[Migraine and non-steroidal anti-inflammatory agents].

Controlled studies of nonsteroidal antiinflammatory drugs (NSAIDs) for the management of migraine attacks or for the prophylactic long-term treatment of migraine are reviewed herein. A large number of NSAIDs have been tested against a placebo or reference drug, including aspirin, indomethacin, mefenamic acid, tolfenamic acid, flufenamic acid, ibuprofen, flurbiprofen, fenoprofen, naproxen and sodium naproxen, diclofenac and lornoxicam. For the treatment of acute attacks, published studies found that the NSAIDs were significantly more effective than the placebo and at least as effective as the reference drugs. Adverse effects were absent or mild in this indication. Studies of NSAIDs as prophylactic treatment of migraine attacks are less numerous but also point to the value of this approach. However, long-term use of NSAIDs is associated with side-effects, mainly involving the gastrointestinal tract.


[Alteration of bacteria induced by subinhibitory concentrations of cefixime: consequences on bactericidal activity of human polynuclear neutrophils].

Subinhibitory concentrations of most parenteral cephalosporins have been reported to alter bacterial infectivity and, in particular, to increase the susceptibility of altered bacteria to the killing effects of polymorphonuclear neutrophils (PMN). Few data on this issue are available for oral cephalosporins. This study investigated the effects of sub-MIC concentrations of the new oral cephalosporin cefixime on two bacterial targets, i.e., S. aureus 209P (MIC 20 mg/l) and E. coli K12 (MIC 0.15 mg/l). After overnight incubation (18 hours) with 10 or 5 mg/l cefixime, susceptibility of S. aureus to the killing effects of PMNs was increased two-fold as compared with control organisms and susceptibility to the O2-independent PMN bactericidal system (PMN extract) was also increased. In contrast, the susceptibility of E. coli to PMN and to cell-free bactericidal systems was identical for cefixime-exposed strains (0.1 and 0.05 mg/l) and for unexposed controls. However, cefixime-exposed E. coli were filamentous, suggesting that bactericidal efficacy in terms of the bacterial mass eliminated was enhanced in exposed strains. These data show that low levels of cefixime are capable of producing major alterations in susceptible and resistant bacteria and of increasing their susceptibility to PMN. These effects may be relevant in vivo, in particular when low concentrations of antibiotics persist over long periods in infected sites.


[Pseudomonas aeruginosa and imipenem: correlation between membrane protein D2 and resistance in fifteen strains isolated from patients with mucoviscidosis].

A characteristic feature of imipenem-resistant strains of Pseudomonas aeruginosa is loss or decreased expression of the outer membrane protein (OMP) D2, whose molecular weight is 45 to 49 kDa. D2 was studied in 15 strains of P. aeruginosa with intermediate susceptibility or resistance to imipenem recovered from the sputum of 15 patients with cystic fibrosis. The OMP was extracted using Sarkosyl and separated by SDS-PAGE electrophoresis. Electrophoresis patterns were compared to those of reference strains 3B and 3C which are resistant and susceptible to imipenem, respectively. Expression of D2 was normal in three strains, weak or very weak in 11 strains and absent in one strain. For 12 strains, the alteration of the D2 protein was consistent with previous reports. However, the finding of normal D2 production in three strains is unusual and suggests the possible presence of another mechanism of resistance.


[Effect of the administration of cefixime on aerobic fecal flora in children].

The ecological effect of cefixime on aerobic fecal flora was evaluated in 6 children aged 2 to 5 years given oral cefixime (8 mg/kg/day in two divided doses) for five days. Serial dilutions of stools recovered at baseline (D0), 2 and 5 days after initiation of therapy (D2 and D5) and two days after completion of therapy (DC + 2) were cultured on selective media. Colonies of Enterobacteriaceae, group D streptococci, staphylococci, and Candida were counted. A moderate but significant (p less than 0.01) decrease in the Enterobacteriaceae count was seen, with a fall from 8 log 10 (4.8 to 9.4) on D0 to 6.4 (3.6-9) on D2, 6 (4.6-7.2) on D5 and 4.7 (2-8.2) on DC + 2. No cefixime-resistant Entrobacteriaceae or Pseudomonas strains were evidenced. A slight, non significant decrease in group D streptococci counts was found, with values of 7.1, 7.1, 5.8, and 8.3 log 10 at the successive time points. All children exhibited fecal staphylococcal strains which were all coagulase-negative and which did not undergo noticeable quantitative changes (mean successive values were 2.5, 1.8, 3.5, and 3.8 log 10). Candida were found in four children and also changed little over time (mean successive values: 2, 1.7, 2, and 2.6 log 10). In sum, oral administration of cefixime was associated with a modest decrease in the number of Enterobacteriaceae, with no development of resistance to cefixime.


[Bacteriostatic and bactericidal activities of cyclines, macrolides and fluoroquinolones against Chlamydia trachomatis].

The in vitro activity of minocycline, doxycycline, erythromycin, roxithromycin, spiramycin, pefloxacin, and ofloxacin against ten C. trachomatis strains recovered from human genital tract specimens was evaluated. Mac Coy cell monolayers in 24-microwell plates were used. The C. trachomatis inoculum was 10(4) IFU/well. Appropriate dilutions of antibiotic were added and inclusions were detected by immunofluorescence using monoclonal antibodies. MICs were determined after 48 hours of exposure to each antimicrobial. The MIC90 for cyclines was 0.2 mg/l. Among tested macrolides, roxithromycin had a lower MIC than erythromycin (0.2 versus 0.4 mg/l) whereas spiramycin inhibited growth only in a concentration of 2 mg/l. Ofloxacin showed better activity than pefloxacin. Bactericidal activity was evaluated by determining two parameters: MBC1 (without transfer to new cells) measured the ability of a C. trachomatis particle to persist in a latent form within cells exposed to an antibiotic and to grow again following removal of the antibiotic, whereas MBC2 (with transfer to new cells) reflected infectivity of the bacteria after 48 hours exposure to the antimicrobial. None of the tested antibiotics was bactericidal according to both parameters. The ability of C. trachomatis to remain within antibiotic-exposed cells in a latent form was clearly demonstrated by the high MBC1 values. This feature may explain why recurrences are common in clinical practice.


[In vitro kinetics of the activity of fusidic acid and fluoroquinolones combinations against staphylococci according to methicillin-resistance phenotype. Implications for the treatment of osteoarticular infections].

The kinetics of the effect of fusidic acid and of two fluoropiperazinyl quinolones (ofloxacin and pefloxacin), used alone or in combination, on ten methicillin-susceptible or methicillin-resistant strains of staphylococci were studied. Little or no bactericidal effects were seen with fusidic acid. With ofloxacin and pefloxacin, the bactericidal effect was delayed and occurred only with high concentrations. Used in combination, fusidic acid and the fluoroquinolones exhibited no synergistic effects and occasionally antagonized each other in vitro. The methicillin-resistance phenotype of organisms had no influence on results.


[Antibiotic sensitivity of forty-four strains of group EF4 bacteria: study of minimum inhibitory concentrations using the agar dilution method].

EF4 bacteria are found in animal saliva and may contaminate bite wounds. Minimum inhibitory concentrations of 36 antimicrobials against 44 EF4 strains were determined using dilution in Mueller-Hinton agar. EF4 bacteria were susceptible to aminopenicillins, carboxypenicillins, ureidopenicillins, third-generation cephalosporins, fluoroquinolones, rifampicin, and trimethoprime-sulfamethoxazole. Susceptibility was intermediate for penicillin G, low for macrolides and variable for aminoglycosides. EF4 bacteria were resistant to lincomycin and trimethoprime. Routine prophylactic treatment of bite-induced Pasteurella infections using an aminopenicillin or a cycline also protects against EF4 infection of the wound.


[In vitro sensitivity to antibiotics of genital mycoplasmas isolated in Toulouse. Study of new molecules (macrolides and quinolones)].

The minimal metabolism-inhibiting concentrations (MMC) of 11 antibiotics were determined for 40 strains each of M. hominis and U. urealyticum using a terminal color change broth method. All strains were recovered in 1990. Resistance to tetracycline (MMC greater than 8 mg/l) was found for 12.5% of strains of M. hominis and U. urealyticum, as compared with 5% in 1985. Rokitamycin was the most active macrolide against M. hominis (MMC 90: 0.06 mg/l). U. urealyticum strains were susceptible to all the macrolides tested, with the greatest activities being seen for rokitamycin and clarithromycin (MMC 90: 0.06 mg/l and 0.12 mg/l respectively). Sparfloxacin was the most active quinolone against both species. Human clinical trials designed to evaluate these new molecules for the treatment of mycoplasmal and ureaplasmal genital infections are warranted.


[Bacteriostatic activity and killing curves of eight antibiotics against seven strains of penicillin G-resistant pneumococci].

Increasing resistance to multiple antimicrobial agents including penicillins is a current problem with Streptococcus pneumoniae. Seven cases of severe infection due to penicillin G-resistant pneumococci were seen in two teaching hospitals in Paris (France) during the first half of 1991; six of the strains were recovered from pulmonary secretions (protected brush specimens) and one from cerebrospinal fluid (CSF). The bacteriostatic activity and killing curves of eight antimicrobials against these seven strains were studied. Antimicrobial agents tested included penicillin G (PEN), amoxicillin (AMX), cefotaxime (CTX), imipenem (IPM), rifampin (RIF), vancomycin (VAN), fosfomycin (FOS), and erythromycin (ERO). MICs were determined using the agar dilution method. Killing curves were obtained using a liquid medium inoculated with 10(5) to 10(6) CFU/ml and subjected to continuous agitation; survivors were counted at baseline and after 1, 3 and 5 hours incubation. MICs of each antimicrobial (mg/l) for the seven strains were in the following ranges: PEN: 0.5-2, AMX: 0.5-2; CTX: 0.125-1; IPM: 0.03-0.25; RIF: 0.12-0.25; VAN: 0.25-1; FOS: 16; ERO: 0.06 greater than 4. Overall, bactericidal activity was greatest with vancomycin, followed by imipenem, then amoxicillin. The cefotaxime-fosfomycin combination proved synergistic and exhibited bactericidal activity (2MIC + 2MIC) for three of the seven strains. This study demonstrated the value of the cefotaxime-fosfomycin combination. Both these antimicrobials seem appropriate for the treatment of meningitis caused by penicillin G-resistant pneumococci provided their dosage is adjusted to achieve adequate drug levels in the cerebrospinal fluid.


[In vitro evaluation of the activity of butoconazole against Trichomonas vaginalis].

An in vitro study was carried out on ten first clinical isolates of Trichomonas vaginalis. Increasing levels of butaconazole were added to 150 microliters of a dilution in Roiron medium adjusted to 50,000 Trichomonas/ml. Results were read after 1, 2, 6 and 24 hours aerobic incubation at 37 degrees C. Minimum lethal concentration was 93 micrograms/microliters after one hour, 23 micrograms/microliter after six hours and 12 micrograms/microliters after 24 hours. These findings warrant in vivo studies of butoconazole against Trichomonas. This drug, which has already been proved effective in fungal infections, may prove very useful since concomitant infection of the genital tract by Trichomonas and Candida is common.


