Chemoprophylaxis for patients with colorectal cancer. Prospective study with five-year follow-up.

The effectiveness of a short-term fluorouracil chemopophylaxis regimen commencing four to six weeks after "curative" surgery was evaluated in a homogeneous group of 213 patients with colorectal cancer. In stage III disease (Dukes class C), five-year survival with no evidence of disease (NED) was 24.3% when treated by surgery alone but was 57.5% when a prophylactic regimen of fluorouracil was added (P less than .01), an increase of 33.2%. In stage II disease (Dukes class B), five-year NED survival was raised from 58.5% to 81.6%, an increase of 23.1% (P less than .02). More striking are the one-, two-, and three-year NED survivals in stage III. The one-, two-m and three-year NED survivals for the chemoprophylaxis group are 100%, 95%, and 75%, respectively, in contrast to 70.7%, 48.8%, and 34.1% in the group with surgery alone. The present data indicate that fluorouracil chemoprophylaxis offers a significant improvement of five-year cure rate of patients with stage II and III disease, an overall increase of 28.1% (P less than .01).


Hepatitis A and B in the family unit. Nonparenteral transmission by asymptomatic children.

Investigation of an outbreak of hepatitis A among members of an adoption organization implicated recently arrived Vietnamese orphans as the source of infection. A serologic study disclosed a 27% prevalence of hepatitis B surface antigen among Vietnamese orphans and a 23.1% (6 of 26) prevalence of hepatitis B antibody among American children of adopting families. Five of the six antibody-positive American children were in families with HBsAg-positive orphans. Thus,healthy orphans from high hepatitis incidence areas may transmit hepatitis B, as well as hepatitis A, in the family unit.


Abdominal manifestations of pulmonary embolism.

The cardiopulmonary manifestations of acute pulmonary embolism are well known. However, abdominal manifestations of thromboembolic disease are less well appreciated. We recently encountered three patients with pulmonary emboli who also had complications of abdominal signs and symptoms. Two patients initially had abdominal complaints that obscured the diagnosis. In the other patient, symptoms and signs developed that were indistinguishable from an acute surgical condition of the abdomen after the diagnosis of massive pulmonary embolism was established. Abdominal manifestations alone may be the presenting features of pulmonary embolism or may complicate the clinical course.


Reversible renal failure following bilateral renal artery occlusive disease. Clinical features, pathology, and the role of surgical revascularization.

Three patients with severe hypertension and rapidly progressive oliguric renal failure who required dialysis were found by aortography to have bilateral renal artery occlusion or stenosis. Each had peripheral arteriosclerosis or an abdominal bruit. Following renal artery reconstructive surgery, all three patients recovered nearly normal renal function in 3 to 12 weeks, though mild hypertension persisted in two patients. The common findings of a normal-sized kidney with collateral blood flow and nearly normal histological features were predictive of recovery of renal function. Prolonged postoperative oliguria in two patients may have been due to increased preglomerular vascular resistance mediated by the renin-angiotensin system.


Aortic insufficiency. A result of intermittent migration of aortic valve prosthesis poppet.

A bizarre mechanism of aortic valve incompetence was observed when the occluder of a Braunwald-Cutter aortic valve prosthesis decreased in diameter, volume, and weight, and from time to time fell into the left ventricle. The patient's symptoms were palpitation, coughing, chocking sensations, and fright. An operation disclosed a small, smooth ball with disrupted cloth on all the struts. The residual torn mesh was removed, and the ball was replaced.


Needle aspiration biopsy. Diagnosis of subcutaneous nodules and lymph nodes.

Needle aspiration biopsies were performed on 130 patients with lymphadenopathy or subcutaneous nodules. Within this group, there were 88 malignant specimens, with 84 interpreted as positive and four as suspicious. There were no false-positive findings in benign-lesion speciemens. The method is rapid, inexpensive, and relatively atraumatic and can be utilized in lieu of ordinary surgical excision.


Benign hemoglobinuria following transfusion of accidentally frozen blood.

A patient was transfused with a unit of red blood cells that had been frozen accidentally prior to transfusion. Although he had received approximately 60 gm of free hemoglobin intravenously, the patient's only clinical reaction was massive hemoglobinuria. The benign clinical response, in the presence of massive hemoglobinuria, is attributed to the absence of immunologic imcompatibility and, thus, failure to activate vasoactive mediators and disseminated intravascular coagulation. The case illustrates revised concepts of the pathophysiology of acute renal failure associated with hemolytic blood transfusion reactions.


Gaining and losing weight in athletics.

Participants in many sports, such as wrestling, gymnastics, and light-weight crew, attempt to reduce body weight to achieve a maximum ratio of muscle strength to body weight. Such weight reduction should result only from reduction in excess body fat. In most instances, weight reduction should be achieved at a rate of no more than 1 kg a week, through a modest reduction in diet and a moderate increase in exercise. More rapid weight reduction by starvation and dehydration compromises strength and endurance. Athletes attempting to gain weight should increase weight as muscle mass, not fat. Muscle mass is increased only through muscle work supported by an appropriate increase in food intake. No food, vitamin, drug, or hormone will increase muscle mass. It is recommended that the high caloric diet required to support muscle growth from increased work should be low in animal fats and cholesterol.


Susceptibility of women athletes to injury. Myths vs reality.

To separate fact from fiction regarding the susceptibility of women athletes to injury, three surveys were conducted. The initial data were collected from the athletic departments of collegiate institutions, and the final material was assembled from certified athletic trainers at these institutions, plus an extensive computer search of applicable publications. The collected statistical data were tabulated, and a written commentary was evaluated by the authors. It was established that injuries sustained by female athletes, aside from those related to different biological structures, were essentially no different than those of men, nor are well-trained women athletes more prone to injury. Ankle and knee injuries are most frequent, and women sustain many contusions, sprains, and shin splints. It is anticipated that the overall number of injuries will decrease as better coaches and trainers become available to women athletes.


Physical fitness levels vs selected coronary risk factors. A cross-sectional study.

Several studies show significant correlations of blood variables, weight, abnormal electrocardiograms, and blood pressure with the incidence of coronary heart disease, but the quantification of fitness and its correlation with coronary heart disease is more difficult. In this study, approximately 3,000 men, average age of 44.6 years, were examined for blood and lipid profile, pulmonary function, percent body fat determination, and Balke maximal performance treadmill stress testing with multilead ECG monitoring. Five age-adjusted cardiorespiratory fitness categories were determined from treadmill times. A consistent inverse relationship among physical fitness categories and resting heart rate, body weight, percent body fat, serum levels of cholesterol and triglycerides, glucose, and systolic blood pressure, was observed. Forced vital capacity was directly related to levels of fitness. These results, although cross-sectional, imply that physical fitness is related to lower coronary risk factors.


Bypass enteropathy. Intestinal and systemic manifestations following small-bowel bypass.

Many manifestations following jejunoileal bypass are due to chronic inflammation of the excluded bowel rather than short bowel malabsorption. Diarrhea, abdominal distention, and gas-fluid levels were common diagnostic features of "bypass enteropathy." Exploration showed the bypassed bowel to be dilated, with serosal inflammation and pneumatosis cystoides intestinalis. The bypassed loops contained a fecal flora and the mucosa demonstrated nonspecific chronic inflammatory changes. Exudative protein losses were noted. Systemic complications of bypass enteropathy were similar to other inflammatory diseases of the bowel. Improvement following treatment with metronidazole or after dismantling of the bypass suggested that bacterial byproducts originating in the excluded bowel were causally related.


Pharmacokinetic approach to the clinical use of lidocaine intravenously.

The time course of lidocaine plasma concentrations following various modes of administration were predicted by computer. Initiating therapy with a single intravenous bolus dose was unsatisfactory; plasma levels during the first hour were potentially toxic after a 200-mg bolus and subtherapeutic after a 50- to 100-mg bolus. After two bolus doses of 100 mg, separated by 20 to 30 minutes, or a rapid loading infusion over 15 to 60 minutes, therapeutic concentrations were achieved and maintained. Pharmacokinetic principles can be of value in devising rational approaches to lidocaine dosage.


Bilateral primary breast cancer.

