baseline and dopamine-stimulated renal haemodynamics but lowered the amino acid-stimulated GFR (98 +/- 4 ml min-1 1.73 m-2, P less than 0.05) and ERPF (381 +/- 18 ml min-1 1.73 m-2, P less than 0.05). Basal plasma glucagon concentrations were not suppressed by octreotide, whereas the amino acid-induced increments in plasma glucagon were partially inhibited. It is concluded that GH is not a necessary factor for the stimulatory effects of amino acids and dopamine on renal haemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)


Early pregnancy and academic achievement of African-American youth.

Competing demands of school and home can thrust adolescent mothers into stressful situations. Meeting the requirements to achieve academically can be a challenge, especially for students previously identified as "slow learners." These students may conclude that academic achievement is an impossibility. How can special educators and service providers help? What environmental variables affect these young mothers' learning capabilities? This study used a case study research approach to study 10 African-American adolescent mothers who were already at risk of dropping out of school programs. Successful strategies to keep these students in school include school-based clinics, teacher training, sex education, and school-community support.


The pitfalls and promises of special education practice.

It is imperative that special education enable children with disabilities to achieve at high levels. Problems of equity and pedagogical validity have hindered our efforts thus far, and many children of minority cultures are far overrepresented in classrooms for students with learning disabilities and mild mental retardation. Studies have shown the importance of culturally and linguistically inclusive programs and of heterogenous groupings, as well as more effective diagnostic, remedial, and assessment practices. This article discussed a model and basic principles for such techniques to ensure that the educational outcomes of all children are improved.


Doctors' perception of pertinent information. Results of a survey of a random sample of French general practitioners. GEP (Groupe d'Etude de la Prescription).

The results of a survey aimed at investigating which tools prescribers have at hand to help them to identify pertinent information from a background of "noise" are reported. A questionnaire was sent to 250 general practitioners randomly selected from a list of those practicing in the Rhône-Alpes region in France, of whom 117 (46.8%) replied. The questionnaire consisted of three sections, the first explored how they dealt with intermediate and clinical outcomes in trials, the second presented a series of statements to identify what would make them prescribe a new drug, and the third looked at their knowledge of therapy assessment methodology. It was found that most general practitioners had not been trained to identify the most salient information for selecting the best treatment. This implies that both medical students and qualified doctors should be taught to recognise pertinent information.


Dose ranging study of lansoprazole, a new proton pump inhibitor, in patients with high gastric acid secretion.

The effects of single doses and of 7 days of lansoprazole 10, 20 and 30 mg PO versus placebo on gastric acid secretion have been evaluated in 8 patients with high gastric acid secretion. The double blind crossover period was followed by a simple blind 7 days on placebo to detect any rebound phenomenon. After the first dose lansoprazole did not modify basal acid output (BAO) but it significantly and dose dependently inhibited peak acid output (PAO) and increased the time during which nocturnal intragastric pH was greater than 3. After 7 days of treatment the same significant, dose-dependent suppression of gastric acid was found, but BAO was also blocked. One week after cessation of lansoprazole administration no rebound increase in gastric acid-secretion was observed. The plasma gastrin concentration remained unchanged throughout the study.


Simultaneous noninvasive evaluation of gastric emptying and orocaecal transit times. Use in studying the actions of cisapride in diabetic patients.

The aim of the study was to use a novel combination of two methods for the simultaneous evaluation of two effects of oral cisapride in 10 diabetic patients with autonomic neuropathy; gastric empyting time was measured by following radio-opaque markers and orocaecal transit time by the sulphasalazine-sulphapridine method. The study was of double-blind, randomized, placebo-controlled, cross-over design. It was possible to evaluate the effect of a prokinetic drug on gastric emptying and orocaecal transit times using these two noninvasive techniques at the same time. Cisapride significantly reduced both the gastric empyting (1.2 h versus 2.1 h) and orocaecal tansit (5.9 h versus 7.7 h) times.


Nocturnal oxygen saturation and sleep quality in patients with advanced chronic obstructive pulmonary disease during treatment with moderate dose CR-theophylline.

The effect of a 24-h controlled-release (CR) preparation of theophylline (Th) on nocturnal arterial oxygen saturation (SaO2) and sleep quality has been evaluated in 7 patients with advanced chronic obstructive pulmonary disease (COPD) in a double-blind cross-over experiment; median values: age 61 y; PaO2 8.0 kPa; PaCO2 5.8 kPa. During treatment with 450-900 mg Th in the evening, morning plasma drug levels ranged from 5.2-12.9 micrograms.ml-1. During Th and placebo treatment, the median evening FEV1 was 0.45 l and 0.46 l, respectively, and the morning FEV1 was 0.53 l and 0.41 l. Sleep was monitored by whole-night polysomnographic recording of oximetric SaO2, airflow, respiratory and body movements (static charge sensitive bed), eye movements and submental electromyogram. There was no significant difference between Th and placebo in sleep quality. Th treatment was associated with a marginal improvement in nocturnal oxygenation in most of the patients; the average nocturnal SaO2 ranged from 84.4%-92.8% during Th and from 82.2-90.5% during placebo treatment, respectively. Only in the morning, during the last 2 h in bed, was the slight difference in SaO2 statistically significant in favour of Th. It is concluded that a moderate dose of CR-theophylline did not alter the sleep quality or substantially improve nocturnal oxygenation in patients with advanced COPD and mild to moderate day-time hypoxaemia.