[Comparative study of two systems for the determination of the sensitivity of yeasts to antifungal agents].

One hundred yeast strains (including 60 Candida albicans) were tested in two laboratories using two different antifungal susceptibility test kits, ATB Fungus and Mycostandard. Tests were carried out under everyday work conditions. Four antifungal agents were compared: amphotericin B, flucytosine, miconazole, and ketoconazole. Results were discrepant in 19.2% (77/400) of cases. Following retesting of discordant cases with both kits, the agreement rate for strain characterization was 95.5%. Few discrepancies were seen with flucytosine. Conflicting results obtained with amphotericin B were due to poor reproducibility of Mycostandard results, especially for species other than C. albicans. In contrast, reproducibility of the ATB Fungus kit was inadequate for miconazole. The rate of discrepant results was greatest for ketoconazole. Intermediate susceptibility was seen more often with ATB Fungus for C. albicans and with Mycostandard for C. glabrata and C. krusei. The lack of reproducibility under routine working conditions should lead gallery manufacturers to strive to achieve clearer readings.


[In vitro evaluation of the sensitivity to fluconazole of different species of yeasts isolated in pathology].

In a previous study, the authors developed a technique for evaluating the in vitro susceptibility (or resistance) of Candida albicans to fluconazole, using casitone broth and agar. Photometric readings of growth in liquid media proved more accurate for evaluating antifungal activity and consistently agreed with clinical findings in all studied cases. This method was consequently extended from C. albicans to other yeasts recovered from high-risk patients (C. glabrata, C. famata, C. tropicalis, C. krusei, C. pseudotropicalis, C. parapsilosis, etc...). High resolution antifungal assay medium (broth and agar) and casitone medium (broth and agar) with or without agitation (Autobac System) were used to study the activity of fluconazole against approximately one hundred yeast strains. MICs above 3.12 micrograms/ml were found for several strains, particularly belonging to the C. glabrata and C. krusei species. These values are equal to or greater than serum levels achieved during treatment with fluconazole, a fact which raises practical questions concerning fluconazole therapy and may explain the failure of fluconazole to eradicate yeasts in some patients.


[Emulsion of amphotericin B in Intralipid 20%: in vitro and in vivo efficacy].

Toxic effects limit the use of amphotericin B (AmB) for the treatment of systemic Candida infections. In vitro and in vivo toxicity can be substantially reduced by mixing AmB with a lipid emulsion used for parenteral nutrition, intralipid 20% (IL). This study was designed to evaluate the potential effects of IL on the activity of Amphotericin B against Candida. A clinical strain of Candida albicans was used. AmB deoxycholate (Fungizone) was reconstituted in a 5% glucoce solution (AmB-G5), in 3 mg/ml IL (AmB-IL3) or in 1.5 mg/ml IL (AmB-IL 1.5). Minimum inhibitory concentrations and minimum lethal concentrations were 0.4 mg/l and 2.5 mg/l, respectively, with AmB-G5, 0.1 mg/l and 1 mg/l with AmB-IL3, and 0.24 mg/l and 1 mg/l with AmB-IL 1.5. In vitro killing curves with 0.1 mg/l, 0.25 mg/l, and 2.5 mg/l AmB were determined with the following results: 1) with 0.1 and 0.25 mg/l AmB, fungicidal activity was seen with AmB-IL3 and AmB-IL 1.5 but not with AmB-G5; 2) with 2.5 mg/l AmB, fungicidal activity was less marked with AmB-G5 (-1.7 log CFU/ml after 24 hours) than with AmB-IL3 and AmB-IL1.5 (-4.3 log CFU/ml and -4.2 log CFU/ml, respectively, after 24 hours; p less than 0.05). In rabbits given a single intravenous injection of 4 mg/kg AmB, analysis of infected subcutaneous fibrin clots detected measurable concentrations of AmB beyond the 24th-36th hour, with levels of 0.5 mg/l for AmB-G5 and 1 mg/l for the two AmB-IL preparations over a period of three days.(ABSTRACT TRUNCATED AT 250 WORDS)


[Treatment and secondary prophylaxis with fluconazole for oropharyngeal candidiasis in HIV-positive patients. A mycological analysis of failures].

This prospective study evaluated the in vitro susceptibility of Candida albicans isolates recovered from the oral cavity of AIDS/ARC patients before and during long-term therapy with fluconazole. Thirty adults (15 with ARC and 15 with AIDS) with a first episode of thrush candidiasis were given oral fluconazole (Triflucan 50 mg; one capsule daily) for at least three months. Fungal susceptibility testing was performed before treatment, after one month, and at last follow-up (range 3.5-12 months; mean 5.7 months). MICs were determined using the agar dilution method with casitone (Difco 259-01) as the test medium at pH 7.2-7.4. There were two initial clinical failures (one with high MICs before and under treatment and one with an intermediate MIC initially and a rise in MIC under fluconazole). Four patients developed a clinical relapse with no change in MICs (which were low or intermediate). In six patients, clinical symptoms resolved but carriage of C. albicans persisted (low MICs). In 18 patients, clinical resolution with eradication of C. albicans was achieved. These data suggest that (1) clinical failures may be associated with in vitro resistance; (2) relapses under fluconazole maintenance therapy may develop in patients with advanced HIV disease despite the lack of change in the susceptibility of strains.


[Comparison of the activity against Streptococcus mutans of a chlorhexidine-based antiseptic as a suspension or as a biofilm].

When bacteria colonize a surface they form a biofilm whose susceptibility to anti-microbials is different from that of the same bacterial species forming a homogeneous suspension in a liquid. This study investigated colonization of an inert solid phase (Tygon) with Streptococcus mutans ATCC 25,175--one of the strains involved in the initiation of cariogenic dental plaque--in a continuous flow of fresh medium sufficiently diluted so as to preclude growth of suspended bacteria. Only those bacteria which adhered to the solid phase grew, forming a biofilm. The antiseptic activity of Eludril (0.1% chlorhexidine) on this biofilm under dynamic (flowing medium) and static (stagnant medium) conditions was studied by comparison with the same strain in a suspension (in compliance with the AFNOR NF T 72-150 norm) and in a confluent culture on a filtering membrane. The biofilm was less susceptible under dynamic than under static conditions; under both conditions, the biofilm was less susceptible than the suspension. According to this model, the concentration of antiseptic recommended by the manufacturer according to studies using AFNOR norm NF T 72-150 (bacteria in a suspension) may be inadequate for bacteria adhering to tooth surfaces or gingival mucosa.


[Kinetics of bactericidal and sporicidal effects of a disinfectant against bacteria isolated from hospital units].

The bactericidal and sporicidal activities of a peracetic acid disinfectant commonly used in hospitals (Acetoper 200) was studied using three bacterial species recovered in water from hemodialysis machines and humidifiers, i.e., Pseudomonas aeruginosa, Serratia liquefaciens, and Bacillus subtilis (spores). The method used was derived from AFNOR norms NF T 72-151 and NF T 72-231. For each strain, three concentrations of disinfectant were tested. Counts were performed every five minutes for one hour to evaluate killing kinetics. For both Gram-negative organisms, survival curves were biphasic, whereas B. subtilis counts decreased logarithmically. Both concentration and time influenced the 5 log10 decrease in counts. With S. liquefaciens and B. subtilis (spores), the 5 log10 decrease was not reached with low levels of disinfectant. In every case, the D value decreased substantially with increasing levels of disinfectant.


[Study of intraocular diffusion of ofloxacin in humans and rabbits].

The diffusion of ofloxacin in infected and healthy human and rabbit eyes was investigated. In the human study, cataract surgery patients were given intravenous ofloxacin either as a single 200 or 400 mg dose or as two 400 mg infusions 12 hours apart. Samples of aqueous humor and plasma were collected between 1 and 12 hours after the end of the infusion. Levels in the anterior chamber increased with the dose; peak levels, which occurred after three hours, were 0.33 mg/l after 200 mg and 1.24 mg/l after two 200 mg doses given 12 hours apart. In the rabbit study, 16 hours after experimental infection of the left eye by injection of S. epidermidis into the vitreous, animals were given an intraperitoneal injection of 20 or 50 mg/kg ofloxacin. Dosages in the various ocular tissues showed that penetration into the eye varied with race (albinos greater than pigmented) and dose. Intraocular ofloxacin levels, including in the vitreous, increased two fold when the eye was infected; however, penetration into the sclera, choroid, and retina was comparable in infected and noninfected eyes. These findings in humans and animals suggest that ofloxacin in a dose of a least 400 mg is a useful agent for the treatment of prophylaxis of ocular infections.


[Diffusion of piperacillin in the eye].

Intraocular diffusion of piperacillin was studied in 42 patients scheduled for cataract surgery (n = 35) or vitrectomy (n = 7). Piperacillin was administered intravenously (4 g/injection). Thirty-four patients were given a single dose and 8 were given two doses 12 hours apart. Peak piperacillin levels in the aqueous (7.3 mg/l) occurred one hour after the injection; levels in the vitreous were low (less than 0.6 mg/l). Intraocular diffusion of piperacillin was also studied in rabbits with an experimental Staphylococcus epidermidis infection of one eye; the other eye served as the control. In pigmented rabbits (6 Fauve de Bourgogne animals), increased diffusion and decreased elimination of piperacillin were seen in the aqueous, iris and cornea of the infected eyes, as compared with uninfected control eyes. In albino rabbits (6 New Zealand animals), results were less conclusive, with a difference between the infected and healthy eyes appearing only during the second hour following the injection. The good diffusion of piperacillin in the aqueous, especially in infected eyes (at least in rabbits), suggests that this drug may be useful for the treatment of ocular infections provided it is initiated early and given in combination with another antimicrobial exhibiting good intraocular diffusion.


[Biliary excretion and hepatic disposal of cefixime: experimental and clinical study].

Cefixime is a new oral cephalosporin with in vitro activity similar to that of third-generation cephalosporins. Renal excretion accounts for only 40% of systemic clearance of cefixime, suggesting that biliary excretion of the drug may be significant. This study was designed to determine to what extent nonrenal clearance of cefixime is due to biliary excretion of the parent compound. In an isolated perfused rabbit liver model, biliary excretion of cefixime was very low, with only 0.28 +/- 0.15% of a single 10 mg dose injected in the system being recovered in the bile after three hours perfusion. The liver biotransformation rate for cefixime was found to be 16.2%. These results are in striking contrast with those obtained in human studies. Cefixime levels in duodenal juice aspirates collected over four hours following an intravenous injection of 200 mg cefixime in six healthy volunteers were at least fivefold concomitant serum levels. Studies of bile collected by external biliary drainage during 24 hours following an oral dose of 200 mg cefixime in ten cholecystectomized patients showed that the Cmax was 56.9 +/- 70 mg/l, i.e., 25-fold the serum Cmax (2.3 +/- 0.85 mg/l). The bile AUC/serum AUC ratio was 20.4 +/- 20.3. Mean bile level of cefixime was still as high as 4.3 +/- 3.7 mg/l 20 hours after dosing. The amount of cefixime excreted in the bile over 24 hours was 10.0 +/- 12.3 mg i.e., 5% of the dose administered. Twenty-four hour renal excretion of cefixime was 53.3 +/- 26.2 mg.(ABSTRACT TRUNCATED AT 250 WORDS)


[Pulmonary and bronchial kinetics of cefuroxime after a single 500 mg intramuscular injection].