Primary carcinoma of breast was treated in 967 patients from 1962 through 1972. Thirty-five of these patients had a second primary tumor of which 50% were discovered simultaneously. A family history for cancer was recorded in 26% of the patients with bilateral cancer. Patients found their tumor more often than the physician except in the simultaneous cases where the physician was more successful. Pathological examination showed 10% of the tumors were comedo, lobular carcinoma in situ, papillary, or tubular cancers. In the metachronous group, 50% of the axillae were involved on both sides. In the simultaneous cases the axilla was less frequently involved. Mammography, biopsies of the second breast, and prophylactic mastectomy in certain high-risk patients should improve survival rates.


Systemic lupus erythematosus with a protein-losing enteropathy.

Anasarca with pronounced hypoalbuminemia developed in a young woman 15 months after the onset of a mild, arthralgic type of systemic lupus erythematosus (SLE) without evidence of active nephritis. Investigation indicated a gastrointestinal rather than a renal site for protein loss. A full clinical remission was achieved with low-dose corticosteroid therapy.


Lysis of donor RBC during plateletpheresis with a blood processor.

Erythrocytes of a normal volunteer blood donor were grossly hemolyzed during plateletpheresis with the use of a continuous-flow centrifuge. Extensive studies of the donor's red blood cells (RBC) showed no abnormalities. Bank blood was then processed in the centrifuge in a manner identical to the prescribed in vivo plateletpheresis. Gross hemolysis consistently resulted when the tubing on the downstream side of the blood pump was partially obstructed by a twist. This experience calls for caution when assembling the harness of an extracorporeal circuit employing a pump. The tubing should be inspected to ensure the absence of obstructions.


Cytogenetic studies in reproductive loss.

Cytogenetic studies were performed on 57 families with pregnancy wastage (eg, two or more spontaneous abortions or stillbirths). Chromosomal abnormalities were ascertained in 17 couples, through offspring with congenital malformations. Seven families had children with neural tube defects, and five families also had a previous child with Down syndrome. One mother had mosaic Turner syndrome; two additional mothers and one father had balanced chromosome translocations. These findings indicate that chromosome analyses should be performed on every couple with repeated miscarriages or malformed children, and subsequent pregnancies at risk should be monitored by amniocentesis.


Genetic screening: whose responsibility?

Genetic screening offers the possibility of reducing the suffering due to genetic defects. For the foreseeable future, genetic screening by lay or governmental organizations can do only a small part of the job needed. Hence, the major responsibility falls on the personal physician. A careful family history is the best single genetic screening device. Discussing genetic risks with patients requires careful attention to the patient's difficulties in understanding the concept of probability, his psychological defense reactions, and differences in individual values. For complex cases, help is available in your region.


Medical injury information. A preparation for analysis and implementation of prevention programs.

The purpose of this communication is to offer the medical community an analytic design for a system to gather data about patients' injuries found in malpractice litigation. The goal of this system is to determine the causes of these injuries. The information to be gained will be of substantial benefit for the development of injury-preventive programs within the health care field.


Heparin as an antithrombotic agent. Low-dose prophylaxis.

Presently available data indicate that low-dose heparin prophylaxis will significantly diminish massive postoperative pulmonary emboli in patients more than 40 years of age subjected to major elective abdominothoracic surgery. The schedule is 5,000 USP units of heparin sodium subcutaneously, beginning two hours before surgery and continued every 12 hours (10,000 units/day) until the patient is discharged. Patients receiving this therapy should have a preoperative screening that includes a hematocrit reading, prothrombin time, partial thromboplastin time, and a platelet count. They should also not be receiving aspirin or other platelet antiaggregating agents for five days prior to surgery. The efficacy of this regimen is complemented by the fact that it is well tolerated by the patient, free of side effects, requires no laboratory monitoring, and produces minimal intraoperative or postoperative bleeding. This low-dose regimen has not proved effective in open prostatectomy or major orthopedic surgery. Data are not available concerning the drug's safety in spinal or epidural anesthesia, nor is it recommended for eye or brain surgery or in patients with an active thrombotic process. Other data are suggestive but still inconclusive that the regimen may reduce the incidence of postoperative acute myocardial infarction. In non-surgical patients hospitalized with acute myocardial infarction and receiving a low-dose heparin regimen, the findings reflect a significant decrease in deep venous thrombosis, though no observations are yet available concerning reductions in pulmonary emboli, mural thrombi, or systemic emboli.


Barium enema examination in acute appendicitis.

The barium enema examination is a safe technique for the prompt and accurate diagnosis of acute appendicitis. Properly performed and correctly interpreted, the examination can serve as a valuable tool for the diagnosis or exclusion of acute appendicitis when this is not possible by clinical and laboratory procedures.


Herbal intoxication. Psychoactive effects from herbal cigarettes, tea, and capsules.

Herbal preparations, designed to be smoked or ingested for "health and happiness", are promoted as legal hallucinogens, euphoriants, and marihuana substitutes. A total of 25 psychoactive substances have been identified in these products, and a number of intoxications have resulted from their short- or long-term use. Physicians should be alerted to the nature of these effects when taking drug histories, and their possible role in the causation of medical complaints should be considered.


A kindred with hemoglobin Lepore.

Four members from three generations of a family of Italian descent were found to have hemoglobin (Hb) Lepore trait. The four affected members were only slightly anemic, yet had definite hypochromic and microcytic red blood cells (RBC). Electrophoresis of hemoglobin demonstrated an abnormal non-sickling hemoglobin of 11% to 14% concentration that migrated like Hb S at alkaline pH. Amino acid analysis confirmed the identity of the abnormal component as Hb Lepore; the non-alpha chain was a fused delta-beta-chain with a crossover between residues 87 and 116. Hemoglobin Lepore trait should be considered in any patients with clinical and laboratory findings consistent with beta-thalassemia trait and with a 10% to 15% concentration of an abnormal nonsickling hemoglobin that migrates like Hb S.


Mutilating lawn mower injuries in children.

Serious injuries from riding power mowers were sustained by 18 children. Eleven children were passangers on the mower and fell into its path. The injuries required an extensive number of hospitalizations and reconstructive procedures. Fifteen patients suffered considerable residual deformities. Operating riding power mowers in the vicinity of children must be actively discouraged.


Studies of factors influencing alveolar lining layer formation in lung homogenate: further isolation and identification of interfering materials.

Materials which inhibit the formation of stable alveolar lining layer by lung surfactant were investigated with the pig lung homogenate. The inhibitory activity was assessed by the bubble stability test on the bubbles formed by mechanical agitation of a mixture of surface active fraction from lung homogenate and inhibitory materials. The most active inhibitory material was identified as free cholesterol. Free fatty acids had a remarkable inhibitory activity. By modified Wilhelmy balance, it was demonstrated that the addition of free cholesterol to the surface active fraction delayed the formation of the stable surface membrane and at a larger dosage it inhibited the lowering the surface tension at the minimum surface area. The significance of this phenomenon in pathological lungs was briefly discussed.


Spontaneous development of autoimmune thyroiditis in neonatally thymectomized mice.

An experimental mouse model of autoimmune thyroiditis induced by neonatal thymectomy (between 2 and 4 days of age) is described. Thymectomy within 24 hours after birth or thymectomy after 5 days of age failed to induce the disease. This type of thyroiditis occurred spontaneously a few months after the operation, lasted until approximately 12 months of age, and appeared to subside with aging. Hybrid mice of (C3H/He X 129)F1 are so far the most susceptible to neonatal thymectomy and the incidence in females (25 per cent) is significantly higher than that in males (6 per cent). Mice with thyroid lesions usually had circulating antibodies to mouse thyroid extract. Histologically, lymphocytes and plasma cells were the main cellular types of infiltrates and lymphoid follicles were seen in some cases. Interestingly, adenoma-like nodular hyperplasia of thyroid epithelium was observed in several thymectomized mice, with or without lymphoid infiltration. Besides those observed in the thyroid gland, lymphoid infiltrations were often observed in such organs as the ovary, the stomach, and the coagulating gland of thymectomized mice. These characteristics are compared with those of Hashimoto's thyroiditis and with those of its other animal models, and possible mechanisms which may be involved in the present disease are discussed.