Factors in hydrazine formation from isoniazid by paediatric and adult tuberculosis patients.

An HPLC method is described for measurement of plasma hydrazine (Hz) concentrations (CHz) at the same time as isoniazid (INH) levels (CINH). Study has been made of CHz during 2-5 after dose in healthy adults (A, n = 34), in adult pulmonary TB patients (B, n = 18) and in paediatric tuberculous meningitis patients (C, n = 25). Although the population has about equal proportions of 'slow' (52%) and 'fast' acetylators, in none of the groups could a correlation be shown between CHz levels or rates of Hz accumulation and any measure of acetylator type. Consequently Hz must be derived both from INH and from its metabolites during the first hours post-dose. For group A and ca. 70% of groups B and C a constant and maximal fraction of dose (ca. 0.6% for adults and 0.4% for paediatric patients) appeared as Hz at 4-5 h. For group B patients small pre-dose concentrations increased with duration of treatment. Four patients in group B showed the highest levels of CHz and rates of Hz accumulation some three times greater than the rest; all four had been identified as alcoholics and one showed evidence of hepatotoxicity at CHz (5 h) = 1.3% of dose. Amongst group C (9/25) episodes of high CHz greater than 0.5% of dose occurred during the first weeks of treatment and one developed CHz ca. 100 ng/ml = 1.3% of dose coincidentally with indications of hepatic damage.


Comparison of salivary miconazole concentrations after administration of a bioadhesive slow-release buccal tablet and an oral gel.

The salivary miconazole concentrations after administration of a bioadhesive slow-release buccal tablet and an oral gel have been compared. The bioadhesive tablet consisted of a mixture of thermally modified starch and 5% polyacrylic acid. Although the amount of drug administered via the bioadhesive tablet was sixfold lower than when the gel was used, the salivary miconazole levels were higher and remained above the MIC value of Candida albicans for more than 10 hours. The mean adhesion time of the tablet was 586 min. The bioadhesive tablet appears to be a promising drug delivery system for the buccal administration of drugs for local therapy.


The effects of omeprazole-induced hypochlorhydria on absorption of theophylline from a sustained-release formulation.

The present study was designed to investigate the effects of raised intragastric pH on the absorption of theophylline from a sustained-release formulation. Six healthy male volunteers participated in the cross-over randomised study and on one of two occasions were pretreated with 240 mg omeprazole, administered in three divided doses over the 22 h preceding the test. The sulphasalazine/sulphapyridine method of assessing oral-caecal transit time was implemented in order to assess upper bowel and colonic absorption. The mean fraction absorbed-time profile was calculated from serial serum theophylline concentration measurements by a modification of the Wagner-Nelson equation. During hypochlorhydria the mean oral-caecal transit time was 4.6 h, mean time to 90% absorption 6.8 h, and the percentage theophylline presumably to be absorbed from the colon 32.3. The corresponding values with normochlorhydria were, respectively, 3.8 h, 8.5 h, and 57.5%. The shorter oral-caecal transit time and lesser upper bowel absorption during normochlorhydria is postulated to result from motilin release due to duodenal acidification. Gastric hypoacidity resulted in significantly increased cumulative fractions of theophylline absorbed during a 3.5 h period, starting 0.5 h after breakfast. Possibly hypochlorhydria amplifies the increased motility which follows the intake of a meal, resulting in increased peristalsis and antiperistalsis, with more rapid drug absorption.


Acipimox-induced facial skin flush: frequency, thermographic evaluation and relationship to plasma acipimox level.

Facial skin flush is the most frequent adverse effect induced by acipimox (ACX), a nicotinic acid analogue used in the management of hyperlipidaemia. The aims of the study were to evaluate the frequency, magnitude and reproducibility of the ACX flush in previously unexposed healthy subjects and to assess any possible relationship with the dose and plasma level of ACX. Seventy four healthy subjects received, on two different mornings, ACX 250 mg and placebo (P), according to a single blind, randomized, cross-over design; 33 had a clear flush after ACX and not after P.25 of those subjects were retested on five different mornings, with P, and with ACX 31.2, 62.5, 125.0, 250.0 mg, according to a double blind, randomized, cross-over design. Any increase in the local skin temperature was recorded by a thermocouple fixed to the left check. Subjective and objective assessment of the flush were strongly correlated with thermographic recordings. They indicated that a 120 min flush occurred after doses of ACX greater than 62.5 mg. In 12 of the 25 subjects, 6 with the highest and 6 with the lowest thermographic recordings, plasma ACX levels were determined. Subjects with different thermographic records had superimposable plasma ACX levels after all doses of ACX. Only the 6 subjects with the highest skin temperatures showed a significant relationship between the thermographic record and the plasma ACX. The data indicate that flush is a frequent, reproducible and dose-related adverse effect of ACX.


The direct effects of diethylstilboestrol and nifedipine on the contractile responses of isolated human and rat detrusor muscles.