Thirty-two patients (28 males; mean age 56 +/- 10 years) who were undergoing bronchopulmonary exeresis surgery were included in this study of the pulmonary (pulm), bronchial (br), and plasma (pl) kinetics of cefuroxime after a single 500 mg intramuscular injection. Twenty-nine bronchial specimens and 38 pulmonary and plasma specimens were taken on average at the following times after the cefuroxime injection: 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 10 h. Cefuroxime was assayed using HPLC on ground tissues, with a correction for contamination by blood. Peak concentrations (C) were found after one hour (Cpl = 11.6 +/- 0.8 micrograms/ml; Cpulm = 7.3 +/- 3.3 micrograms/g; Cbr = 3.7 +/- 1.5 micrograms/g) with the following residual values after 8 hours: Cpl = 0.94 +/- 1.04 micrograms/ml, Cpulm = 0.49 +/- 0.45 micrograms/g, Cbr = 0.15 +/- 0.07 micrograms/g (means +/- 1 SD). Elimination kinetics were monoexponential and similar in plasma, lung tissue and bronchial tissue (elimination half-lives: 1.74 h, 1.66 h, and 1.56 h, respectively), suggesting that all three elements belong to the same pharmacokinetic compartment. Mean intrapolated area-under-the-curve values (AUC) were 33.58 micrograms.ml-1.h (plasma), 20.08 micrograms.g-1.h (lung), and 10.22 micrograms/g-1.h (bronchus). The AUCpulm/AUCpl and AUCbr/AUCpl ratios were 0.60 and 0.30, respectively, in agreement with mean values of tissue level/simultaneous plasma level ratios (lung: 0.59; bronchus: 0.33).


[Detection of extended-spectrum beta-lactamases by the rapid ATB E technique. Value of the API V2.1.1 expert system].

Twenty-two extended-spectrum betalactamase-producing strains of enterobacteriaceae recovered in the authors' hospital were tested using the Rapid ATB E coupled with the API V2.1.1. expert system. The expert system detected 90.9% of ESBL-producing strains. Two strains producing a SHV2 and a CTX1, respectively, escaped detection by the expert system despite concomitant resistance to aminoglycosides.


[Resistance to antibiotics of vibrio cholerae strains isolated in Angola].

Among 87 strains of Vibrio choleare (78 Ogawa serotype and 9 Inaba serotype strains) isolated in Angola in 1987-1990, 86% exhibited multiple resistance to antimicrobials. Eighty-four to 86% of strains were resistant to ampicillin with beta-lactamase production (MIC greater than or equal to 512 mg/l), streptomycin (MIC greater than or equal to 64 mg/l), spectinomycin (MIC greater than or equal to 1,024 mg/l), and trimethoprime-sulfisoxazole (MIC greater than 1,024 mg/l). Seventy-four per cent of strains were resistant to kanamycin (MIC = 512 mg/l), 26% to chloramphenicol (MIC = 32 mg/l), 10% to tetracycline (MIC = 16 mg/l), and 10% to gentamycin (MIC greater than or equal to 32 mg/l). Transfer to E. coli K12 was associated with a substantial increase in expression of resistance to tetracycline and chloramphenicol (CAT type I), with MICs in the 128-512 mg/l range. Transfer rates to E. coli K12 of plasmids for the various resistance phenotypes were 10(-6)/10(-8). The size of the isolated plasmids was 100 Md in diameter and belonged to the incompatibility group inc 6-C.


[Spread in hospital units of a Pseudomonas aeruginosa phenotype producing a beta-lactamase highly inducible by clavulanic acid in vitro].

Pseudomonas aeruginosa strains belonging to the serogroup O:11 exhibiting susceptibility to ticarcillin (TIC) and resistance to the ticarcillin-clavulanic acid (CA) combination were found in 19 inpatients over a 14 month period. Mean inhibition diameters obtained using the agar diffusion method were 21.75 mm around the TIC disks (75 micrograms) and 15.96 mm around the TIC+CA disks (75 + 10 micrograms). With control PaO:11 strains, these diameters were 25.27 and 25 mm, respectively. MIC for ticarcillin determined using the checkerboard method rose to 64 mg with CA levels of 16 mg/l or more. CA exhibited dose-dependent antagonism on TIC killing curves when TIC levels approximated the MIC; this effect was no longer present with higher TIC levels. In the crude bacterial extract, a betalactamase of the cephalosporinase type was detected in the absence of induction and increased threefold after exposure to cefoxitin (100 mg/l) and fourfold after exposure to CA (5 mg/l). All these PaO:11 strains exhibited the same antimicrobial resistance phenotype with decreased susceptibility to ureidopenicillins and resistance to aminoglycosides and fluoroquinolones. The induction of a chromosome-encoded cephalosporinase by CA proved useful as an epidemiologic marker. Nosocomial spread of this phenotype was likely the result of selection due to use of antimicrobials.


[Resistance to antibiotic treatment produced in a model of experimental Pseudomonas aeruginosa peritonitis].

A mouse model of experimental Pseudomonas aeruginosa peritonitis was used to evaluate the emergence of resistant mutants during antimicrobial therapy. Mice were infected intraperitoneally with a large inoculum (10(8) CFU + 125 mg talcum) of one of eight strains of Pseudomonas aeruginosa and treated for eight hours with imipenem (IPM) (2 mg/kg/60 min), ciprofloxacin (CIP) (5 mg/kg/45 min), ceftazidime (CAZ) (2 mg/kg/45 min), and amikacin (AN) (2 mg/kg/45 min), alone or in combination. Dosages were selected to achieve and maintain for 8 hours intraperitoneal concentrations similar to those seen in human bronchial secretions. Emergence of resistant strains occurred in 88% of mice after IPM, 29% after CIP, and 31% after CAZ. MICs for resistant strains were increased 8-fold to 512-fold above baseline. Given in combination, IPM and CIP use was followed with lower rates of resistance to each drug (6% and 2% respectively) than use of each antimicrobial alone (p less than 0.001). Combination with amikacin reduced resistance rates for all the antimicrobials studied. No resistant strains occurred with the CIP-CAZ combination. Under the experimental conditions used, the CIP-CAZ combination provided the best results, although the difference with the CIP-IPM combination was not statistically significant.


[Epidemiology of Chlamydia trachomatis using analysis of gene encoding of the major outer membrane protein].

One hundred and eight clinical strains and 24 reference strains of C. trachomatis were typed using differential restriction mapping of omp1, the gene which encodes the major outer membrane protein. The gene was obtained by polymerase chain reaction (PCR). This molecular typing method correlated well with serological typing. Eighty-four per cent of clinical strains were typed using the enzyme AluI alone. Heterogeneity was looked for among the most common serovars (E, F, and D; 62%, 17%, and 9%, respectively). Analysis of the PCR-amplified fourth variable domain of omp1 using denaturing gradient gel electrophoresis followed by direct sequencing of the variants disclosed substantial heterogeneity within the D serovar. Conversely, serovars E and F were homogeneous, with however a single variant strain of serovar E.


[Characterization of Alcaligenes species using analysis of esterase electrophoretic polymorphism and analysis of antibiotic resistance profiles].

The species of an Alcaligenes bacterial strain may be difficult to determine on the basis of conventional phenotype features. Esterase pattern analysis using acrylamide-agar gel electrophoresis and determination of the antimicrobial resistance profile (agar diffusion method) were performed for A. faecalis (34 strains). A. denitrificans subsp xylosoxydans (16 strains) and A. piechaudi (5 strains). The Cistat program (D2 Software) was used for statistical representation of results. The homogeneous, species-specific esterase patterns ensured correct assignment of each strain to one of the three species. Antimicrobial susceptibility was greatest for A. faecalis which was susceptible to both cephalosporins of all generations and aminoglycosides. A. xylosoxydans was the species with the greatest resistance to antimicrobials. A. piechaudii exhibited intermediate susceptibility.


[Peripheral blood cells secreting specific antibodies after oral stimulation with a ribosomal vaccine].

This investigation was designed to investigate mechanisms underlying oral immunization in humans after ingestion of the ribosomal vaccine D53. Immunofluorescence and ELISA (Enzyme-Linked ImmunoSorbent Assay) spot techniques were used for peripheral blood studies. The first part of the investigation was a double-blind placebo-controlled study of 12 healthy volunteers; counts of cells containing immunoglobulins and cells producing specific antibodies were higher in the individuals given the oral ribosomal vaccine than in the placebo-treated controls. In the second part of the investigation, analysis of the kinetics of apparition of the immunoglobulin-containing and specific antibody-producing cells suggested prompt stimulation of Peyer patch B lymphocytes following ingestion of the vaccine. Lastly, a study of 5 children given the vaccine on a long-term basis demonstrated increased counts of both above-described cell types after one month treatment.


Cardiopulmonary response to exercise in anorexia nervosa.

Malnutrition is associated with a number of systemic diseases that are often accompanied by severe exercise limitation. Anorexia nervosa (AN) is a disease characterized by malnutrition due to psychological factors rather than systemic disease. Diminished exercise capacity in AN has been attributed to a loss of muscle mass, dysfunction of remaining muscle, and impaired cardiovascular responses. In order to evaluate the role of malnutrition in the cardiopulmonary response to exercise, nine adolescent girls with AN were evaluated during progressive and steady-state exercise testing using a cycle ergometer. Nutritional status was assessed by body mass percentile (BMP) and percent ideal weight (PIWT). Cardiac output was measured by the indirect (CO2 rebreathing) Fick method. Maximum work capacity (Wmax) was expressed as a percent of predicted for sex and height, and cardiac output as a percent of predicted for oxygen consumption. To ensure that the laboratory values were comparable to the predicted values, a control group consisting of ten adolescents was studied concurrently. Wmax was below the 95% confidence interval in six of nine of the AN group (mean +/- SD: 70 +/- 22% predicted), whereas two of ten controls were below and one above this interval (112 +/- 37%). Wmax correlated with nutritional status (BMP: r = 0.75; P less than 0.001; PIWT: r = 0.8, P less than 0.001). Ventilatory responses for CO2 production at steady state and for Wmax were appropriate in both groups. Cardiac output was appropriate in both the controls (103 +/- 12%) and the AN group (104 +/- 14%).(ABSTRACT TRUNCATED AT 250 WORDS)


High-frequency jet ventilation and surfactant treatment of newborns with severe respiratory failure.