Pharmacokinetics of Cytembena in chronic renal impairment.

Renal excretion of Cytembena in subjects with a normal renal function amounted on the average to 7.8% of the given dose during 15 hours following a single intravenous administration of 200 mg of this cytostatic drug. In patients with an impaired renal function there was a further decrease in the urinary Cytembena excretion and this in direct relation to the decrease in endogenous creatinine clearance rate. The decline in renal Cytembena clearance is slower than that of glomerular filtration rate due, probably, to a lowered tubular reabsorption of Cytembena in residual nephrons. This change in tubular resorption of Cytembena is related to a decrease of the fractional reabsorption of sodium in residual nephrons. Serum Cytembena concentrations proved to be significantly lower in patients with impaired renal functions than in subjects with normal renal functions. This peculiarity of the pharmacokinetics of Cytembena is discussed from the aspect of a possible increase of its distribution volume in consequence of an increased concentration of the diffusible component.


A safe method of amniocentesis for lecithin/sphingomyelin determination in late pregnancy using ultrasound.

Two hundred consecutive amniocenteses for lecithin/sphingomyelin (L/S) determination in late pregnancy are reviewed. These procedures were performed under ultrasonic control before induction of labor or elective cesarean section in a prospective study to determine a safe method for aminocentesis. Complications included 3 failures, 14 blood-stained samples, 2 cases of labor occuring within 24 hours after amniocentesis, and 1 maternal abdominal wall hematoma. There was no cases of perinatal morbidity or mortality. It is proposed that this is a safe method of abdominal amniocentesis for L/S determination in late pregnancy.


Mechanism of the teratogenic effect of thalidomide.

The mechanism of the teratogenic effect of thalidomide is unknown. The hypothesis that this drug acts on the sensory nerves of the embryo was derived from radiological observations of two series of thalidomide-deformed children. Supplementary evidence was found in neurological, embryological and other literature, to support the hypothesis of embryonic neuropathy. The concept can be extended to include visceral as well as skeletal deformities. Evidence for and against the hypothesis is presented, and its application to a broad spectrum of congenital deformities provides an explanation of a number of previously unrelated facts. Areas for further research are suggested.


Fractionation studies on a factor in linseed meal protecting against selenosis in chicks.

Growth rate of Single Combe White Leghorn cockerels fed a casein-gelatin-glucose diet was significantly depressed at two weeks when 10 p.p.m. or more selenium was added to the diet. When 20% linseed meal was included in the diet, growth was not reduced with 10 p.p.m. selenium and only slightly reduced with 20 p.p.m. selenium. Including 20% soybean meal failed to modify the toxicity. Levels of 5 and 10% linseed meal were less effective in counteracting selenosis than was 20%. Fractionation studies showed that a protective factor in linseed meal was extracted by methanol and ethanol and was not destroyed by autoclaving. Ashing the ethanol extract destroyed its activity. The factor was readily extracted by chlorform:methanol (2:1) but less effectively by acetone and diethyl ether. Washed chloroform:methanol extract was inactive but the washings contained the factor. Concentrates of the factor were active at less than 1% of the dry matter of the diet. The results of these studies show that linseed meal contains a heat stable, organic, polar factor that modified selenium toxicity in the chick.


Suitability of the C57 black mouse as an experimental animal for the study of skeletal changes due to ageing, with special reference to osteo-arthrosis and its response to tribenoside.

Histological studies in male C57 black mice revealed a high incidence (39-61%) of osteo-arthrotic changes in the knee joint from about the 17th month of life. In animals of the same strain aged 15 1/2 months the incidence was only 19%. The incidence of gonarthroses in 16-month-old female mice was considerably lower (4%). In male mice aged 17-20 months, the oral administration of tribenoside in doses of 500 and 1,200 mg/kg weekly led to a significant (p less than 0.05) reduction in the overall arthrotic involvement. A possible relation between the effect of tribenoside and other anti-inflammatory agents on osteo-arthroses in the mouse and their influence on mucopolysaccharide metabolism in connective tissue is discussed. The incidence of the formation of gaps in the epiphyseal growth zones and of osteoporosis of the femur and tibia in the same strain increases distinctly with advancing age. Except in animals treated with the highest dosage tested, in which there was a significant decrease in the development of osteoporosis, tribenoside in the range of doses used had no influence on these skeletal changes.


Saturation kinetics and choleretic effects of iodoxamate and iodipamide.

The biliary excretion and choleretic effects of iodoxamate (Cholevue) and iodipamide (Cholografin) were compared in unanesthetized dogs with biliary fistulas in order to assess the potential of the two contrast agents for use in intravenous cholangiography. For any equimolar infusion rate, more iodoxamate was secreted in the bile than iodipamide was the same. At the constant basal bile flow maintained in these studies, there was no difference in the maximum biliary concentration of the two compounds. With the presently recommended doses, it is unlikely that iodoxamate will offer a striking improvement over iodipamide for intravenous cholangiography in patients with normal liver function.


Computed tomography of spinal cord after lumbar intrathecal introduction of metrizamide (computer-assisted myelography).

Computed tomography (CT) of the thoracic and cervical spine was carried out after lumbar intrathecal introduction of a water-soluble radiographic contrast medium (metrizamide). By choice, no head-down position of the patient was used to facilitate craniad movement of the contrast medium; rather, advantage was taken of the normal CSF flow. This technique, referred to as computer-assisted myelography (CAM), permits the demonstration of the metrizamide-containing subarachnoidal spaces surrounding the thoracic and cervical cord. Some examples of the diagnostic possibilities of the method are discussed.


Differences in the in vitro response of lymphocytes from leukotic and normal cattle to concanavalin A.

The response of cultured peripheral blood lymphocytes from cattle affected with bovine leukosis and from animals free of detectable leukosis to the nonspecific mitogen Concanavalin A ws determined by the measurement of 3H-thymidine incorporation. The stimulatory effect of the mitogen was significantly decreased in leukotic lymphocytes in comparison with normal lymphocytes. This depression was dependent on the severity of the disease. Leukotic lymphocytes showed high basal levels of spontaneous thymidine uptake possibly due to their low maturity. It is suggested that leukotic lymphocytes are not stimulated by Concanavalin A because of their B cell characteristics. A residual cell population of normal reacting lymphocytes--enriched by nylon wool column fractionation--is probably responsible for the remaining but weak in vitro reaction of leukotic lymphocytes.


Dynamic surface tension properties of mixed lecithin-cholesterol films related to the respiratory mechanics.

A bubble method was used to record dynamic area/surface tension diagrams of mixed lecithin-cholesterol films prepared at different weight ratios. The lecithin/cholesterol weight ratios were: 1:2, 1:1, 4:1, 6:1, 8:1 and 12:1. The minimum surface tension is about 20 dyn/cm for all weight ratios at amplitudes of 75, 25, 12.5, 6 and 3% area oscillation. The maximum surface tension depends on both the amplitude of area oscillation and the lecithin/cholesterol weight ratio. The maximum surface tension increases with increasing amplitude. At the amplitudes 25, 12.5, 6 and 3% the maximum surface tension is significant higher at the weight ratios 1:2 and 1:1 compared to the other ratios. In addition, equilibrium surface tensions during interruptions of the oscillation at maximum and minimum area were recorded. The equilibrium surface tension increases with increasing amplitude up to 25% area oscillation. A static hysteresis seems to remain. Some consequences regarding the pulmonary respiratory mechanics are discussed.


Ruptured mycotic aortic aneurysm.

A right flank mass, in a patient with fever of unknown origin, pain, and superiorly displaced right kidney on excretory urogram, was explored through a subcostal incision. Finding of a retroperitoneal abscess was anticipated; instead of a ruptured mycotic aortic aneurysm was encountered. An awareness that entities such as this may exist is imperative in the differential diagnosis of flank  masses. Treatment through a flank incision presents an elusive if not impossible feat. Because of the gravity of the underlying disease, misdiagnosis almost always results in death.


Bilateral ureteral obstruction due to malignant lymphoma.