We have studied the direct effect of 2 mumol.l-1 diethylstilboestrol on isolated rat and human detrusor muscles. Diethylstilboestrol significantly reduced the amplitude of the contractile response of rat detrusor muscle to stimulation with acetylcholine, carbachol, electrical field stimulation, and 5-hydroxytryptamine. In isolated human bladder it also significantly reduced contractions stimulated with acetylcholine, carbachol, and electrical field stimulation. In depolarized rat detrusor muscle stimulated with different concentrations of calcium ions, the contractile responses were significantly reduced by the addition of diethylstilboestrol. Diethylstilboestrol also significantly reduced the amplitude of contractile response to potassium chloride. The inhibitory action of diethylstilboestrol was enhanced by the reduction of extracellular calcium ions, the maximum contractile response to acetylcholine, carbachol, and electrical field stimulation being reduced by a further 32%, 23%, and 45% respectively. Diethylstilboestrol did not have a significant effect on carbachol-induced contractions in depolarized rat detrusor muscle suspended in a calcium-free environment. Diethylstilboestrol was effective in blocking rat and human detrusor muscle contraction. The likely mechanism is a reduction of the influx of calcium ions into the cell during contraction rather than an effect on intracellular calcium release. These results give support for treating incontinent patients with drugs that block calcium ion uptake, and may suggest a further beneficial effect of oestrogen therapy in postmenopausal women.


Dose-response relationship of topically applied methylprednisolone aceponate (MPA) in healthy volunteers.

Topical glucocorticosteroids are useful in the treatment of various skin diseases. Although many corticosteroids are available today, there is still a need for highly potent compounds with minimal adverse effects. Methylprednisolone aceponate (MPA) has recently been synthesized. Its activity has been evaluated using the vasoconstrictor assay and the poison ivy test (rhus dermatitis) in 19/20 healthy volunteers of either sex. Comparable blanching was found with MPA in a cream vehicle, in an ointment and a fatty ointment. Vasoconstriction and suppression of experimentally-induced poison ivy contact dermatitis were dose-dependent in the concentration range 0.01% to 0.5% MPA. Concentrations of MPA of at least 0.05% were significantly active. Following the highest dose, blanching was close to the maximum which can be obtained. This finding, and the improvement of rhus dermatitis, suggest that MPA belongs to the highly potent local glucocorticosteroids.


Pharmacokinetics of cyclosporine in hyperlipidaemic long-term survivors of heart transplantation. Lack of interaction with the lipid-lowering agent, fenofibrate.

Cyclosporine (Cy) binds to lipoproteins in plasma. In order to test if its pharmacokinetics would be modified when efficient lipid-lowering treatment is introduced, a study has been done of Cy pharmacokinetics and any interaction with the lipid-lowering agent fenofibrate in hyperlipidaemic long-term, survivors of heart transplantation. Fenofibrate 200 mg once daily significantly reduced blood lipids (cholesterol 6.5 vs 7.7 mmol/l; apoprotein B 1.2 vs 1.6 g/l) but did not modify mean whole blood Cy trough levels (113 before fenofibrate vs 103 ng.ml-1), Cmax (812 ng.ml-1 by RIA and 757 ng.ml-1 by HPLC before fenofibrate versus 865 and 741 respectively, during fenofibrate); tmax (1.6 and 1.7 h before fenofibrate versus 1.4 and 1.4 h respectively), and t1/2 (13.9 and 11.1 h versus 9.5 and 10.7 h). The only adverse effect was an increase in creatinine (157 vs 145 mmol/l). Further studies are needed to investigate the mechanism of Cy-fenofibrate nephrotoxicity and to evaluate the long-term efficiency and safety of fenofibrate after heart transplantation.


Urinary caffeine metabolites in man. Age-dependent changes and pattern in various clinical situations.

In an exploratory study the 24-h urinary excretion pattern of caffeine and 14 of its major metabolites was studied in 32 volunteers (adults, adolescents and children), 14 patients either with end stage renal disease or liver cirrhosis, 7 heavy smokers and 27 patients on therapy with cimetidine, allopurinol, theophylline or phenytoin. Caffeine and its metabolites were quantified by UV-absorption after liquid/liquid-extraction and HPLC-separation, which ensured proper analysis of 1-methyluric acid. In adults the renal excretion of caffeine derivatives corresponded to an intake of 509 mg caffeine/day, with 1-methyluric acid as the predominant metabolite. About 69% of caffeine was degraded by the paraxanthine pathway, and theobromine- (19%) and the theophylline pathway (14%) were less important. The ratio of paraxanthine formation to urinary caffeine concentration (= clearance equivalent) was about 2.2 ml.min-1.kg-1 in adults, and the corresponding ratios for theophylline and theobromine were 0.43 ml.min-1.kg-1 and 0.59 ml.min-1.kg-1, respectively. As expected, caffeine degradation was impaired in patients with cirrhosis and was increased in persons who smoked heavily or who were on phenytoin therapy. The results document the possibility of noninvasively investigating gross differences in caffeine disposition by analysis of the urinary pattern of its metabolites.


Bacterial acetylation of 5-aminosalicylic acid in faecal suspensions cultured under aerobic and anaerobic conditions.

After oral administration of 5-aminosalicylic acid a substantial proportion of the acetylated form is excreted in the faeces. We have studied the role of the faecal microflora in acetylating 5-aminosalicylic acid. In faeces incubated under both aerobic and anaerobic conditions there was acetylation of 5-aminosalicylic acid. Of the anaerobic bacteria isolated from a 10(8) faecal dilution 44% were able to acetylate 5-aminosalicylic acid. We conclude that the normal faecal microflora contribute to the acetylation of 5-aminosalicylic acid.


Increase in cerebrospinal fluid pressure in normocapnic volunteers in response to nalbuphine.