Twenty-eight newborn infants (birthweight, 2.4 +/- 1.1 kg; gestational age, 34.6 +/- 6.1 weeks) with respiratory distress syndrome (RDS), meconium aspiration syndrome, or pneumonia who deteriorated in spite of optimal conventional mechanical ventilation (CMV) and exogenous surfactant therapy were treated with high-frequency jet ventilation (HFJV) and continued surfactant therapy. For enrollment, infants had to have a limited response to surfactant therapy and conventional ventilation, and meet clinical criteria that confirmed clinical deterioration and severity of illness. Study infants had received exogenous calf lung surfactant extract (CLSE) and conventional ventilation prior to the start of HFJV at 46.3 +/- 8.2 hours of age. Patients initially responded to HFJV alone with significant improvement in several respiratory variables, but deteriorated subsequently and receive additional doses of exogenous surfactant on HFJV. Exogenous surfactant and HFJV resulted in significant and sustained improvement in several respiratory variables. Only ten patients deteriorated to meet criteria for a second surfactant dose on HFJV, and two patients received a third dose. Twenty-five of the 28 patients studied survived (89%). No patients received extracorporeal membrane oxygenation or were discharged home on oxygen. The results of this pilot study suggest that the combination of HFJV and exogenous surfactant replacement may be effective in treating infants with more severe respiratory failure, and indicate the need for more extensive controlled investigations.


Cardiorespiratory effects of changing inspiratory to expiratory ratio during high-frequency oscillation in an animal model of respiratory failure.

To examine the effects of varying inspiratory/expiratory ratio (I/E) on cardiorespiratory function during high-frequency oscillation (HFO), 11 saline-lavaged rabbits were ventilated at I/E = 1:2, 1:1.5, 1.5:1, and 2:1 in a paired comparison to a baseline of I/E = 1:1. HFO was delivered by a SensorMedics model 3100 oscillator at a frequency of 10 Hz. Pressure amplitude and proximal mean airway pressure (PPaw) were held constant as I/E was varied from baseline to the experimental I/E. During each paired observation, PaO2, PaCO2, cardiac output, blood pressure, and distal mean airway pressure (DPaw) were measured. We found that as I/E was increased or decreased from 1:1, no significant changes in PaO2, PaCO2, blood pressure, or cardiac output occurred. We conclude that in this model, varying I/E has no significant effect on oxygenation, ventilation, or cardiovascular function.


[Approach to the study of suicide in the essays of Enrico Morselli (1879) and in the successive hypotheses of Durkheim and Freud].

Scientific investigations on suicide began at the beginning of the XIX century. The aim of such investigations was the evaluation of the epidemiological and statistical distribution of the phenomenon in order to set up preventive intervention, as well as the establishment of the psychological and psychopathological characteristics of the subjects choosing this solution to their life. E. Morselli's work on the matter (1879) can be considered the main Italian contribution to the discussion that was troubling and antagonizing the most competent authors in all the civil world from the half a century and it was regarded in due consideration by his contemporaries too. The second author taken into consideration is E. Durkheim, whose monograph issued twenty years later presents elements having such originality and accuracy that they represent even today a constant reference for the suicide studies. S. Freud, on his side, did never write any monograph on this matter, but fundamental observations on the self-suppression psychodynamic interpretation can be found in his works.


A bench test evaluation of a neonatal closed tracheal suction system.

We tested the hypothesis that a possible mechanism for reduced hypoxia during suctioning with closed tracheal suction systems (CTSS) is the provision of uninterrupted gas delivery and the maintenance of airway pressures. This was accomplished by using a neonatal ventilator and test lung model to permit the insertion of a CTSS (with and without suction applied), measurements of inspiratory and end-expiratory airway pressures proximal and distal to the endotracheal tube (ETT) and measurements of inspired and expired tidal volumes (sampled distal to the ETT). An 8 Fr CTSS was evaluated with 4.5, 4.0, and 3.5 mm ETT, and a 6 Fr CTSS with a 3.5, 3.0, and 2.5 mm ETT. We found that catheter placement without suction caused no changes in proximal airway pressures but distal peak inspiratory pressures decreased as the relationship between suction catheter size and ETT lumen increased, while distal end-expiratory pressures were unchanged. Similarly, distal tidal volumes progressively decreased as the size of the suction catheter occupied more of the ETT lumen. During suctioning with the 6 Fr catheter, proximal airway pressures were virtually unchanged; however, as ETT size decreased, distal airway pressures also decreased. The application of suction only modestly augmented the substantial decrement in measured tidal volumes when compared to catheter insertion alone. For the 8 Fr catheter, suction markedly reduced both proximal and distal airway pressures and tidal volumes. We conclude that the use of the CTSS tested in this neonatal ventilator/test lung model does not preserve continuity of volume or pressure delivery during suction procedures; therefore these cannot be the sole explanation for the reported reduction in suction related hypoxia.


Malignant primitive neuroepithelial tumour of soft tissues mimicking a cellular ependymoma.

A malignant small blue-cell soft tissue tumour in a 13 year-old girl is reported. By light microscopy the tumour showed prominent pseudo-rosettes suggesting peripheral neuroepithelial tumour (PNET) with ependymal differentiation or extraspinal cellular ependymoma. Ultrastructural and immunocytochemical findings helped in excluding an ependymal neoplasm (low-grade malignancy) and supported the diagnosis of malignant primitive PNET mimicking a cellular ependymoma (high-grade malignancy).


[Human dirofilariasis: discovery of a gravid female of Dirofilaria repens in a subcutaneous nodule].

A case of human subcutaneous dirofilariasis occurred in a 53 years old woman from Scafati (Salerno province). It was localized in the left submammary region. The patient was operated 16 years ago for a papillary carcinoma of the thyroid. For this reason a metastasis was clinically suspected. The histological examination revealed the presence of a granulomatous nodule formed around a Dirofilaria repens gravid female in the subcutaneous tissue. The presence of microfilariae in the uterus of the nematode would suggest that also a mature male was present at the same time in the patient, although it was not possible to localise it. Haematic eosinophilia was observed.


Dissociation of symptom scores and bronchial hyperreactivity: study in asthmatic children on long-term treatment with inhaled beclomethasone dipropionate.

The aim of the study was to evaluate the effects of inhaled steroids (IS) on the improvement of clinical asthma symptoms and on the decrease in bronchial hyperreactivity (BHR). Twenty-four children with severe asthma were given 1,000 micrograms beclomethasone dipropionate (BDP) daily and compared with ten asthmatic control children. The study included the evaluation of daily clinical score, of exercise induced asthma, of bronchial obstruction (forced expiratory volume in 1 sec, FEV1), and of BHR at months 0, 1, 2-3, and 4-5 (M0, M1, M2-3, and M4-5). BHR was assessed by standardized inhaled carbachol provocation measuring plethysmographic specific airway resistance (SRaw). The carbachol dose causing a 40% decrease in specific conductance (SGaw) was determined (PD40 SGaw). Clinical scores decreased at M1 (P less than 0.01) and throughout the study. FEV1 increased at M1 (P less than 0.05), M2-3 (P less than 0.01), and M4-5 (P less than 0.05) compared to M0. PD40 SGaw only increased significantly at M1 and M2-3. No individual correlation was found between clinical scores and PD40 SGaw at any testing, or between the decrease of clinical scores and the decrease of BHR. We conclude that bronchoconstrictive challenge tests do not adequately assess the clinical efficacy of IS. In clinical practice non-specific BHR should be preferentially measured for diagnosing atypical forms of asthma.


The effects of airway hyperresponsiveness, wheezing, and atopy on longitudinal pulmonary function in children: a 6-year follow-up study.

We examined growth of spirometric lung function in 696 children of European ancestry who were followed from ages 9 to 15 years and stratified according to their degree of responsiveness to methacholine inhalation challenge, atopic status, and respiratory symptoms. Subjects were participants in the longitudinal Multidisciplinary Health and Development Study in Dunedin, New Zealand. Forced expired volume in 1 second (FEV1), and vital capacity (VC) were measured at 9, 11, 13, and 15 years of age, concurrently with assessment of airway responsiveness determined by the concentration of methacholine causing a 20% fall in FEV1 (PC20 FEV1). Atopic status was assessed at age 13 by skin-prick testing to 11 allergens. In children demonstrating airway hyperresponsiveness, FEV1 increased with age at a slower rate, and the FEV1/VC ratio had a faster rate of decline through childhood, compared to non-responsive children. Subjects with positive skin tests to house dust mite and cat dander also had lower mean FEV1/VC ratios than the control group. Any reported wheezing was associated with slower growth of FEV1 and VC in males. We conclude that in New Zealand children with airway responsiveness and/or atopy to house dust mite or cat growth of spirometric lung function is impaired.


Elastase alpha 1-proteinase inhibitor and lactoferrin concentrations in endotracheal aspirates of ventilated newborns.

Bacterial colonization of the tracheo-bronchial tree is common and an established risk factor for infection in ventilated newborns. Elastase, a highly active proteinase, and lactoferrin, an iron-binding protein and potential modulator of the inflammatory process, are both major constituents of either azurophilic or primary granules of neutrophilic granulocytes, released by activation of these cells during the inflammatory response. Since both elastase, complexed with its major inhibitor alpha 1-proteinase inhibitor (E alpha 1-Pl), and lactoferrin (Lf) are indicators of granulocyte activation during bacterial infection, they may indicate infectious inflammation at the tracheobronchial site. To study whether these substances in a single suction probe may serve this purpose, we obtained 82 tracheo-bronchial aspirates routinely from 16 ventilated newborns with a median gestational age of 31.5 (range, 25-39) weeks for laboratory analysis and bacterial cultures. Systemic inflammatory response by differential white blood cell count and C-reactive protein (CRP) was monitored simultaneously. The median E alpha 1-Pl level was significantly elevated in culture-positive aspirates (1,005 micrograms/L; range, less than 30-29,240 micrograms/L) in contrast to culture-negative samples (158 micrograms/L; range, less than 30-1,408 micrograms/L). In addition to a diagnostic sensitivity of 77%, E alpha 1-Pl offered a high specificity of 88%, a positive predictive value of 97%, and a negative predictive value of 73%. In contrast, median Lf concentration (10.6; range, 0.3-58.3 mg/L vs. 11.7; range, 1.6-158 mg/L) showed no correlation with culture results. Of the culture-positive aspirates 36% corresponded with systemic signs of an acute inflammatory response, such as elevated I/T-ratio and CRP.(ABSTRACT TRUNCATED AT 250 WORDS)


Pediatric asthma deaths in Victoria: the mild are at risk.