Two cases are presented of bilateral ureteral obstruction and uremia due to pressure from nodes involved in disseminated lymphoma. Their successful managment is reported.


Experiments on placental circulation and transplacental transfer in exteriorized foetuses in hypoxia and after asphyxia in guinea pigs.

Experiments were carried out on near term pregnant guinea pigs. Cesarean section was performed and by exteriorization of the foetuses the placental stage of labor was simulated. In one group of foetuses, chosen at random, we induced hypoxia, and in an another series of experiments asphyxia, each group with its own control. The results of acid-base values, experimental antipyrine transplacental transfer studies and the survival rate of foetuses, showed that it is advantageous for the newborn animal if we preserve the placental function in such conditions immediately post partum. Further study is necessary to determine to what degree and under what conditions our experimental observations are applicable to human perinatology.


Computerized axial transverse tomography in the diagnosis of orbital tumors.

CT scanning demonstrated orbital tumors in 15 patients with progressive unilateral proptosis in whom the diagnosis was confirmed by surgery or biopsy. The CT scan was the only abnormal study in 13 patients. In two patients, standard roentgenogram studies and CT scan were both abnormal, but the CT scan was of greatest value in identifying the tumor. Orbital structures are clearly demonstrated when scans are performed at lower level than those used in standard cerebral studies. The large fat content of the orbit is of low density and appears dark on the cathoderay tube. The tumors were of higher densities and appeared as white homogenous or speckled masses against the dark background. Surgical findings confirmed the accuracy of CT scanning in determining the tumor size and location. A new 160X160 grid provides remarkable resolution of orbital structures such as the optic nerve and extraocular muscles. Moreover, it is now possible to visualize ten consecutive ventral to dorsal slices of orbital tissue providing greater detail of orbital pathology. CT scanning will probably be an indispensable tool in the diagnosis of orbital tumors.


Somatomedin A in human serum, determined by radioreceptor assay.

Somatomedin A was determined by radioreceptor assay in serum from patients with various disorders. The mean values of somatomedin A in serum from 20 adult subjects, 21 patients with acromegaly, and 17 patients with hypopituitary dwarfism were 1.08 +/- 0.08, 3.02 +/- 0.33 and 0.44 +/- 0.03 U/ml, respectively. In children below 2 years of age, low levels were found (mean 0.40 +/- 0.04 U/ml). Normal levels were found in patients with Turner's syndrome and primary hypothyroidism, increased levels in uraemic patients, and decreased levels in Laron dwarfs.


Studies on the postponed growth hormone secretion following the infusion of somatostatin.

It is well known and also confirmed in this study that somatostatin (growth hormone inhibiting factor, GHIF) prevents the noctural GH secretion, as long as the peptide is infused. Following the infusion a rapid rise in GH levels is seen in sleeping subjects with peak values of 26.8 +/- 9.7 ng/ml compared to 31.7 +/- 4.7 ng/ml (+/- SEM) in control nights. Delayed GH peaks were seen even in the absence of slow wave sleep. No postponed GH rise was observed when subjects fell asleep again. These data demonstrate that the postponed nocturnal GH peak does not represent a rebound phenomenon to a previous trigger mechanism but is acutely sleep induced.


Comparative immunological studies between canine prolactin and prolactin from other species.

Canine pituitary extracts contained material which was capable of inhibiting the binding between antisera to different prolactins and labelled non-canine prolactins. Maximum inhibition of binding was observed in the system consisting of antisera to ovine prolactin and labelled rat prolactin. This system was used to investigate the immunological activity of canine pituitary extracts and partially purified fractions. A rabbit antiserum which was raised against a canine pituitary extract and had significant immunological activity in the above system, together with labelled rat prolactin, was used to develop an assay capable of detecting material in canine pituitary extracts. This material gave parallel dose-response curves to a canine prolactin-rich fraction, D864C and purified ovine and bovine prolactin.


Whisky: a new provacative test for calcitonin secretion.

Oral whisky is a potent stimulus of calcitonin secretion. Peak increments of immunoreactive calcitonin are observed within 15 min after the ingestion of 50 ml of whisky; the magnitude of the response is similar to that observed during a four-hour calcium infusion. This procedure has several advantages over standard methods of stimulating calcitonin release in patients at risk of developing medullary carcinoma of the thyroid, and this is shown by a study in a large family with familial chromaffinomatosis.


Reciprocal effects of thyroxine and triiodothyronine on their deiodination by rat tissues in vitro.

The reciprocal effects of loading doses of thyroxine (T4) or triiodothyronine (T3) on the deiodination of their 125iodine-labelled isotopes by rat muscle and liver homogenates were studied. In 21 experiments muscle homogenates deiodinated a mean 45.0% of a tracer dose of [125I]T4 and 18.0% of [125I]T3. On addition of graded amounts of nonradioactive T4 or T3 the percentual deiodination of both labelled hormones progressively declined. This effect was significantly greater in homogenates incubated with non-radioactive T4, thus reflecting a stronger affinity of this hormone for muscle deiodinating sites. This correlate with the greater displacment of [125I]T3 as revealed by the percentage of recovered labelled hormone. In 18 experiments liver homogenates deiodinated a mean 14.6% of a tracer amount of [125I]T4 and 8.5% of [125I]T3. The addition of a T4- or a T3-load was followed by a smaller decrease in percentual deiodination of both labelled hormones as compared to muscle homogenates. Unlike the effects observed in muscle, the breakdown of [125I]T4 and [125I]T3 by liver homogenates was equally affected by similar amounts of stable T4 or T3. It is concluded that in the present in vitro system T4 and T3 share cellular sites of deiodination in rat muscle and liver and that, at least in muscle, which constitutes over one-half of the rat body weight T4 appears to be preferentially deiodinated.


Thyroid iodine uptake, thyroid iodine secretion and plasma TSH levels in male rats during the day and night.

Experiments were performed to assess whether the diurnal changes in thyroid 131I metabolism are paralleled by variations in endogenous iodine. The uptake of iodide by the thyroid gland was determined by a double isotope technique. The T/S iodine ratio and the rate of 131I and 127I secretion from the thyroid gland were determined in rats fed LID during 20 days. The accumulation of iodine by the thyroid gland was prevented by CK1O4 and organic iodine formation was blocked by PTU. The absolute uptake of iodide by the thyroid gland was twice as high during the night than during the day. The thyroid/serum iodide ratios were highest during the night. The rate of release of 131I and 127I from the thyroid gland was augmented in the afternoon. The concentration of TSH in the plasma, measured by radioimmunoassay, was elevated in the afternoon as compared to other times during the day and night. The close association between the diurnal changes in thyroid iodine secretion and plasma TSH concentrations suggest that TSH may be responsible for the differences in iodine secretion observed during the day and night. On the other hand, the intake of iodine in the diet and the urinary clearance of iodine showed diurnal rhythms; the highest values occurred during the night. In addition, about twice as much iodine was available to the thyroid gland at night than during the day. These factors might also contribute to the diurnal variations observed in thyroid iodine metabolism.


The serotonin retaining effect of lithium in the rat thyroid.

The hypothesis of a lithium induced serotonin retention in the rat thyroid has been tested. It has been found that the thyroid in rats treated with lithium contains double the amount of serotonin compared with glands from untreated animals. The ability of TSH to stimulate serotonin release is inhibited by lithium. The ability of serotonin to stimulate thyroid hormone secretion in vitro is documented. The inhibitory action of lithium on both TSH and serotonin stimulation of hormone release is documented. The serotonin retaining effect of lithium as part of the goitrogenic effect of this ion is discussed.


Thyroid peroxidase activity in iodine deficient rats.

The evolution of peroxidase activity was followed during the course of iodine deficiency in the rat. The enzymatic activity was determined in vitro by oxidation of iodide or by iodination of bovine serum albumin using a peroxide-generating system. An inverse relationship between the stable iodine content in the gland and the peroxidase activity is observed; this relation is not linear and the highest increase is found when the iodine content in the gland is below 5 mug per thyroid gland, at 35 days of the treatment. In animals maintained on a low iodine diet, a triphasic effect on enzymatic activity is observed: early (10 and 20 days) and late (70 and 80 days) effects when the increase in peroxidase activity is 3 times higher than the increase in weight, DNA and total protein content; and an intermediar effect (between 20 and 70 days) when the peroxidase activity says approximately at the same level. In any case, the enzymatic activity increases to a greater extent than do thyroid weight, and total protein and DNA content, suggesting that high cellular activity is due to a specific enzyme induction comparable to that we obtained recently in human sporadic goitre.