We have carried out a double-blind randomized study of the effect of nalbuphine (0.2 mg.kg-1 i.v.) or placebo on mean lumbar cerebrospinal fluid (CSF) pressure, mean cerebral perfusion pressure (CPP), transcutaneous PCO2 (tcPCO2), mean arterial blood pressure (MAP), and heart rate (HR) in 10 spontaneously breathing volunteers using invasive CSF pressure measurement. Nalbuphine increased CSF pressure from 9.2 mmHg to 16.4 mmHg and decreased CPP from 83.6 mmHg to 74.4 mmHg without significantly changing tcPCO2, MAP, or heart rate. In the placebo group there were no significant changes in CSF pressure, CPP, tcPCO2, MAP, or heart rate. These findings suggest that nalbuphine should be used with caution in patients at risk of intracranial hypertension.


The effect of haemodialysis on the pharmacokinetics of tenoxicam in patients with end-stage renal disease.

We have studied the pharmacokinetics of tenoxicam after single and multiple oral doses of 20 mg in five patients (2 men and 3 women) with end-stage renal disease undergoing haemodialysis. After a single dose, tenoxicam had a half-life (t1/2) of 33 h, an apparent clearance (CL.f-1) of 4.3 ml.min-1, and an apparent volume of distribution (Vz.f-1) of 11.81. The maximum tenoxicam concentration (Cmax) was 4.3 mg.l-1 at a median tmax of 1.7 h. There were no significant differences between the values calculated from the pre- or post-dialyser port plasma samples. Tenoxicam plasma concentrations measured during once daily dosing before and after haemodialysis showed that tenoxicam does not accumulate. Our findings suggest that dosage adjustment may not be required in patients with end-stage renal disease on haemodialysis taking tenoxicam.


Effect of single- and multiple-dose carbamazepine on the pharmacokinetics of diphenylhydantoin.

A three-phase trial has been done in 11 volunteers. They were given 600 mg phenytoin (Dilantin capsules) in each phase after an overnight fast. In the first study, phenytoin was given alone. In the second phase 400 mg carbamazepine (CBZ) was given at the same time as the phenytoin, and in the third part, 200 mg CBZ t.d.s. was given for one week prior to the phenytoin. Blood samples were taken for 72 h in each phase. Plasma levels of phenytoin and CBZ were determined by HPLC, and plasma protein binding was determined by equilibrium dialysis. The unbound fraction of phenytoin was 0.082, 0.085, and 0.077 in the control, single-dose CBZ, multi-dose CBZ phases, respectively. Single and multiple doses of CBZ decreased the plasma level of phenytoin. The 72-h AUC of phenytoin was 276, 237, and 176 mg h.l-1 in the 3 phases, respectively, and the 72-h AUC of unbound phenytoin was 22.8, 20.5, 13.0 mg h.l-1. The AUC of phenytoin (unbound and total) after multiple doses of CBZ was significantly lower than in the other two phases. The apparent volume of distribution (Vz/f) was 89.9, 110.3, and 121.3 l in the 3 phases, respectively. Through pharmacokinetic analyses, the decreased AUC and increased Vz/f were attributed to decreased bioavailability of phenytoin when CBZ was co-administered.


Bezafibrate lowers plasma lipids, fibrinogen and platelet aggregability in hypertriglyceridaemia.

The effects of bezafibrate 400 mg/day (slow release formulation) on plasma lipids/lipoproteins and on selected haemostatic parameters were evaluated in a double blind cross-over study in patients with Type IIb and IV hyperlipoproteinaemia. Placebo treatment did not influence any of those parameters, but the drug significantly reduced plasma triglycerides (-45%) and VLDL cholesterol, as well as causing a 12% fall in total cholesterol and a 20% increase in HDL cholesterol. Apo AI levels were significantly increased following bezafibrate and Apo B was reduced by about 20%. In addition to changes in the plasma lipid profile, bezafibrate reduced the sensitivity of platelets to the aggregatory effect of collagen, with no effect on TXB2 production. Fibrinogen levels after bezafibrate treatment were significantly lowered, the effect being more marked in patients with hyperfibrinogenaemia. Bezafibrate did not influence the plasma fibrinolytic profile. It is concluded that bezafibrate, besides its beneficial effects on the plasma lipoprotein profile, can exert beneficial changes on specific haemostatic parameters.


Evaluation of lipid metabolism during antihypertensive treatment with nicardipine sr.

The antihypertensive and metabolic effects of oral nicardipine SR 40 mg b.i.d. have been studied in 18 (15 m, 3 f; age 52.7 y) hypertensives with mild hypercholesterolaemia, treated for 3 months after a 2 week period on placebo. An iv Fat Tolerance Test (FTT) was also performed in 8 patients following placebo, treatment with acute nicardipine 20 mg and chronic administration of nicardipine SR. There was a significant fall in BP from 160/97 on placebo to 147/87 after 3 months on nicardipine SR with no change in heart rate. Blood lipids did not change significantly. The disappearance rate of the lipid emulsion in the ivFTT showed no significant change (K2 was 1.93%/min after placebo, 1.84 after nicardipine 20 mg and 1.71 after chronic treatment). The results suggest that nicardipine is an effective antihypertensive drug and that it is devoid of untoward effects on lipid metabolism.


Surrogate endpoints: a basis for a rational approach.

In clinical trials, the clinical endpoint is often replaced by an intermediate endpoint, known in some instances as a "surrogate" endpoint. The reasons for the substitution are often both practical and financial. At present, no theoretical basis or practical guidelines exist to help in the choice of surrogate endpoints. An approach is proposed here, based on three provisos which can be verified using one of a series of equations, if sufficient data on the pathophysiology and epidemiology of the disease are available. It is shown that even a strong statistical correlation is not a sufficient criterion for the definition of a surrogate endpoint. It is apparent that results obtained with the commonly used "surrogate" endpoints should be cautiously considered, and that the assessment of treatments should, when possible, be based on clinical rather than intermediate endpoints.