Previous reviews of pediatric asthma mortality have mostly been from hospital-based clinic populations and suggest that only those with severe asthma are most at risk. This report summarizes an investigation, by interviewer-administered questionnaire, into the circumstances surrounding the death in all patients aged 20 years or less who died from asthma in the State of Victoria over a 3 year period from May 1, 1986. During this period, 51 deaths due to asthma were reported. Thirty-three percent of these were judged to have a history of trivial or mild asthma, and 32% had no previous hospital admission for asthma. However, 36% were judged to have had severe asthma, 43% were taking regular inhaled beclomethasone or sodium cromoglycate, and 10% were taking regular oral steroids. Twenty-two percent had a previous admission to an ICU. Death occurred outside hospital in 40 (78%) subjects. In the final attack 63% had sudden onset and collapse within minutes, 12% were found dead, and 25% had acute progression of an established attack. The investigators assessed 39% of the deaths to have had potentially preventable elements. The preventable factors included: inadequate assessment or therapy of prior asthma (68%), poor compliance with therapy (53%), and delay in seeking help (47%). The majority of subjects in this survey could not be classified as "high risk." Therefore, clinicians should ensure that all young patients with asthma are aware of optimal maintenance management, can recognize deteriorating asthma, and follow a clear individualized crisis plan.


Women and AIDS: sociopolitical issues.

HIV infection and AIDS in women will continue without adequate diagnosis and treatment as long as women are not treated as full partners in society. Until issues related to women and their place in society are considered within the sociopolitical context, women who are at risk for HIV infection, those infected with the HIV virus, and those with AIDS will continue to receive inadequate attention. The National Center for Nursing's National Action Agenda, Nursing and the HIV Epidemic, provides some direction for addressing these issues and those that relate to practice, education, research, and health policy. It is incumbent on nurse researchers to conduct research related to the critical issues associated with HIV infection and AIDS in women, disseminate the findings of that research, and use those findings to inform and move health policy in this area forward. It is equally important to understand the issues that affect women--ethnic considerations, sexual practices, IV drug use--within the context or present political climate of our society. That climate allowed an NIH study that could identify risky sexual behaviors of adolescent and adult subjects who consent to participate in such a study to be called to a halt--not because of concerns about the study design or the scientific rigor of the study, but because of an elected official's fear that asking such questions will encourage these behaviors and his personal belief that such issues should not be discussed in polite society. These issues must be brought forward, acknowledged, and discussed if they are to be dealt with effectively. Otherwise, the relentless course of AIDS will continue.(ABSTRACT TRUNCATED AT 250 WORDS)


Lipid metabolism in type II diabetes.

Hypertension, dyslipidemia, insulin resistance, and hyperinsulinemia--acknowledged risk factors for coronary artery disease--are all more common in persons with non-insulin-dependent diabetes than in nondiabetic persons. The interrelationships of these risk factors are becoming increasingly recognized. This article discusses the dyslipidemias commonly seen in type II diabetes and describes their relationship to glucose metabolism.


Office management of common anorectal problems.

Common anorectal problems can often be treated in the office setting. Hemorrhoids are usually relieved with use of bulk laxatives or stool softeners; if this fails, coagulation or rubber band ligation may be effective. Surgical therapy is still preferred for third- and fourth-degree hemorrhoids. Perirectal and perianal abscesses are treated by drainage, but in up to 30% of cases a fistula occurs following treatment. Surgical evaluation is appropriate when a fistula is suspected. Acute anal fissures often heal with conservative management; sphincterotomy may be needed for chronic fissures. Anal warts tend to recur and require several treatment sessions with use of ablative techniques.


A framework for the transition from nursing records to a nursing information system.

The future of patient record keeping is being developed now. Critical aspects are in place with the development of computer communication standards for health care. The Institute of Medicine's report on the computerized patient record has galvanized many in the health care field to rethink their methods of record keeping. Nurses need to examine the history of the nursing record and look toward the development of a comprehensive nursing information system. Nurses, along with the other disciplines, must examine what they want the system of the future to encompass. A suggested framework for the information system has four major nursing components: (1) data storage component, (2) transaction log, (3) nursing decision support systems, and (4) an engine to link and combine the first three components and to present a consistent easy-to-use interface to the nurse. Done properly, this approach will reduce the amount of time nurses spend charting, add dimension to their notation, and increase the efficiency of data usage for clinical practice. The nursing information system must allow information availability in a manner that accentuates quality practice while releasing the nurse from time-consuming record keeping. These goals are possible to meet, but only if nurses plan for the design now, before it becomes a fait accompli.


Relief from situational insomnia. Pharmacologic and other options.

Although most adults in the United States experience insomnia from time to time, many minimize the problem and fail to seek treatment. This occurs despite accumulating evidence that lack of sleep can seriously impair work performance, reflex response, cognitive abilities, and sense of well-being. Physicians should routinely inquire into a patient's sleep habits and be attuned to complaints of insomnia. A good working partnership between physician and patient may prevent complications of insomnia (eg, overconcern with the condition, demoralization, misuse of drugs and alcohol, disturbances of the circadian sleep-wake cycle), which might otherwise perpetuate and exacerbate the problem. Patients with situational insomnia can usually be treated by their primary care physician, who can offer thoughtful approaches to nonpharmacologic and pharmacologic treatment. In cases of chronic insomnia, referral to a sleep specialist or other authority may be advisable.


The focused physical examination. Should checkups be tailor-made?

The "complete physical examination" taught in medical schools is not always the best approach to clinical assessment of asymptomatic adults. The authors of this article review the controversy surrounding the utility of routine physical examination, advocating evolution in medical practice from use of the complete physical examination toward the focused physical examination.


Sudden death during exercise. A cruel turn of events.

The causes of sudden death in exercisers age 35 and younger are generally not preventable because they are typically structural and difficult to detect. The best a physician can do is be alert to important information in the family and patient history and to the occasional sign or symptom that may warrant further evaluation. For the over-35 exerciser, screening tests may be appropriate, especially if the person is just beginning an exercise program, although this remains an area of controversy. The screening tests available are far from perfect. If exercise testing is performed, the asymptomatic patient must be apprised of the possibility of a false-positive result and the consequences and attendant risks of overdiagnosis or additional testing (coronary angiography). Physicians should be alert to suspicious symptoms in physically active patients, but they should avoid the tendency to have these patients stop their exercise program. Instead, after appropriate diagnostic testing, they should advise a modified exercise program that is safely within the limits of the disease process involved. It is important to realize that physical activity can be a preventer of cardiac disease but also a provoker of sudden death. Even so, the benefits of regular exercise clearly outweigh the risk.


Nephrotic syndrome in adults. A diagnostic and management challenge.

The adult with nephrotic syndrome presents diagnostic and treatment challenges for the primary care physician. Early consultation with a nephrologist is advisable to assist in choosing between empirical therapy or renal biopsy to identify the specific causative lesion. Some patients respond to treatment of either the specific disorder or the underlying cause. All patients should be afforded specific therapy, where available, and nonspecific therapy to minimize the severity of the nephrosis and attenuate the incidence and severity of complications. Although the cause of most disorders resulting in nephrotic syndrome remains unclear, active research into the syndrome's pathogenesis and treatment options should prove fruitful.


How to avert impending stroke.

Patients "lucky" enough to have a nondisabling transient ischemic attack as a warning sign of impending stroke deserve the best possible prophylactic treatment in an attempt to avert that catastrophe. Dr Edmeads provides a step-by-step discussion of diagnostic studies and therapeutic regimens that help avoid stroke in middle-aged and older patients who are at risk.


Respiratory infections in children. What helps and what doesn't?

Respiratory disorders are common in children. Upper respiratory infection is particularly common in children who receive day care or group care. Frequently used methods of treating the common cold (eg, heated vapor, over-the-counter antihistamines and decongestants) have not been proven objectively to be beneficial in young children. Sinusitis is usually diagnosed through history taking (eg, complaints of more than 9 days of non-improving nasal congestion and/or cough), but radiographs may be necessary. Antibiotics effective against specific causative agents are the treatment of choice. Data do not support routine use of myringotomy to treat acute otitis media, but combined with tube placement, this method is useful for recurrent infection. Antibiotic prophylaxis may help prevent recurrent episodes of acute otitis media. Before tonsillectomy is considered for pharyngitis, a history of recurrent episodes must be documented. Epiglottitis, although increasingly rare, should still be considered when certain specific clinical signs are present.


Amenorrhea and chronic anovulation. Finding and addressing the underlying cause.

Amenorrhea is a common problem with a complex etiology. However, the same diagnostic approach can be used in evaluation of all amenorrheic patients. Complete history taking and physical examination are important for determining the presence of congenital abnormalities and chronic conditions. Pregnancy is the most common cause of amenorrhea and should be ruled out in initial laboratory evaluation. Progesterone can then be given to assess endogenous estrogen production and the functioning of the uterus and vagina. Response to this hormone suggests the presence of ovarian, hypothalamic, or pituitary dysfunction, which can be confirmed with further testing. Lack of response to progesterone indicates hypoestrogenism or obstruction of the outflow tract. An estrogen-progesterone challenge helps differentiate these conditions. Chronic anovulation is the second most common cause of amenorrhea. Treatment of chronic anovulation is important to prevent the effects of unopposed estrogen stimulation of the endometrium and to reduce the risk of endometrial adenocarcinoma.


Antiatherosclerotic effects of calcium channel blockers.

Hypertension is a constellation of abnormalities, including metabolic disorders. The current approach to treatment of hypertension should not be dictated solely by measures to lower blood pressure. It must also take into consideration the effect of antihypertensive drug treatment on the development of atherosclerosis and many other important factors. Evidence from rabbit models and cell cultures indicates that calcium channel blockers are antiatherogenic through a variety of mechanisms. In addition to preserving endothelial function, these agents inhibit the following: Platelet aggregation Migration of monocytes and smooth-muscle cells into the intima Incorporation of low-density lipoprotein cholesterol into these cells Matrix formation Calcium overload in atherosclerotic lesions However, additional studies are needed to delineate the antiatherogenic effects of these and other antihypertensive agents.


Rational use of sulfonylureas.

The clinical use of sulfonylureas described in this article is both rational and effective for diabetic patients. Sulfonylureas are not used (1) in patients with insulin-dependent (type I) diabetes, because they are completely ineffective or (2) in patients with non-insulin-dependent (type II) diabetes who respond satisfactorily to diet, because they are unnecessary. In a patient with type II diabetes who has few or no symptoms but does not respond satisfactorily to diet, a sulfonylurea is introduced at a low dose, with gradual increases until a satisfactory response occurs, thus avoiding hypoglycemia. When symptoms of type II diabetes are marked, initiation of therapy with maximum doses of a sulfonylurea quickly distinguishes patients who need insulin therapy from those who have a good chance of responding to an oral drug. Abuse of sulfonylureas occurs when patients who could benefit from diet alone are treated with the drugs unnecessarily or, more often, when patients with poorly controlled disease continue to take maximum doses of the drugs. The usual situation is one in which the patient refuses insulin therapy or the physician does not suggest starting it. In other cases, the poorly controlled patient may be allowed to continue with a combination of a sulfonylurea and an ineffective dose of insulin. In this circumstance, the oral drug should be discontinued and insulin doses increased until control is more satisfactory. Because evidence is so compelling that near euglycemia has a beneficial effect on diabetic retinopathy, nephropathy, and neuropathy, physicians really do patients a disservice by misusing sulfonylureas.