Plasma insulin and growth hormone concentrations in pregnant sheep I: diurnal variations in mid- and late pregnancy.

Two or three foetal lambs regularly result in a varying degree of carbohydrate shortage in mother ewes in late pregnancy. We have investigated the correlation between plasma insulin, growth hormone and energy substrate concentrations in ewes 8 and 1 weeks before lambing. Plasma growth hormone was fairly constant (2-3 ng/ml) throughout the 24-h cycle 8 weeks before parturition. Seven weeks later higher average levels and increased diurnal fluctuations were observed in 3 out of 4 multiparous ewes. The average post-absorptive insulin levels were reduced by 50 per cent during the same interval. Simultaneously decreased post-absorptive sugar and increased acetoacetate levels were observed. It is concluded that the hormonal adaptations to the increasing carbohydrate deficit in late pregnancy, especially among multiparous ewes, include: a) reduced post-absorptive plasma insulin levels, b) reduced insulin responses to feeding, and c) increased levels of growth hormone in the plasma.


Plasma insulin and growth hormone concentrations in pregnant sheep II: post-absorptive levels in mid- and late pregnancy.

The pregnant ewe compensates the reduced carbohydrate availability in late pregnancy by increased fat combustion. The purpose of the present study was to examine the adaptation of plasma growth hormone (GH) and insulin levels to this change in energy substrate metabolism. Two groups of ewes were bled in the post-absorptive state at different stages of pregnancy. One group (7 animals) was fed adequately throughout pregnancy, while the other received a maintenance ration for non-pregnant sheep (28 animals). Plasma GH increased from averages from 2-3 to 8-14 ng/ml during the last month before lambing. Shearing of the wool combined with a cold stress resulted in a clearly detectable peak in plasma GH in the underfed sheep. No significant difference in plasms GH attributable to differences in diet could be detected in late pregnancy. Plasma insulin decreased steadily the last 5 weeks towards lambing, most in mothers with 3 lambs. Plasma free fatty levels (FFA) increased the last 2 months of pregnancy, most in the underfed sheep. GH and FFA were positively correlated (r= 0.50 and 0.30 in the two groups). It is concluded that the adaptation of the maternal metabolism to reduced carbohydrate - and eventually energy-availability in late pregnancy included lowering of insulin and enhancement of plasms GH levels. These adaptations were detectable under the present conditions the last 5-6 weeks before term.


Studies on the pattern of circulating steroids in the normal menstrual cycle. 2. Levels of 20alpha-dihydroprogesterone, 17-hydroxy-progesterone and 17-hydroxypregnenolone and the assessment of their value for ovulation prediction.

Plasma levels of 20alpha-dihydroprogesterone, 17-hydroxyprogesterone and 17-hydroxypregnenolone were assayed daily in 15 normally menstruating women during a complete menstrual cycle. In order to ascertain the normalcy of the cycles studied, LH, progesterone and oestradiol were also determined daily. The pattern of 20alpha-dihydroprogesterone was very similar to that of progesterone. The levels found during the proliferative phase (around 240 pg/ml) increased significantly on the day of the LH-surge and reached values of approximately 3.7 ng/ml at the peak period of luteal activity. The plasma levels of 17-hydroxyprogesterone in the proliferative phase were around 380 pg/ml. The first significant increase occurred one day before the LH-surge and was followed by a sharp peak (approximately 1.5 ng/ml) which coincided with the LH peak. A significant decrease occurred after this peak, which reached a nadir two days after the LH-surge. This was followed by a second rise with a rather broad peak (about 1.8 ng/ml) around the 5th to 7th days after the LH-surge. The levels of 17-hydroxypregnenolone did not show any cyclic variation: from all figures a geometric mean value of 1.62 ng/ml was calulated with tolerance limits at 0.241 and 10.8 ng/ml. Individual day-to-day changes in steroid levels were assessed with regard to their potential for the early identification of the day of the LH-surge. A 17-hydroxyprogesterone value of 1.0 ng/ml, or more, was seen for the first time in the cycle on the day of the LH peak in 13 cycles and a progesterone + 17-hydroxyprogesterone level of at least 1.8 ng/ml in 14 of the 15 cycles studies. These data seem to warrant a study of the predictive value of progesterone and 17-hydroxyprogesterone assays in a much larger population.


The normal development of the ovary in childhood.

The development of the ovary during childhood has been evaluated in 52 organs obtained from autopsy of children who died in accidents or after a brief acute disease. The ovaries at all ages showed follicle growth. 93% of the organs were actively growing ovaries containing healthy and degenerating follicles in progressive stages of development with and without follicle fluid. Three ovaries showed follicle growth up to pre-antral stages. None of the 52 ovaries were quiescent in which follicle development was not in progress. It is therefore argued that the normal ovary in childhood shows follicle growth at all ages. The number and size of antral follicles increases after the age of 6 years coinciding with the progressive increase in FSH and oestrogen output in childhood.


Permeability of ovarian follicles to electron-dense macromolecules.

Ferritin (m.w. 500 000) perfused into the ovarian arteries of sheep permeated the theca interna and was also found in the membrana granulosa of both non-atretic and atretic Graafian follicles. Colloidal gold (m. w. 1 000 000) similarly perfused, was found in the theca interna but not in the granulosa. The results are discussed in terms of the blood-follicle barrier.


Testosterone production by isolated rabbit follicles in the presence of luteinizing hormone and inhibitors of steroidogenic enzymes.

Rabbit ovarian follicles were incubated with luteinizing hormone (LH) and various inhibitors of steroidogenesis in order to determine what enzymes were necessary for testosterone production. Incubations were carried out in minimum Eagle's medium: normal rabbit serum: 95:5 with medium being changed every 15 min and stored at -15 degrees C until assayed for testosterone by radioimmunoassay. Inhibitors and LH were added at different times after the start of the incubations. Of the inhibitors tested only SU 10603, an inhibitor of the 17alpha-hydroxylase enzyme completely prevented the testosterone response to LH while aminoglutethimide (inhibitor of 20alpha-hydroxycholesterol dehydrogenase) and U 30870 (inhibitor of 3beta-hydroxysteroid dehydrogenase) only showed partial inhibition. These results suggest that cholesterol is an obligatory intermediate for the production of testosterone by rabbit ovarian follicles and that normal LH stimulated endocrine function can resume after treatment with inhibitors. The results are also in agreement with previous data using inhibitors of protein synthesis in the presence of LH.


Effects of testosterone propionate treatment of neonatally ovariectomized rats on growth and subsequent responsiveness to oestrogen.

There was no significant difference in body weight between neonatally ovariectomized (OvX) rats whether given oil treatment or 90 mug testosterone propionate (TP) on day 3, when examined up to 23 weeks of age. When these two animals were injected with oestradiol benzoate (3 mug/day for 2 weeks), the neonatally OvX TP treated rats showed a significantly smaller depression in body weight than did the control neonatally OxX rats. Measurement of food intake also showed that TP treated rats responded significantly less to the depressant effects of oestrogen than did the controls. These data are consistent with the hypothesis that the ovary does restrain body weight in TP rats but that androgen treatment in the neonatal period may not have a specific effect on growth but may alter the sensitivity of growth regulating processes to the inhibitory effects of oestrogen.


Studies on the conversion of oestradiol linked to a cytostatic agent (Estracyt) in various rat tissues.