Relationship between arterial and peripheral venous catecholamine plasma catecholamine concentrations during infusion of noradrenaline and adrenaline in healthy volunteers.

Noradrenaline and adrenaline were infused IV at 5 different rates (0.01-0.2 micrograms.kg.min-1) for 30 min to volunteers. The plasma catecholamine concentrations were determined by HPLC and electro-chemical detection. At the highest infusion rate, the arterial and venous plasma concentrations of noradrenaline increased from 1.18 to 44.1 nmol.l-1 and from 1.14 to 31.9 nmol.l-1, respectively, and of adrenaline from 0.29 to 23.9 nmol.l-1 and from 0.28 to 19.3 nmol.l-1, respectively. The peripheral venous plasma concentration of noradrenaline averaged 76% of the arterial concentration, and of adrenaline it was 73%. There was a linear relationship between the peripheral venous and arterial plasma noradrenaline and adrenaline concentrations at therapeutic doses.


Lack of effect of mianserin on the symptoms of diabetic neuropathy.

The effect of the non-tricyclic antidepressant mianserin on symptoms of diabetic neuropathy has been studied in 18 patients in a double-blind, cross-over study with imipramine as a positive control. The patients were treated with placebo, mianserin, and imipramine, each for two weeks, in randomized order, with 1-3 weeks between the treatments. The symptoms were assessed by observer and self-rating scales. Mianserin was given in the fixed dosage of 60 mg per day, whereas the dose of imipramine was adjusted to yield the optimal plasma concentration of imipramine plus desipramine of 400-600 nmol.l-1. The mianserin plus desmethylmianserin plasma concentration ranged from 85 to 850 nmol.l-1, with the highest concentration in a patient who was a poor metabolizer of both sparteine and mephenytoin. The symptoms of neuropathy were significantly reduced during imipramine treatment, although somewhat less than in earlier studies. In contrast, mianserin produced no change in symptoms in comparison with placebo. As there was no evidence that higher mianserin (plus metabolite) steady-state concentrations were associated with a more favourable effect, the negative outcome appeared not to be related to underdosing with mianserin. In contrast to drugs with documented effects on the symptoms of diabetic neuropathy, mianserin has a very weak or no inhibitory effect on 5-HT and noradrenaline reuptake and this may explain its poor clinical effect.


Effect of cigarette smoking and of a transdermal nicotine delivery system on glucoregulation in type 2 diabetes mellitus.

The effect of nicotine absorbed transdermally from a patch (TNS) and from cigarette smoking on insulin secretion and action in Type 2 diabetes has been compared. Twelve Type 2 diabetic smoking patients, aged 51 y, with diabetes for 9 y, treated either with diet and/or oral hypoglycaemic agents, were studied on three occasions, according to a double-blind, placebo-controlled, cross-over design. The subjects were investigated 12 h after their last cigarette or application of one patch of TNS 30 cm2 or TNS placebo, or whilst smoking their usual cigarette. Insulin secretion was assessed by a glucagon (1 mg IV) stimulation test. On a second occasion, insulin action was assessed by a hyperglycaemic-hyperinsulinaemic clamp, the spontaneous hyperglycaemia of the fasting state (8.61 mmol.l-1) being maintained during a 4 h insulin infusion (at 0.1 mU.kg-1.min-1 for the initial 2 h, and 1 mU.kg-1.min-1 during the last 2 h). TNS and the cigarette did not affect endogenous insulin secretion as compared to placebo. During the initial 2 h of the clamp study, plasma insulin increased from 88 to 155 pmol.l-1, hepatic glucose production (3-3H-glucose) was less suppressed after TNS (4.31 mumol.kg-1.min-1) than after placebo (2.5 mumol.kg-1.min-1), but was more suppressed than after cigarette smoking (5.61 mumol.kg-1.min-1). In the last 2 h of the clamp (plasma insulin 646 pmol.l-1), glucose utilization was less stimulated after TNS (36.1 mumol.kg-1.min-1) vs placebo (39.8 mumol.kg-1.min-1), but more than after cigarette smoking (33.6 mumol.kg-1.min-1), primarily because of a decrease in glucose storage.(ABSTRACT TRUNCATED AT 250 WORDS)


Plasma protein binding of catecholamines, prazosin and propranolol in diabetes mellitus.

In the present study equilibrium dialysis has been used to determine the degree of protein binding of the catecholamines adrenaline and noradrenaline and the adrenergic receptor blockers, prazosin and propranolol in diabetics. The binding of the catecholamines in plasma from Type I and II diabetic patients was not significantly different from that of healthy subjects. The ratio of the bound and free catecholamine concentrations was correlated with the level of albumin (HSA). Significantly reduced protein binding of prazosin was observed in Type I and II diabetic subjects compared to healthy volunteers. The binding of propranolol was significantly reduced in Type I patients. The ratios between the bound and unbound concentrations of prazosin and propranolol were significantly correlated with the levels of alpha 1-acid glycoprotein (AAG). The results suggest that non-enzymatic glycosylation of plasma proteins may increase the unbound fraction of the adrenergic blockers prazosin and propranolol.


Altered pharmacokinetics of lignocaine after epidural injection in type II diabetics.