Combining insulin and sulfonylurea. A therapeutic option for type II diabetes.

Non-insulin-dependent (type II) diabetes mellitus is a progressive disease that requires sequential therapy to achieve optimal control. When diet and sulfonylurea fail to maintain glycemic control, the addition of a single daily injection of insulin may be indicated. The best candidates for this combined therapy are patients with typical adult-onset disease that has been present less than 10 to 15 years.


Polyalkylcyanoacrylate nanoparticles as polymeric carriers for antisense oligonucleotides.

Adsorption of oligothymidylates on polyisobutyl- or polyisohexylcyanoacrylate nanoparticles was achieved in the presence of hydrophobic cations such as tetraphenylphosphonium chloride or quaternary ammonium salts. Results suggested that oligonucleotide adsorption on the nanoparticles was mediated by the formation of ion pairs between the negatively charged phosphate groups of the nucleic acid chain and the hydrophobic cations. The adsorption efficiency of oligonucleotide-cation complexes on nanoparticles was found to be highly dependent upon several parameters: oligonucleotide chain length, nature of the cyanoacrylic monomer, hydrophobicity of cations used as ion-pairing agents, and ionic concentration of the medium. Carrier capacity of polyisohexylcyanoacrylate nanoparticles for oligothymidylates (16 nucleotides) complexed with cetyltrimetylammonium bromide in the presence of 0.15 M NaCl was determined to be 5 mumol/g polymer. The in vitro protection of oligothymidylates adsorbed to nanoparticles against degradation by a 3'-exonuclease (snake venom phosphodiesterase) was also demonstrated. These results showed that nanoparticles can be considered as convenient carriers for the protection and delivery of oligonucleotides to cells in culture and for future applications in vivo.


Correlation of in vitro release rate and in vivo absorption characteristics of four chlorpheniramine maleate extended-release formulations.

An in vitro/in vivo correlation was established for four formulations of chlorpheniramine maleate (histamine, H1-blocker) extended-release tablets exhibiting different in vitro release rate characteristics. In vitro release rate data were obtained for 12 individual tablets of each formulation using the USP Apparatus 2, paddle stirrer at 50 rpm in 1000 ml of distilled water at 37.0 +/- 0.5 degrees C. Inspection of the individual and mean release rate data indicated that the in vitro release rate of chlorpheniramine maleate was consistent with the intended design of the four extended-release formulations. The in vivo bioavailability and pharmacokinetics of these formulations were evaluated in 24 healthy subjects under fasting conditions. Wagner Nelson analyses of the in vivo data revealed extended release absorption profiles for all four formulations. Linear regression analyses of the mean percentage of dose absorbed versus the mean in vitro release resulted in a statistically significant correlation (r2 greater than 0.98, P less than 0.001) for each formulation. Qualitative rank-order correlations were observed among all combinations of in vitro and in vivo parameters. These data support a Level A correlation between the in vitro release rate profiles and the in vivo absorption for chlorpheniramine maleate determined under fasting conditions.


Pharmacokinetic and pharmacodynamic comparison of immediate-release and sustained-release adinazolam mesylate tablets after single- and multiple-dose administration.

The effect of adinazolam release rate on psychomotor performance and sedation was assessed by administering 40 mg adinazolam mesylate immediate-release (CT) tablets, 60 mg sustained-release (SR) tablets, and placebo in a double-blind crossover study in 15 healthy male subjects. A separate panel of 16 subjects received the above single doses and multiple-dose regimens of 40 mg CT tablets every 8 hr and 60 mg SR tablets every 12 hr according to a crossover design. Psychomotor performance was assessed by digit symbol substitution test, card sorting tasks, and sedation ratings. Following single-dose administration, dose-corrected adinazolam and N-desmethyladinazolam (NDMAD) AUC values were equivalent for SR and CT tablets. Peak adinazolam and NDMAD levels were lower and occurred later for the SR tablets. Decrements in card sorting were 50 and 3% at 1 hr and 17 and 20% at 6 hr for the CT and SR tablets, respectively. Maximal sedation scores were lower for the SR tablets compared to the CT. Dose-corrected AUC was comparable between single and multiple doses for both adinazolam and NDMAD; no differences were observed in 24-hr AUC at steady-state between CT and SR tablets. Fluctuation ratios were reduced for both adinazolam and NDMAD following SR tablets. Psychomotor and sedative effects were attenuated upon multiple dosing. Thus, the reduction in peak plasma NDMAD following SR tablet administration results in a lesser sedation and psychomotor impairment on acute administration, and tolerance to these effects occurs on multiple dosing.


The pharmacokinetics of trilostane and ketotrilostane in an interconverting system in the rat.

The pharmacokinetics of trilostane and one of its metabolites ketotrilostane are described and characterized in the rat following the separate intravenous administration of trilostane and ketotrilostane. It was noted during these studies that the parent compound and its metabolite undergo metabolic interconversion-trilostane producing ketotrilostane and ketotrilostane generating trilostane. This result means that trilostane is conserved in the body by interconversion--being metabolized to ketotrilostane and then subsequently back to the "parent" drug, trilostane.


Saturable tissue binding and imirestat pharmacokinetics in rats.

To investigate the hypothesis that the pharmacokinetics of imirestat, an aldose reductase inhibitor, are influenced by saturable binding to tissues, three experiments were done. (1) The nature of the dose dependence was characterized in rats. Two groups of nine adult male Sprague-Dawley rats received iv 14C-imirestat at doses of 2 or 8 mg/kg. Serial blood samples were obtained over 15 days. Volume of distribution at steady-state was significantly different between the high- and the low-dose groups (0.744 +/- 0.103 l and 1.10 +/- 0.228 L, respectively). Clearance was independent of dose over this fourfold range (approximately 15 ml/hr). (2) The effect of either statil or AL3152, both aldose reductase inhibitors and potential competitors for aldose reductase binding, on the pharmacokinetics of a single 0.2-mg/kg iv dose of imirestat was assessed. A 2.4-mg/kg loading dose of statil was administered and a constant-rate infusion (56 micrograms/hr/kg) was begun 16 hr before imirestat. A 2-mg/kg loading dose of AL3152 and a constant-rate infusion (115 micrograms/kg/hr) were also administered 16 hr before imirestat. The infusions were maintained throughout the study. AL3152 administration decreased the imirestat steady-state volume of distribution by a mean of 63%. Statil administration decreased it by a mean of 39%. (3) The dosing regimen of the second study was repeated and, at two sampling times, nine tissues and plasma were obtained from four rats per sampling time for determination of imirestat tissue-to-plasma concentration ratio. The tissue/plasma imirestat concentration ratio in the adrenals 24 hr after imirestat administration was 56.9 +/- 20.0 in the imirestat group, 17.7 +/- 1.27 in the statil-coadministered group, and 12.3 +/- 2.59 in the AL3152-coadministered group.(ABSTRACT TRUNCATED AT 250 WORDS)


The in situ acetylation of an immobilized human serum albumin chiral stationary phase for high-performance liquid chromatography in the examination of drug-protein binding phenomena.

The in situ modification of an immobilized human serum albumin (HSA) high-performance liquid chromatographic chiral stationary phase by p-nitrophenyl acetate is reported. This procedure, which is thought to affect primarily a single reactive tyrosine residue within the protein structure, influenced the chromatographic retention and enantioselectivity factors of a wide range of solutes. For certain solutes, increases in both capacity factor and chiral resolution were observed. Ultrafiltration studies on representative test solutes using free HSA, treated in a similar manner to the immobilized protein, gave similar results as the chromatographic observations, indicating that the latter effects are not artifactual results of immobilization. The effect of the modification of HSA on the binding behavior of drugs reportedly sharing the site predominantly affected by the derivatization, namely, the indole-benzodiazepine binding site, varied greatly. This observation suggests that the affected binding area is not a single, tightly structurally defined site.


An air-gap enzyme electrode: development and applications.

A novel air-gap enzyme electrode was developed by amalgamating the principles controlling ion-selective electrodes, enzyme kinetics, and diffusion of molecules across membranes. Commercially available ammonia and carbon dioxide gas-sensing electrodes were modified to measure the respective gases over a head-space. A plexiglass cell was designed and fabricated to house the modified electrodes. The air-gap electrodes exhibited superior sensitivity and response characteristics compared to the original membrane electrodes. The plexiglass cell was divided into two compartments by virtue of a selectively permeable membrane. Enzymatic reactions were conducted in the cell to determine quantitatively the concentration of the substrate. L-Phenylalanine ammonia lyase was used to determine L-phenylalanine with the ammonia electrode and L-glutamate decarboxylase was utilized for the determination of L-glutamic acid by the carbon dioxide electrode. Near-Nernstian slopes were obtained for the response of the enzyme electrodes. In addition to the good reproducibility, the method provided unique ability to reuse the same enzyme solution for several determinations of various concentrations of the analyte. The performance of the two compartment cell and air-gap enzyme electrode was found to be superior in comparison to conventional enzyme electrodes.


Stereoselective enzymatic hydrolysis of various ester prodrugs of ibuprofen and flurbiprofen in human plasma.

The hydrolysis kinetics of various alkyl, glycolamide, aminoethyl, and 2-(1-imidazolyl)ethyl esters of ibuprofen and flurbiprofen in 80% human plasma were investigated using a direct high-performance liquid chromatographic assay for the enantiomers of these acids. In each case, the R-isomer ester was found to undergo faster plasma-catalyzed hydrolysis than the corresponding S-isomer. The difference in the hydrolysis rates between the enantiomeric forms ranged from a factor of 1.4 for the N,N-diethylglycolamide ester of ibuprofen to a factor of 50 and 25 for the 2-(1-imidazolyl)ethyl ester of ibuprofen and flurbiprofen, respectively. Therefore, enantioselective differences in plasma-catalyzed ester prodrug hydrolysis must be taken into account when evaluating prodrugs of racemic mixtures of chiral drugs.


The in vitro enzymic labilities of chemically distinct phosphomonoester prodrugs.