Estracyt, a compound of nitrogen-mustard linked to oestradiol phosphate, is used in the treatment of human prostatic cancer. The metabolism of this compound has been studied in different tissues of the rat both in vivo and in vitro. The phosphate group in position 17 of the oestradiol moiety is rapidly split off from the compound. An oestrone-cytostatic compound was extractable from the liver half an hour after the injection of Estracyt. In addition the in vitro results showed that only the liver was able to convert the oestradiol-cytostatic compound to an oestrone-cytostatic one. When animals were killed 24 h after a 3-day period of Estracyt treatment, the dominating metabolite in the ventral prostate was an oestronecytostatic compound, but traces of free oestrone could also be demonstrated. No such compound, however, was found in liver, diaphragm or blood at this time. It is concluded that in vivo an oestrone-cytostatic compound seems to be preferentially retained in the ventral prostate after Estracyt injection whilst the metabolic conversion of the oestradiol-cytostatic compound into an oestrone-cytostatic one possibly occurs in the liver.


Lymphokines and thrombosis. II. Procoagulant activity produced by human lymphocytes stimulated with concanavalin A (con-A).

Human lymphocytes stimulated with concanavalin-A produce a coagulant activity which decreases the clotting time as expressed through the recalcification time of citrated plasma, the partial thromboplastin time, the thrombin clotting time of citrated plasma and the thrombin clotting time of fibrinogen solutions. The culture supernatants of human lymphocytes stimulated with concanavalin-A also have a direct coagulant effect on human fibrinogen solution. They decrease the lag period of recalcification time of citrated plasma but do not modify the duration of polymerization as measured with a spectrophotometric method.


A prospective study on some immunological changes occurring in the first year of grass pollen desensitization.

Some immunological parameters were followed up during the first year of grass pollen desensitization in 15 patients. The skin reactions with grass pollen extract in a series of tenfold dilutions were diminished in all patients during treatment. In nearly all patients a distinct increase in blocking antibody titre was seen. Serum reagin titres as measured by RAST remained constant or decreased somewhat during desensitization. No significant correlations between all three parameters could be demonstrated.


Comparison between the direct capillary tube leucocyte migration technique (LMCT) and the direct agarose leucocyte migration technique (LMAT) as indicators of tumour-directed cell-mediated hypersensitivity (TCMH) in patients with renal carcinoma.

A comparison was made between the direct capillary tube leucocyte migration technique (LMCT) and the direct agarose leucocyte migration technique (LMAT) using crude homogenates of tumour tissue as antigen in patients with renal carcinoma. A state of specifically altered reactivity of leucocytes from patients with renal carcinoma as compared with normal control persons towards allogeneic hypernephroma extracts could be detected in the LMCT but not in the LMAT. The reactivity in the LMCT was manifest at protein concentrations of 300 and 400 mug/ml. The study indicates that in contrast to the LMCT, the LMAT cannot be used for detection of TCMH towards allogeneic hypernephroma tissue extracts in patients with renal carcinoma.


Asthma mortality in Sweden among children and adolescents during the period 1952-1972.

Asthma mortality in Sweden during the period of 1952-1972 in the age-group of 1-24 years, comprising a total of 183 cases, has been studied. As compared with the 1950's, there is a conspicuous increase in the number of deaths during the greater part of the sixties, reaching a maximum in 1967. Since then the mortality has shown a marked decrease. Further, a trend towards an averagely higher age at death has been ascertained in the latter part of the investigation period. The factors underlying the conspicuous variations in mortality rate were discussed. It was emphasized that the abuse of sympathomimetics in pressurized aerosols could not be accepted as the one and only cause. In all probability, the increase in the mortality during the 1960's can be attributed to a number of factors.


Urticaria from alcoholic beverages.

Three cases of urticaria/angioneurotic oedema produced by alcoholic beverages are presented. In two of them, the causative agent was probably yeasts in wines. An intracutaneous test with Candida, a conjunctival provocation test with Candida, and peroral challenge tests with wines were positive in both cases. The symptoms disappeared when the patients went on a low-yeast diet. In the third case, ethanol itself and acetic acid apparently were the factors underlying urticaria. Peroral challenge tests with ethanol, brandy and acetic acid were positive, but those with acetaldehyde remained negative. The patient has been asymptomatic after giving up alcoholic drinks alone.


Platelets in rat anaphylaxis.

The number of circulating platelets dropped abruptly in the early phase of severe anaphylactic shock (AS) of the rat and could be inhibited by Persantin but not by heparin pretreatment. The results strongly suggest that an aggregating agent, perhaps "platelet aggregating factor", formed or released during anaphylaxis is responsible for the decrease of platelet number. The organ distribution of 51Cr labelled platelets showed that in AS the aggregated platelets were removed from the circulation mostly by the spleen and part of them were trapped in the lung and the small intestine. The remaining platelets retained their functional integrity. The loss of circulating platelets is manifested by the prolongation of rat tail bleeding time and is one of the factors participating in the haemostatic disturbances during anaphylaxis.


Lymphokines and thrombosis. I. Thrombocyte aggregating activity released by human lymphocytes stimulated with concanavalin-A.

Supernatants from Con-A stimulated human lymphocytes containing leucocyte migration inhibitory activity were measured for thrombocyte aggregation activity and for influence on thrombocyte rich plasma clot retraction and whole blood clot retraction. The lymphocyte released activity of the supernatants produced thrombocyte aggregation and an acceleration of clot retraction. The activity resisted heating at 56 degrees C for 30 min and was inactivated at 80 degrees C for 30 min. The active substance seems to have a molecular weight above 10,000 daltons. The findings suggest that thrombotic processes associated with cell-mediated (type IV) immune inflammation could be due, at least partially, to lymphokine effects on thrombocytes.


Utilization of a low-lactose milk.

This study was undertaken to determine if a milk containing prehydrolyzed lactose, yet affording full nutritional benefits, could be ingested by a milk intolerant (MI) population without the symptoms of lactose intolerance. MI was defined by the failure of serum glucose to rise greater than 20 mg/100 ml after ingestion of 50 gm of lactose as well as by subjective and objective symptoms and signs after consumption of both 12.5 gm of lactose in water and 250 ml of skim milk. Lactose tolerance (LT) was evidenced by both lack of symptoms and a concomitant rise in serum glucose of greater than 20 mg/100 ml after ingestion of 50 gm lactose in water. A series of four, two hr tolerance tests were given to 12 MI patients and 12 LT controls. The following solutions were employed: 12.5 gm lactose, 250 ml skim milk. 250 ml low-lactose skim milk, and 6 gm glucose plus 6 gm galactose. In the MI group, significant differences were apparent between the tolerance test utilizing skim milk and that using low-lactose skim milk; no such differences were observed in the LT group. These observations indicate that in the MI population the lactose in skim milk was poorly absorbed or tolerated, but after hydrolysis the low-lactose skim milk was well tolerated. A MI individual then, appears able to absorb the monosaccharides of the prehydrolyzed milk and can, furthermore, tolerate the low-lactose skim milk without suffering from symptoms normally associated with lactose intolerance.


Comparative trial of influenza vaccines. I. Immunogenicity of whole virus and split product vaccines in man.

Groups of about 100 persons aged 6 to 88 years were given 1 of 6 commercially prepared whole virus or split-product bivalent (A/England-B/Mass) influenza vaccines and 6 weeks later were given 1 of 5 monovalent (B/Hong Kong) vaccines. Hemagglutination-inhibiting (HI) antibody titers in serum specimens taken 6 and 12 weeks after inoculation were compared to those obtained before immunization. Overall antibody responses in all groups were adequate, yielding HI titers that are associated with relatively good levels of protection from infection. No differences were noted among the vaccines in their ability to boost pre-existing antibody. The tributyl phosphate (TBP) split-product vaccine, however, induced significantly lower homologous seroconversion and geometric mean antibody titers (GMT) to A/England and heterologous antibody titers to A/Aichi in persons without pre-existing antibody than did equivalent whole virus vaccines. Both the TBP and the ether-treated monovalent B/Hong Kong vaccines also induced lower heterologous GMT's to B/Mass in initially seronegative individuals. These data agree with previous observations that the primary response to influenza and other viral vaccines prepared from disrupted virions results in lower levels of antibody than does that to equivalent whole virus preparations. Studies are underway to determine whether the lesser immune response induced by these vaccines in seronegative persons is the result of smaller amounts of antigen in such preparations or because the antigen may be processed less efficiently by humoral or cellular immune mechanisms.


Screening large numbers of compounds in a model based on mortality of Trypanosoma rhodesiense infected mice.