The pharmacokinetics of lignocaine has been compared after epidural anaesthesia in diabetics and non-diabetic patients. Epidural lignocaine 8 mg.kg-1 was given to 8 well controlled Type II diabetic and 8 non-diabetic patients and the plasma drug concentration in serial blood samples were measured by HPLC. The plasma level of lignocaine was lower in diabetics compared to non-diabetics. The peak level was attained at 20 min in both groups. The clearance of the drug was significantly higher, (39.9 vs 16.7 ml.min-1.kg-1) associated with a decreased elimination half-life and mean residence time. The study suggests that the rate of absorption of lignocaine is not altered after epidural administration and that its hepatic metabolism is increased in diabetics compared to non-diabetics.


Pharmacokinetic profile of a novel slow release preparation of molsidomine.

A novel slow release preparation containing 24 mg molsidomine has been investigated in 6 healthy subjects. Individual concentration/time-profiles after the tablet showed two separate concentration peaks at 2.2 h and 15.0 h. The relative bioavailability of the slow release preparation in comparison to an aqueous solution of molsidomine was 0.67. The in vivo dissolution profile revealed either a progressive decrease in dissolution velocity caused by altered physico-chemical conditions in the ileum and the colon or a progressive reduction in the absorption constant. In all subjects deconvolution revealed a punctual increase in absorption about 15 h post-dose, coinciding with the second peak of the concentration/time-profile. Therapeutic plasma levels of molsidomine (greater than 5 ng.ml-1) were not maintained over 24 h by this slow release formulation.


Dose-dependent absorption of amoxicillin in patients with an ileostomy.

Amoxicillin was given as single doses of 375, 700, 1500, 3000 and 6000 mg an oral suspension to four volunteers with an ileostomy and with no active intestinal disease after an overnight fast. The excretion of amoxicillin and its penicilloic acid was followed in samples taken from the ileostomy and in urine produced over 6 h. Beta-lactamase activity was measured in ileal fluid and none was found. The percentage of the dose recovered from the ileostomy increased successively from 8% at the lowest dose to 77% at the highest dose. A complementary excretion pattern of amoxicillin was found in the urine, amounting to 70% recovery at the lowest dose to 23% at the highest dose. The results confirm the dose-dependence of the absorption of amoxicillin, which could at least in part be due to specialised absorption of this drug in humans.


Nonlinearity of amoxicillin absorption kinetics in human.

Specialised gastrointestinal absorption of amoxicillin has been suggested in man and has been demonstrated in animals. In order to study the rate and extent of amoxicillin absorption, six healthy subjects were given 500 mg IV and two oral doses (500 mg and 3 g as a suspension). Absorption kinetics was analysed by compartmental modelling, noncompartmental methods and by calculation of absorption rates using deconvolution. Dose-dependency of the extent of amoxicillin absorption was observed, with a lower than expected mean maximum plasma concentration (49%), and fraction of the dose absorbed (39%) after the 3 g dose calculated from the 500 mg dose, assuming kinetic linearity. Zero-order kinetics of absorption was apparent in some subjects after the 500 mg dose, both from model fitting and absorption rate profile. However, no pattern consistent with pure first-order or zero-order absorption was observed after both oral doses in any individual. The dose-dependency of amoxicillin absorption was confirmed by a trend to an increased time of absorption for the high dose. The results show the variable nature and nonlinearity of the gastrointestinal absorption of amoxicillin and indicate the involvement of a number of factors, in addition to simple diffusion.


Pharmacokinetic estimations from microdialysis data.

Microdialysis has recently been adapted for sampling the extracellular fluid of various organs in order to measure drug concentrations, and the first clinical application has been published. My aim here is to provide simple rules about how to analyse pharmacokinetic data from such studies. The plotting of data on a time scale and the estimation of C (0) and slopes is not a trivial problem when multicompartmental models are assumed or sampling intervals are unequal. I have developed formulae and algorithms to solve the problem. A simple rule of thumb is given, suggesting when these formulae need to be applied. It is shown that the calculations of half-life and slopes is similar to standard methods for equal sample intervals and that calculation of AUC and clearance may be even more accurate for microdialysis data than for ordinary blood sampling, because of the time-integral character of the dialysis method. I have dealt with both zero-order and first-order kinetics.


Effect of age on the disposition of sodium fluoride.

Sodium fluoride (NaF) is used in the treatment of axial osteoporosis and so is mostly given to old patients. Since its pharmacokinetics has not been studied in the elderly, the pharmacokinetics of an enteric-coated tablet containing 50 mg NaF has been investigated in 15 aged inpatients (aged 65 to 75 y) and 12 young healthy volunteers (aged 21 to 26 y). The serum AUC of fluoride was 1.7-time higher in older than in younger subjects. There was a strong inverse correlation between the AUC and either body surface area (BSA) or glomerular filtration rate (GFR), both of which were very much lower in the elderly. This concluded that if efficacy or safety are related to the bioavailability of fluoride, it may be valuable to adjust the dosage of fluoride accordingly to the GFR and BSA.


Time-dependent change in the effect of probucol in subjects with elevated cholesterol.