The kinetics of decomposition of phosphomonoesters of hydroxymethyl-5,5-diphenylhydantoin (1), estrone (2), 17 beta-testosterone (3), 1-phenylvinyl alcohol (4), and 17 alpha-testosterone (5) were studied in rat whole blood at 25 and/or 37 degrees C. As the acidity of the leaving hydroxyl group of the phosphomonoester increased, there was a tendency for the rate of hydrolysis to increase, except for the anomalous behavior of 4, which was consistent with its relative rate of hydrolysis in aqueous solutions (1). In addition, the kinetics of hydrolysis of 1-5 and p-nitrophenyl phosphate (p-NPP) were studied in the presence of isolated alkaline phosphatases from a variety of sources. The initial rate of production of 17 alpha- and 17 beta-testosterone from their respective phosphate esters (5 and 3), in the presence of human placental alkaline phosphatase, revealed that 3 was hydrolyzed 5.3-fold more rapidly than 5. This difference in reactivity might have been the result of differences in the stereochemical and/or steric nature of the two isomers. For p-NPP, 1, 2, and 4, the kcat and kcat/Km values determined in the presence of the various alkaline phosphatases showed little variation, whereas for 3, the catalytic constants, kcat and kcat/Km, were found to be dramatically less than those found for p-NPP, 1, 2, and 4.(ABSTRACT TRUNCATED AT 250 WORDS)


Amino acid side-chain contributions to free energy of transfer of tripeptides from water to octanol.

The location of amino acids in soluble or membrane proteins is related to the hydrophobicity of the side chains. Amino acid hydrophobicity values are based upon the thermodynamics of transfer from an aqueous to a nonaqueous environment. However, for certain hydrophilic residues uncertainty exists on the appropriate hydrophobicity values. We have measured the octanol-water partition coefficients (Po/w) of tripeptides of the sequence N-14C-acetyl-Ala-X-Ala-NH-tButyl (AcAlaXAlaNHtButyl), where the central residue X was either Gly, Ala, Phe, Trp, Pro, His, Asp, or Glu. The Po/w for the tripeptides agreed reasonably well with values calculated by the fragment method of D. J. Abraham and A. J. Leo (Proteins Struct. Func. Gen. 2, 130-152, 1987). The log Po/w of the uncharged form was 1.6, 2.7, and 2.5 greater than the log Po/w of the ionized form for the His, Asp, and Glu peptide, respectively. The new data on the pH dependence of the ionizable side chains, His, Asp, and Glu, should result in better prediction of the partition coefficient of peptides as a function of pH. The thermodynamic parameters were determined from the temperature dependence of partitioning. In the temperature range studied (2 to 65 degrees C) the transfer of tripeptides from water to octanol was entropy governed except for the ionized peptides. A heat capacity term was necessary to account for the transfer of tripeptides containing non polar residues. The heat capacity change for transfer from water into octanol was -45, -73, -81, and -88 cal/mol K for Ala, Phe, Trp, and Pro peptides, respectively. Peptides containing Gly, His (pH 7.2), and the uncharged forms of Asp, Glu, and His did not show a significant change in heat capacity. The side-chain contribution of the central residue X (delta Gx) to the free energy of transfer was obtained from the difference between the free energy of transfer of the peptide containing the central residue X and the Gly peptide; delta Gx = delta G(AcAlaXAlaNHtButyl) - delta G(AcAlaGlyAlaNHtButyl). The relative order of hydrophobicity of the side chains correlated well with previous studies. However, a significant difference was found for the absolute hydrophobicity between the present study and experimental data on N-acetyl amino acid amide derivatives (J. Fauchere and V. Pliska, Eur. J. Med. Chem. 18(4), 369-375, 1983).(ABSTRACT TRUNCATED AT 400 WORDS)


Nebulization of liposomes. III. The effects of operating conditions and local environment.

Multilamellar liposomes (MLV) of saturated phosphatidylcholine and dipalmitoyl phosphatidylglycerol (DPPG) (9:1 mole ratio) containing 5,6-carboxyfluorescein (CF) were prepared and extruded through 1.0-micron polycarbonate membranes. Diluted aqueous dispersions were aerosolized for a total of 80 min using a Collison nebulizer under a variety of conditions. The effects of air pressure, temperature, buffer osmotic strength, and pH on nebulized liposome dispersions were studied. Changes in air pressure produced large changes in the percentage release of CF and ranged from 1.3% (4 psig) to 88.2% (50 psig) after 80 min of nebulization. The temperature of the nebulizer dispersions dropped during experiments. The extent of the temperature drop varied according to the air pressure used and ranged from 5 degrees C (4 psig) to 11 degrees C (greater than or equal to 30 psig). The temperature of dispersions caused no increase in CF release until the gel-to-liquid crystalline transition temperature was exceeded (54.6 degrees C), whereupon a 20% increase in leakage was observed after 80 min of nebulization. Aerosol mass output was relatively unaffected by the starting temperature of experiments when conducted within the ambient temperature range. Leakage from the liposomes was increased in hypotonic solution but decreased in hypertonic solutions. At a buffer pH of 2.85 the percentage leakage of CF was increased approximately 18% compared to that at pH 7.2 and pH 10.75. Results show that the stability of liposomes composed of saturated phosphatidylcholine and DPPG (9:1 mole ratio) is affected by the operating and environmental conditions under which aerosolization takes place, with air pressure having the greatest effect.


Infrared imaging of pharmaceutical materials undergoing compaction.

The goal of this study was to use infrared thermography as a new technique to investigate the heat released during compaction and consolidation of pharmaceutical powders and granules. Real-time temperature measurements without physical contact with tablets were provided by a highly sensitive (+/- 0.1 degrees C at 30 degrees C) infrared camera (Agema Infrared Systems, Model 470 with CM-SOFT software). High-resolution images were captured at the takeoff point, i.e., less than 1 sec after compaction, stored on floppy disks, and then analyzed on a regular PC equipped with a VGA color monitor. Thermal surface profiles of tablets were obtained with high geometric and temperature resolution. Reproducibility of the camera readouts was better than 3%. The model granulation used was a direct compression blend of microcrystalline cellulose, spray-dried lactose, and magnesium stearate. This blend was compressed using an instrumented Korsch PH106 rotary press fitted with 1 station of 19.1 x 7.9-mm (0.750 x 0.312-in.) capsule-shaped tools. The effects of compaction force (6-20 kN), rate (130- to 360-msec contact time), and lubricant level (0.5 and 1.0%) on postcompaction temperature rise, caused by heat released during compaction, were investigated. The presence and location of nonhomogeneous heat distribution were assessed as well. Results have shown that the heat released during compaction increases with compaction force. Tablet surface temperatures of 33.8 +/- 0.7 degrees C were observed at 20 kN compaction force in contrast to 29.5 +/- 0.3 degrees C at 6.7 kN.(ABSTRACT TRUNCATED AT 250 WORDS)


Aminopeptidase activity in the jejunal and ileal Peyer's patches of the albino rabbit.

The objectives of this study were (a) to compare the aminopeptidase activity in the Peyer's patches of the jejunum and ileum of the albino rabbit against that in the adjacent patch-free segments and (b) to determine the relative sensitivities of the aminopeptidase activity in the Peyer's and non-Peyer's patches to aminopeptidase inhibitors and penetration enhancers. The results indicated that the Peyer's patches were about equal in aminopeptidase activity in the jejunum and in the ileum but were only 20-30% as rich in aminopeptidase activity as their neighboring patch-free areas. Compared to non-Peyer's patches, the aminopeptidase activity in the Peyer's patches was not as sensitive to the inhibitory effect of amastatin. It was, however, much more sensitive to the inhibitory effect of puromycin and p-chloromercuribenzoate and was somewhat more sensitive to the inhibitory effect of Na deoxycholate, Na glycocholate, and polyoxyethylene-9-lauryl ether. Therefore, based on substrate preferences and on the relative sensitivity of aminopeptidase activity to inhibition by aminopeptidase inhibitors and penetration enhancers, the relative proportions of various aminopeptidases in the Peyer's patches and in the non-Peyer's patches are likely different.


Phagocytosis of nanoparticles by human immunodeficiency virus (HIV)-infected macrophages: a possibility for antiviral drug targeting.

Human monocytes/macrophages (MO/MAC) were isolated from peripheral blood and cultivated on hydrophobic Teflon membranes. This culture system is suitable for HIV infection of MO/MAC in vitro. After transfer into 24-well plates the mature macrophages (infected or uninfected) were used for measurements of phagocytosis. The uptake of different, radioactively labeled nanoparticles (NP) made of polyalkylcyanoacrylate, polymethylmethacrylate (PMMA), and human serum albumin (HSA) by the macrophages was determined. In addition, the influence on phagocytosis of size and composition, concentration, and surface of the NP was studied. Further, macrophages of different state of activation were tested. NP made of polyhexylcyanoacrylate (PHCA) or human serum albumin with a diameter of about 200 nm were found most useful for targeting antiviral substances such as azidotymidine to macrophages. Cells infected in vitro with HIV-1D117/III, a monocytotropic HIV isolate from a perinatally infected child, possessed an even higher phagocytotic activity than noninfected cells. Macrophages isolated from HIV-infected patients also showed good incorporation of NP. Thus, the concept of a specific targeting of antiviral substances to macrophages in HIV-infected individuals appears quite promising.


Bioadhesion by means of specific binding of tomato lectin.

The possibility of developing bioadhesive drug delivery systems on the basis of molecules which selectively bind to the small intestinal epithelium by specific, receptor-mediated mechanisms was investigated using a lectin isolated from tomato fruits (Lycopersicum esculentum). The tomato lectin (TL) was found to bind specifically onto both isolated, fixed pig enterocytes and monolayers of human Caco-2 cell cultures with a similar affinity. TL-coated polystyrene microspheres (0.98 micron) also showed specific binding to enterocytes in vitro. Lectin binding was found to be favored at neutral pH and to be reduced in an acidic environment. Crude pig gastric mucin, however showed a marked cross-reactivity in vitro, indicating that lectin binding to the cell surface in vivo might be inhibited by mucus.


Influence of supersaturation on the pharmacodynamic effect of bupranolol after dermal administration using microemulsions as vehicle.

Transdermal absorption of drugs is limited by the stratum corneum, which serves as a diffusion barrier. This barrier might be overcome by enhancing the thermodynamic activity of the drug vehicle. Thermodynamic activity is particularly high in supersaturated systems because it is directly correlated with the degree of saturation. Since supersaturated systems are not stable, they were formed in situ by application of water-free microemulsion bases. These water-free microemulsion bases saturated with the drug were applied to New Zealand albino rabbits with an occlusive patch. Occlusion leads to water uptake from the skin due to hydratation and changes the microemulsion base into a microemulsion. The microemulsion will become supersaturated as a result of decreasing solubility of the drug with increasing water content. The pharmacodynamic effect of the model drug bupranolol in vivo was investigated over a 10-hr time period. The in vitro solubility of bupranolol was examined with respect to the water content. The solubility vs water content curves were compared to the effect vs time curves. The microemulsions and their individual components were studied, and the effect vs time curves were inversely correlated with the solubility vs water content curves.


Sonophoresis. I. The use of high-frequency ultrasound to enhance transdermal drug delivery.