A test system has been developed to evaluate the trypanosomicidal activity of large numbers of candidate drugs. Based on mortality of mice with blood induced Trypanosoma rhodesiense infections, it serves as a primary screen or as a secondary and confirmatory test for active compounds. Over 5,500 selected compounds have been tested; more than 6% were active.


Lymphosarcoma in a rabbit.

Generalized lymphosarcoma was observed in a 7-month-old New Zealand White rabbit. Numerous grayish white nodules were found in the kidney and liver. The mucosal surface of the stomach was hemorrhagic and ulcerated. Virus-like particles were observed in neoplastic tissue from the kidney on electron microscopic examination. Significance of the presence of virus-like particles was not determined.


Systemic chemotherapy for psoriasis: a national survey.

A questionnaire that was mailed to 510 randomly selected dermatologists in the United States surveyed their use of three systemic chemotherapeutic agents for the treatment of psoriasis during the two-year period of 1973 to 1974. Methotrexate was used by 52% of the surveyed dermatologists, while hydroxyurea and azaribine were used by 10% and 2%, respectively. Seventy-five percent of the dermatologists who used methotrexate treated ten or fewer psoriatic patients with this drug. Multiple dose therapy with methotrexate divided over a period of 36 hours each week was the preferred schedule of 66% of the dermatologists. Liver biopsy specimens and creatinine clearance tests were obtained for only 17% and 35% of patients, respectively, prior to initiating methotrexate therapy. The estimated number of dermatologist-treated psoriatics nationwide receiving methotrexate is 25,000.


Cows' milk allergy in the syndrome of thrombocytopenia with absent radius.

A girl with the syndrome of thrombocytopenia with absent radius had severe diarrhoea and dehydration relieved by withdrawal of cows' milk and aggravated by its reintroduction on three occasions. Deterioration in gastrointestinal symptoms was associated with haematological relapse with thrombocytopenia, leucocytosis, anaemia, and eosinophilia. There appeared to be a correlation between milk exposure and the haematological and gastrointestinal disturbances. Supporting evidence from published reports for such a correlation is reviewed. Cows' milk protein intolerance may be a factor in precipitating haematological relapse in susceptible infants with radius aplasia. Early withdrawal of cow's milk protein should be tried in thrombocytopenia with absent radius, especially in cases with prominent gastrointestinal upset.


Calcium, phosphorus, and magnesium concentrations in plasma during first week of life and their relation to type of milk feed.

Serial changes in plasma levels of calcium, phosphorus, magnesium, alkaline phosphatase, and total proteins have been investigated in 138 healthy, term Caucasian infants. Blood samples were obtained for each infant from cord blood and on day 1 and day 6. The infants were studied in three groups according to whether they were breast fed, received 'Ostermilk No. 1' or 'Cow and Gate V' formulas. Levels of calcium, phosphorus, magnesium, alkaline phosphatase, and total proteins did not differ between the groups at birth or on day 1. By day 6 calcium levels were higher and phosphorus levels lower in the breast-fed infants compared with either of the artificially-fed groups. Phosphorus levels were lower in the V Formula group compared with the Ostermilk group but the mean calcium levels of these two groups did not differ significantly. However, only 2-8% of the V Formula group developed hypocalcaemia compared with 18-2% of the Ostermilk group. The only infant developing clinical tetany belonged to the group fed Ostermilk. Evidence is also given which suggests that those infants with low calcium levels on day 1 who were fed the high-solute milk tended to show a fall in calcium by day 6. This did not apply to the two other groups. It is concluded that the use of adapted cows' milk preparations for infant feeding should lead to a reduction in the incidence of neonatal tetany.


Agenesis of the trachea: report of a case and review of the literature.

Immediately after birth, a full-term infant was noted to be in severe respiratory distress and died approximately five hours later, despite resuscitative efforts. Postmortem examination revealed agenesis of the trachea with a 1-mm fistula joining the esophagus and the main stem bronchi at the carina. The right kidney, ureter, Fallopian tube, and cornu of the uterus were also absent. The 25 previously reported cases of agenesis of the trachea are summarized, with special emphasis on associated abnormalities.


Scanning electron microscopy of Mycoplasma-infected tracheal rings.

Sequential changes visualized by scanning electron microscopy are described in hamster tracheal ring cultures exposed to 10(5) colony-forming units/ml of Clyde strain M-129 Mycoplasma pneumoniae. Loss of cilia, elevation of cell borders, and clumping of microvilli were induced within six hours after incubation of the rings in media containing mycoplasmas and in sterile used media. This finding lends support to the theory that the toxicity of Mycoplasma infection is partially attributable to alterations in the growth medium or elaboration of a toxic substance by the organisms. Mycoplasmas were observed attaching to tracheal ring surfaces eight hours after infection. With increasing periods of incubation, cell death and alterations occurred in tracheal surface structure that might be confused with the organisms.


Pathological features of the placenta in fetal death.

Few studies of the histopathological features of the placenta in cases of fetal death are available. We will describe the placental findings from 24 midtrimester spontaneous abortions and 54 stillborn infants of more than 28 weeks' gestation. In almost 100% of midtrimester abortions and in 48% of the placentas from stillborn infants of more than 28 weeks' gestation, chorioamnionitis, deciduitis, and/or villitis were present. Because of this very high percentage of lesions, which suggests an infectious causation, it is mandatory that studies be performed that might identify pathogens. One third of the stillborn infants of more than 28 weeks' gestation were associated with maternal complications (diabetes, preeclampsia, and urinary tract infection), in addition to placental fetal vasculopathy, ischemia, infarcts, and chorangiosis (villous capillary hyperplasia). We emphasize the use of the placenta for the recognition of maternal diabetes.


Regression of advanced atherosclerosis in swine.

Advanced complicated atherosclerosis was produced in the abdominal aorta of swine by a combination of mechanical injury and high-cholesterol, high-fat diet for four months. After removal of the high-cholesterol diet and placing the animal on swine mash for 14 months, there was a significant (P less than .005) decrease in size of lesions with remodeling of the intima toward a smooth surface. Sudanophilia had virtually disappeared and atheromas were almost absent in the regression group, as were thrombosis and hemorrhage in plaques. Cell proliferation, as judged by the number of labeled cells in autoradiography, was less pronounced in this group. There was no decrease in the numbers of segments showing calcification; however, the size of the calcified areas was smaller in the regression group than in the base line. The data suggest that advanced atherosclerosis is susceptible to regression on removal of the atherosclerotic stimulus.


Regression of advanced atherosclerosis in swine: chemical studies.

Advanced complicated atherosclerosis was produced in the abdominal aortas of swine by a combination of mechanical injury and of a four-month high-cholesterol, high-fat diet. After discontinuation of the atherogenic diet, the animals were given swine mash for 14 months; subsequent chemical studies showed that regression of lesions had occurred, as delineated by decreased levels of DNA and DNA synthesis, total and esterified cholesterol, and phospholipid but no change in the levels of free cholesterol and triglycerides. The rate of DNA synthesis, but not that of total protein synthesis, had decreased. Collagen content had increased. By all criteria studied, the regressed lesions did not differ greatly from the abdominal aortic tissue of animals that had received only a mash diet for 18 months after mechanical injury. These findings, if extrapolated to man, would make the prognosis for possible regression of atherosclerosis under strictly controlled dietary regimens excellent.


Rhabdomyosarcoma of the urinary bladder with intraepithelial spread in an adult.

Rhabdomyosarcoma of the urinary bladder in adults is exceedingly rare. Reported cases have been of the embryonal botryoid type, as seen in children. We will describe a case of pleomorphic rhabdomyosarcoma occurring in the urinary bladder of an adult. In this case, we noted striking intraepidermal migration of tumor cells, resembling the epidermotropic growth characteristic of tumor cells in Paget disease of the breast. The pathological features of this apparently unique case form the subject of this report.


[Histochemiscal characteristics of lipids in different forms of goiter].