A time-dependent change in the cholesterol-lowering effect of probucol has been evaluated in 20 subjects with elevated cholesterol. Probucol 500 mg was given once daily at 07.00 h (day trial) or 19.00 h (night trial) for 3 months according to a crossover design. Fasting blood samples were obtained during the control period and at the end of each treatment period. Serum concentrations of total and HDL-cholesterol were significantly decreased by both the treatments with probucol [total cholesterol (mmol.l-1): control 6.58; day trial 5.41; night trial 5.10; HDL-cholesterol (mmol.l-1): control 1.35; day trial 1.06; night trial 0.96]. These parameters were significantly lower in the night trial than in the day trial. The data indicate that the cholesterol-lowering effect of probucol varies with its time of administration in subjects with elevated cholesterol.


Effects of various prostaglandin synthesis inhibitors on the tone of the lower oesophageal sphincter in man.

The role of endogenous prostaglandins in the modulation of lower oesophageal sphincter (LES) function has been assessed by giving three structurally unrelated cyclooxygenase inhibitors and monitoring their acute effects on LES tonus and platelet thromboxane (TX) B2 production in 20 healthy volunteers. In a double-blind, placebo-controlled, cross-over study, IV injection of soluble salts of acetylsalicylic acid and indomethacin elicited a transient increase in LES tonus of approximately 50% over baseline. A similar pattern was observed after the rectal administration of indomethacin. In contrast, indoprofen had no measurable effect on LES tones, despite comparable inhibition of platelet cyclooxygenase activity. This may have been due to the markedly different tissue distribution of the drug. The results suggest that endogenous prostaglandins physiologically exert an inhibitory influence on LES function.


Effect of dipyridamole with or without aspirin on urine protein excretion in patients with membranous glomerulonephritis.

The antiproteinuric effect of the antiplatelet agent dipyridamole has been assessed after inhibition of thromboxane B2 (TxB2) synthesis in 8 patients with confirmed membranous glomerulonephritis. There were three study periods, each of 30 days, and 45 days apart, namely a washout period, treatment with dipyridamole 300 mg/d, and dipyridamole 225 mg/d plus aspirin 150 mg/d. On Days 1 and 30 of each study period serum and urine creatinine, 24-h excretion of protein, creatinine clearance, platelet aggregometry on whole blood and serum TxB2 were measured. Treatment with dipyridamole alone or with aspirin produced significant inhibition of platelet aggregation and a fall in 24-h protein excretion; the latter amounted to 54% with dipyridamole alone and 56% with dipyridamole plus aspirin (NS). Dipyridamole plus aspirin caused an 82% reduction in serum TxB2.


Effects of thiopentone/suxamethonium on intraocular pressure after pretreatment with alfentanil.

The effects of pretreatment with alfentanil on intraocular pressure (IOP) were investigated in 40 patients undergoing ophthalmic surgery. Patients were randomly allocated to two study groups. Group 1 patients (n = 20) received alfentanil 15 micrograms.kg-1, vecuronium 0.01 mg.kg-1, thiopentone 3-4 mg.kg-1, and suxamethonium 1 mg.kg-1 for anaesthetic induction, whereas patients in group 2 (n = 20) received vecuronium 0.01 mg.kg-1, thiopentone 3-4 mg.kg-1, and suxamethonium 1 mg.kg-1. A total of seven measurements of intraocular pressure were taken in each patient, starting before premedication and ending after extubation of the trachea. In group 2 patients, there was an increase in IOP after endotracheal intubation. In group 1 patients, a decrease in IOP occurred which was related to the decrease in arterial blood pressure. We conclude that alfentanil pretreatment can prevent the increase in IOP following suxamethonium administration.


Comparative bioavailability of two different rectal preparations of piroxicam in man.

A comparative pharmacokinetic study was performed with two types of suppository each containing 20 mg piroxicam. The bioavailability of piroxicam was studied in 24 healthy volunteers in a double blind, randomised, cross over study. No significant difference was found in the pharmacokinetic parameters [AUC(0-72 h), AUC, Cmax, t1/2 beta] calculated from plasma concentration time curves, indicating that the two preparations were bioequivalent.


Medication utilization and patient information in homes for the aged.

A random cross-sectional sample of 198 residents was taken from a convenience sample of 20 Flemish, community-based nursing homes for the aged. Twenty trained interviewers reviewed the medication list of these residents and interviewed the nurses responsible for their daily care to assess their activities of daily living (ADL) and cognitive status. Direct interview was possible of 128 residents (65%); communication with the other 70 residents was impossible because of dementia (55 patients) or communication problems, such as aphasia and deafness (15 patients). An average of 4.5 different medicines was mentioned on the medication lists of the 198 residents. Drug use increases with age but stabilises after the age of 80 y. Medicines are ordered from local community pharmacies and are delivered to the ward rooms in original drug dispensing packs. The nursing staff is responsible for distribution inside the institution. Nursing personnel read the inserts of the medicines given to 98% of the residents and keep the inserts of 77% in the nursing office. Only 11% of the residents maintained some autonomy in ordering, keeping and taking their medication, although 42% were evaluated by the nurses as functionally and cognitively fit. Only 4% of the 128 residents able to respond to an interview had a notion of the potential adverse effects of their medication; the two most important sources of information about medicines mentioned by those residents were the general practitioner and the nursing personnel; 4% mentioned relatives and friends, or the pharmacist, as information sources.


Predominance of Th1-type T cells in synovial fluid of patients with Yersinia-induced reactive arthritis.