Previous attempts to use ultrasound (less than or equal to 1-MHz frequency and 1 to 3-W/cm2 intensity) to enhance transdermal drug delivery (so-called sonophoresis) have produced inconsistent results. Theoretical analysis of ultrasound propagation in tissue predicts that higher-frequency ultrasound (greater than 1 MHz) will increase the concentration of energy deposition in the stratum corneum (SC) (typically, the rate-limiting barrier to percutaneous penetration). This hypothesis was tested by comparing the passive transdermal delivery of salicylic acid with that under the influence of ultrasound at 2-, 10-, and 16-MHz frequency; measurements were performed in vivo in hairless guinea pigs. Total drug absorbed was quantified by determining the amount of salicylic acid (1) present in SC tape strips and (2) eliminated in urine. Sonophoresis for 20 min at 2 MHz caused no significant increase in salicylic acid delivery over passive diffusion; treatment with ultrasound at 10 and 16 MHz, on the other hand, significantly elevated salicylic acid transport, by 4-fold and 2.5-fold, respectively. Kinetic analysis of the sonophoretic data at 10 and 16 MHz also revealed that the diffusion lag time associated with transdermal drug delivery (TDD) was reduced. A shorter period (5 min) of sonophoresis again resulted in enhanced TDD (relative to the corresponding control) at the higher frequencies; the delivered dose, and the level of enhancement, however, were lower than those after the 20-min treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Physicochemical properties of the novel heteropolyanion antiviral hexapotassium-alpha-vanado-11-tungstoborate (DuP 925).

Hexapotassium-alpha-vanado-11-tungstoborate (DuP 925) is a yellow irregular-shaped crystalline powder. The DSC thermogram indicates that decomposition begins to occur above 250 degrees C. The compound exhibits a volatile loss of 3.7% by thermogravimetric analysis. The drug substance adsorbs water reaching a 7.1% volatile loss after 3 weeks at 85% relative humidity. The solubility of DuP 925 in water is high (1.6 g/ml at pH 4.8). Changes in pH have a negligible effect on the solubility with values of 1.3 g/ml in 0.1 N HCl and 1.4 g/ml in 0.1 N NaOH. The solubility is minimally affected by changes in sodium ion concentration. The compound ion pairs with tetrabutyl-ammonium ions at 1:2 and 1:6 ratios, with the 1:6 ion pair having an affinity over six orders of magnitude greater than that of the 1:2 ion pair. The degradation of DuP 925 in solution follows apparent first-order kinetics over the pH range of 0.6 to 12.6 at 80 degrees C. Citrate, EDTA, and phosphate buffers are catalytic at the pH minimum, with citrate and EDTA being stronger catalysts than phosphate. Acetate buffers appear to have negligible catalytic effects at pH 4 to 5. The degradation proceeds through the formation of the symmetrical dodecatungstoborate [BW12O40]-5. In acid, the dodecatungstoborate is stable, while in base it degrades further. Increasing the ionic strength has a catalytic effect on the degradation of DuP 925, while changes in the initial concentration of DuP 925 have a negligible effect on the stability. The pH-rate profile indicates a pH minimum of approximately 3.


1H-nuclear magnetic resonance (NMR) studies on the inclusion complex of prostaglandin E1 (PGE1) with alpha-cyclodextrin.

Prostaglandin E1 is currently marketed as a freeze-dried injectable inclusion complex with alpha-cyclodextrin for the treatment of peripheral arterial diseases. alpha-Cyclodextrin is used as a stabilizing agent and to improve the dissolution characteristics of prostaglandin E1. Upon dilution with the infusion medium, the inclusion complex dissociates almost completely as shown by NMR chemical shift measurements of the complexed and uncomplexed prostaglandin E1. Nuclear Overhauser effect (NOE) measurements of the interacting atoms of alpha-cyclodextrin and prostaglandin E1 provide insight into the structure of the complex.


[Pulmonary function tests after pneumocystis carinii pneumonia in HIV infected patients].

Significant impairment of lung volumes and gas exchange in HIV-infected patients with acute Pneumocystis carinii pneumonia (PCP) has been reported, whereas little is known about lung function compromise following successful therapy. In 9 patients with acute PCP and 9 patients 1-5 month after PCP lung function testing including spirometry, diffusing capacity for carbon monoxide and exercise blood gas analysis were performed serially at monthly intervals. The results were summarized in a total score. The mean period of follow-up for each patient was 7.2 +/- 2 months. A decrease in lung volumes (FEV1 67 +/- 14.2% pred.norm., VC 72.7 +/- 11.9% pred.norm.) and gas exchange (CO-transfer factor 53.2 +/- 18.5% pred.norm., CO-transfer coefficient 67.8 +/- 14.2 pred. norm.) was observed in all 9 patients with acute PCP. Post-PCP lung volumes normalized within 1 month, whereas disorders in gas exchange persisted for 1-3 months. The total score normalized in 16/18 patients. One of the remaining patients with persisting functional impairment had chronic obstructive airway disease, whereas in the other dysfunction was even observed prior to PCP and no diagnosis could be obtained. 2-6 months following acute disease a second period of decreased lung function occurred in 6 pts. In 3 of the 6 there were no clinical signs of infection (rebronchoscopy refused), in 1 patient infection with cytomegalovirus was suspected. In the other 2 patients a relapse of PCP was diagnosed by bronchoscopy. Acute PCP compromises lung mechanics and gas exchange. During recovery deficits in gas exchange persist longer than diminished lung volumes.(ABSTRACT TRUNCATED AT 250 WORDS)


[Results of CT-controlled puncture of the thorax].

Results of 56 CT-guided biopsies in 45 patients are presented. Aspiration biopsies (n = 23) had a usable result in 75% of the cases; cutting biopsies (n = 33) in 80%. The main complication was the pneumothorax with 9%; in one patient the procedure caused a haemoptoe.


[The "sarcoidosis-lymphoma syndrome"--a lymphocyte dysregulation?].

Sarcoidosis and malignant lymphoma can occur in the same patient; sarcoidosis appears first, the malignant lymphoma follows later. The case histories of three patients illustrate what Brinker first coined as the "sarcoidosis-lymphoma syndrome". In two patients a pulmonary sarcoidosis stage I was diagnosed over 30 years respectively 4 years prior to the histological diagnosis of highly malignant Non-Hodgkin lymphoma. The third patient suffered from generalized sarcoidosis with splenomegaly, , granulomatous hepatitis and interstitial lung disease, in addition to which a lymphoproliferative syndrome was diagnosed. Comparing the pathogenesis of malignant lymphoma and sarcoidosis, parallels such as T-cell dysfunction, which probably facilitates malignant transformation of B-cells, become apparent. In both diseases the transforming gene could be the Ebstein-Barr virus.


[Thoracic endometriosis--2 case reports and review of the literature].

Thoracic endometriosis is characterised by recurring pulmonary symptoms in association with the menstrual period. Pleural endometriosis manifests itself as recurring pneumothorax or hematothorax while pulmonary endometriosis is characterized by hemoptysis. The pathogenetic mechanism is not completely understood but it appears that hematogenous and lymphangitic embolization of endometrial tissue may play a significant part in parenchymal and pleural endometriosis respectively. Clinical symptoms begin with ovulation. Hemoptysis is explained by sloughing off of decidual tissue and an increased capillary fragility during menstruation. Rupture of pleurally based alveoli in the vicinity of endometrial tissue or necrosis of the diaphragm at the side of diaphragmatic endometrial implants might be causative for the development of a pneumothorax. Therapy of both forms of thoracic endometriosis consists in hormonal suppression but in some cases surgical intervention might become necessary.


[Invasive aspergillosis in cavitary lung sarcoidosis].

Pulmonary sarcoidosis is a granulomatous disorder of unknown origin with a favorable outcome in most patients. However in about 5-10% progressive fibrosis is observed and may lead to further complications. We report on a 49 year-old woman with sarcoidosis with fibrotic changes and cavities in both upper lobes, who developed an upper lobe infiltration resistant to antibiotic treatment. Histologic examination of bronchial biopsy specimen revealed invasive aspergillosis. Therapy with Amphotericin B and Flucytosin was followed by marked clinical and radiological improvement.


Ultrastructure of the developing protonephridial system of the cercaria of Philophthalmus sp. (Trematoda, Digenea).

The fully developed flame bulb of Philopthalmus exhibits the structure characteristic of Trematoda and Monogenea: external and internal ribs forming a weir, external and internal leptotriches, and two longitudinal cytoplasmic cords connected by a septate junction. The proximal canal has a septate junction and surface lamellae. In developing cercariae, perikarya of terminal and proximal canal cells are close together, and sheet-like outgrowths of the terminal cell are externally surrounded by cytoplasm of the proximal canal cell containing a septate junction. Internal outgrowths and external cytoplasm are connected by many "membranes", i.e. desmosome-like structures. Internal sheets break up into internal ribs, and the external cytoplasm breaks up into external ribs, external and internal ribs connected by the filtration "membrane". The developing distal excretory duct possesses a septate junction and many branching and looping lamellae. A comparison of Philopthalmus with the cestode Austramphilina elongata, the only other platyhelminth species in which the development of the protonephridia has been studied at the ultra-structural level, revealed that the two species differ in the presence and absence, respectively, of a septate junction in the flame bulb at an early stage of development.


Comparative investigations of the morphology and chemical composition of the eggshells of Acanthocephala. III. Eoacanthocephala.

Eggshells of the eoacanthocephalans Neoechinorhynchus rutili (Neoechinorhynchidae) and Paratenuisentis ambiguus (Tenuisentidae) were investigated for their fine structure and their chemical composition. The acanthor larvae of P. ambiguus are surrounded by four eggshells (E1-E4) separated by electron-lucent interstices (G1-G4). This resembles the stratification of the eggshells of archiacanthocephalans and palaeacanthocephalans. However, an additional outer envelope (E0) exists in N. rutili. In mature eggs of this species, the broad interstice between E0 and E1 is densely packed with polysaccharides, but the other interstices also showed an intense Thiéry label. In both species, E2 along with its outer protuberances contains keratin, as does E2 in archiacanthocephalans and palaecanthocephalans, whereas E4 does not contain chitin, which contrasts with findings in the eggs of the two other classes of acanthocephalans. The results are discussed with respect to the classification of the Acanthocephala and to their transmission to the intermediate hosts.


Worm burden and leukocyte response in Angiostrongylus malaysiensis-infected rats: the influence of testosterone.

Gonadectomized male albino rats aged 7 weeks were given 1.5 mg/kg testosterone propionate daily and inoculated with 50 third-stage larvae of Angiostrongylus malaysiensis. The treatment significantly increased the number of larvae and adult worms recovered from the brain and pulmonary arteries, respectively, and the rats exhibited smaller thymus glands. The total numbers of leukocytes, monocytes, neutrophils, and especially eosinophils increased significantly post-infection, but the counts were higher in the untreated infected controls. Presumably, immunosuppressive effects of testosterone may at least partly be responsible for the higher loads of A. malaysiensis worms found in male rats as compared with females in the field.