The pathogenetic mechanisms underlying the development of reactive arthritis and the functional capacities of synovial T cells specific for Yersinia enterocolitica are still unclear. In this study we have determined the cytokine secretion patterns of 24 CD4+ synovial fluid (SF)-derived T cell clones from 2 patients with Yersinia-induced reactive arthritis, 16 clones specific for different Yersinia antigens and 8 clones as controls. The clones specific for Yersinia antigens predominantly belong to the T helper cell 1 (Th1) subset with production of interferon (IFN)-gamma and interleukin (IL)-2, but no IL-4, whereas SF T cells not reactive with Yersinia antigens produce IL-2, IL-4 and IFN-gamma and thus belonged to the Th0 subset. Moreover, short-term T cell lines established from SF and peripheral blood showed the same pattern. To further analyze the functional relevance of these data we investigated the influence of IFN-gamma and IL-4 on the intracellular killing of Yersinia in a human glioblastoma cell line. Our data show that the Th1 cytokine IFN-gamma promotes intracellular killing of Yersinia, whereas this effect is antagonized by the Th2 cytokine IL-4. Furthermore, the Th2 cytokine IL-10 inhibited the antigen-specific proliferative response and IFN-gamma and IL-2 production by the Th1 cells. These results provide insight into the antibacterial mechanisms at work in reactive arthritis after infection with Yersinia enterocolitica and, for the first time, reveal the cross-regulatory properties of cytokines derived from Th1 and Th2 cells in a human immune response to bacterial antigens.


Human Golgi beta-galactoside alpha-2,6-sialyltransferase generates a group of sialylated B lymphocyte differentiation antigens.

The role of the human beta-galactoside alpha-2,6-sialyltransferase (hu alpha-2,6-ST) in the generation of B cell surface antigens was investigated by selecting subclones of COS cells (monkey kidney epithelial cells) constitutively expressing a transfected cDNA which encodes the hu alpha-2,6-ST (COS alpha-2,6-ST cells). Expression of hu alpha-2,6-ST in COS cells was sufficient to generate sialylated cell surface epitopes on different glycosylated antigens recognized by monoclonal antibodies to CDw75, CD76, and the unclustered monoclonal antibodies HB-4 and EBU-65. These epitopes were sensitive to sialidase treatment and are likely to contain terminal alpha-2,6-linked sialic acid residues. A novel antiserum raised against bacterially expressed hu alpha-2,6-ST fusion protein was used to localize the sialyltransferase in two cell lines with high expression of either endogenous (B cell line JOK-1) or recombinant (COS alpha-2,6-ST cells) hu alpha-2,6-ST. In both cell lines, the enzyme was detected only intracellularly in the juxtanuclear region and not on the cell surface. In contrast, CDw75, formerly proposed to be identical with an alpha-2,6-ectosialyltransferase, was strongly expressed on the cell surface. The different expression patterns show that neither the CDw75 antigen nor any of the other sialylated antigens analyzed is identical with the hu alpha-2,6-ST. Furthermore, the presence of a surface-expressed alpha-2,6-ST appears unlikely in these cell lines. We propose that CDw75, CD76, HB-4, and EBU-65 represent a unique group of B cell differentiation antigens the production of which requires the enzymatic activity of alpha-2,6-ST.


Interleukin-3-treated non-B, non-T cells switch activated B cells to IgG1/IgE synthesis.

The switch of activated B cells to IgE synthesis is an interleukin (IL)-3-dependent process. It is currently thought that specific T cells activated by antigen presented in the context of class II major histocompatibility complex are the major source of IL-4. Recently it has been demonstrated that a splenic non-T non-B cell population (termed NBNT) has the capacity to produce IL-4 following IgE and IgG receptor cross-linkage. In this study we demonstrate that IL-4 producing NBNT cells can induce the switch of lipopolysaccharide-activated B cells to the synthesis of IgG1 and IgE antibodies. Furthermore, it was found that not only IgE receptor cross-linkage but IL-3 was able to stimulate NBNT cells to produce IL-4 and induce the switch of B cells to IgE synthesis. NBNT cells derived from the spleen and bone marrow of SCID mice were able to produce IL-4 on exposure to IL-3. This suggested that the ability of IL-3 to stimulate IL-4 production was not dependent on prior exposure of the NBNT cells to antibody complexes in vivo. Taken together these findings represent the first observation that enough IL-4 is produced by NBNT cells to actually influence a B cell IgG/Ig response. The findings also clearly demonstrate that B cells do not need high concentrations of IL-4 to be directed to switch to IgG1 and IgE synthesis.


Differentiation-specific expression of a novel G protein-coupled receptor from Burkitt's lymphoma.

Deregulation of the proto-oncogene MYC by specific chromosomal translocations has been shown to be essential but not sufficient for the development of Burkitt's lymphoma (BL). To identify other genes which either mark important steps in tumorigenesis or which reflect the cellular differentiation state of BL cells we have compared tumor cells to immortalized lymphoblastoid B cells by subtractive hybridization. We have identified a complementary DNA clone which encodes a novel member of the superfamily of GTP-binding (G) protein-coupled receptors, designated BLR1. The corresponding mRNA is expressed in BL and lymphatic tissues but not in other cell lines either of the B cell lineage or of other hematopoietic or non-hematopoietic origin. This exclusive expression of BLR1 and the oncogenic potential of this receptor class supports the hypothesis that BLR1 exerts a regulatory function in BL lymphomagenesis and/or B cell differentiation. Moreover, the protein sequence is highly related to that of receptors for the cytokine interleukin (IL)-8 and other neutrophil chemoattractants. We conclude that BLR1 may represent a potential candidate involved in the process of physiologic trafficking, cell-cell interactions, and activation of mature B lymphocytes in lymphatic tissues.