Histochemical studies were carried out of the content and localization of neutral and acid lipids, cholesterol and its ethers, phospholipids, free fatty acids and soaps in various forms of goiter (96 of the thyroid glands removed during during the operation in connection with goiter). It was shown that thyreo-toxic strumas were characterized by a very small amount of neutral lipids in the apical part of thyreocytes and some small amount in the stroma. The greatest amount of lipids (predominantly acid ones, free fatty acids and soaps) were identified in euthyroid macro-microfollicular strumas which were characterized by cystic degeneration of the glandular parenchyma and by a marked process of desquamation of the follicular epithelium. Histochemically, the desquamated Kulesh-Lauer's cells were found to contain moderate and insignificant amounts of neutral lipids, cholesterol and its ethers, with the help of the reaction with Nile bleu sulphate a great amount of acid lipids was identified, by Fischer's method--a great amount of free fatty acids. The results obtained also showed that Ashkinazi's cells were free from lipids. C-cells, which hardly identifiable in thyreotoxic colloid-parenchymatous strumas, were found to be rich in phospholipids, whereas in other cellular elements of the thyroid gland they were not detected, which in the authors' opinion, may serve as a histochemical test of C-cells.


Fluorescein angiographic findings in familial exudative vitreoretinopathy.

We describe the fluorescein angiograms in four cases of familial exudative vitreoretinopathy. The vascular nature of the temporal retinal masses is confirmed. Primary abnormalities within the peripheral retinal circulation are demonstrated. We stress the similarity between familial exudative vitreoretinopathy and retrolental fibroplasia.


[Rotatory instability of the knee joint in cases of previously treated "Unhappy Triad" (author's transl)].

The combined injury of the ligaments and capsular structures of the knee joint always causes rotatory instability as the sum of all or some a.m. injuries (Slocum; Nicholas). This has to be taken into account in the operative treatment. We have followed 14 patients with old "unhappy triad" injuries who had been operated upon with the question in mind whether the usual procedures with reefing of the ligaments or plastic replacements including meniscectomies, but without paying attention to the lax posterior capsule could correct the typical anteromedial rotatory instability. The results showed that this was true only in about half the cases. The remaining patients continued to complain about instability in the operated knee joint. Objectively, the pre-operatively positive rotatory drawer sign remained unchanged. Therefore we conclude that the anteromedial rotatory instability of the knee joint can be improved by the procedure devised by Slocum and Nicholas.


[Estimation of protein binding by means of the HMO-LCAO-method (author's transl)].

Calculating the protein binding of six drug series the value sigma/sigma net charge/Mol turned out to be characteristic if the effects of substitutents were considered. Single- and multiple-substituted compounds were calculated in separate groups. For aliphatic-substituted compounds a classification resulted from the length of the substituted chain and from characteristic atoms. Substitution in 3- or 4-position made no significant differences. As an additional value sigma SAP/Mol may be applied to aromatic-substituted compounds.


Kallikrein and renal enzyme excretion in rats.

Using the model of renal enzyme excretion in rats it was investigated whether a chemically defined kininogenase (kallikrein) exerts shock-inducing activity. Following i.p. injections of kallikrein in doses of 1000 or 7000 KU/kg body weight, an increase in urinary AP- and LAP-activities was encountered as well as an increase in creatinine excretion. These effects were attributable to increased diuresis and could not be related to any anaphylactoid activity (elicitation of vascular shock) of the injected enzyme preparation. According to these experimental results, kallikrein may not be considered as anaphylactoid drug, at least not in the rat.


Specificity of ethacrynic acid as a sulfhydryl reagent.

Ethacrynic acid is not an absolutely specific SH-reagent. It reacts rapidly and reversibly with cysteine, imidazole, histidine, and lysine. The reaction products increase with increasing pH. LDH is rapidly and reversibly inhibited by ethacrynic acid.


Development of an agar-diffusion method for the assay of quaternary ammonium germicides.

Five quaternary ammonium germicides (QAGs) were tested for their adsorption by agar. This was found to be in the following ascending order: alkylbenzylmethyl-ammonium chloride, alkyltrimethylammonium bromide, cetyltrimethylammonium bromide, cetylpyrimidinium chloride and cetylbenzyldimethylammonium chloride. An inverse relationship was established between the extent of agar binding of the QAGs and their inhibition zones. In an attempt to develop a sensitive cup-plate assaying technique suitable for QAGs, important factors affecting the agar-diffusion of QAGs were investigated. These included the influence of various polysorbates, buffer ions, agars and test organisms. Furthermore, the effect of the pH and/or the concentration of the selected polysorbate and the buffer were studied. The best medium developed for the sensitive agar-diffusion assay of QAGs was nutrient agar-Tris (0.05 M, pH 8) provided that distilled water and polysorbate 20 (0.5%) were used as diluents for the mixed alkyl and the pure cetyl QAGs, respectively.


[MASCA-Model of biochemical-pharmacological drug research/part 7: Computing scheme for the MASCA-model (author's transl)].

In this paper a computing scheme is given which allows a coupling between the multivariate bio-assay and the multivariate structure-activity relationship (MASCA-model).


[On the inhibitory effect of chloramphenicol on mitochondrial protein synthesis as a possible cause of its selective toxic side effects (author's transl)].

The inhibition of protein synthesis by tetracycline and chloramphenicol in mitochondria isolated from rat liver or rabbit bone marrow was investigated in vitro. It could be demonstrated that there is but little difference between the inhibitory effect of both substances in regard to mitochondria protein synthesis. Therefore, a selective interference of chloramphenicol with bone marrow mitochondria cannot be concluded. In in vitro tests the concentrations required for inhibiting the mitochondria protein synthesis are comparable to those found in blood levels measured under usual therapeutic conditions. It can be assumed that in the living organism the mitochondria are protected against tetracycline or chloramphenicol interference. This hypothesis is supported by the fact that due to the increase in the substrate concentration (phenylalanine), the expected inhibition of mitochondrial protein synthesis does not occur. There may be an inhibition of influx of the antibiotic by competition with substrate for transport through mitochondrial membrane. The reason for myelotoxicity of chloramphenicol is not an increased sensitivity of mitochondrial ribosomes located in the bone marrow to chloramphenicol. But the existence of special conditions for chloramphenicol influx into mitochondria of bone marrow must be concluded.


Sensory effects of capsaicin congeners. Part II: Importance of chemical structure and pungency in desensitizing activity of capsaicin-type compounds.

The characteristic insensitivity of sensory nerve endings to chemically induced pain brought about by capsaicin could be reproduced on the rat's eye by pungent vanillylamides, homovanilloyl-alkylamides and piperine, while homovanilloyl-cycloalkylamides, -azacycloalkylamides, - alkylesters, -alkyl-homovanillylamides, undecenoyl-3-aminopropranololand zingerone were practically ineffective in this respect. Desensitizing potency was not parallel with the stimulating effect of the compounds, e.g. the strongly pungent homovanilloyl-octylester failed to desensitize the receptors, while the less pungent homovanilloyl-dodecylamide proved to be a more potent desensitizing agent than capsaicin itself. It is concluded that the inverse position of the acylamide linkage does not modify, while its replacement by an esteric group completely abolishes the desensitizing activity. In contrast to the stimulating effect, in desensitizing action the presence of an alkyl chain is essential and its optimal length corresponds to 10-12 C atoms. On the basis of these results the possible molecular interactions at the site of action are discussed.


A new apparatus for measuring diameter changes of the rat paw and tibiotarsal joint.

A new apparatus for the study of hind-limb inflammation in the rat is described. It measures with high precision the diameters of the hind paws and tibiotarsal joints at anatomically well defined reference points. Inflammation induced by subplantar carrageenin injection and by inoculation of adjuvant in the tail is accompanied by readily detectable and pronounced increases in diameters. Results obtained with this rapid and simple method are reliable and the method offers practical advantages over volume measurements.


Increased incidence of adjuvant arthritis in Wistar rats.

The moderate incidence of arthritis in Wistar rats after inoculation of a suspension of Mycobacterium butyricum in oil increased to nearly 100% by two modifications. Inoculation with  4 week- as compared to 1 week-cultured. M. butyricum raised the incidence from 34 to 63%. Inoculation of this more arthritogenic material into the F1-descendants of M. butyricum sensitive parents raised the incidence of 96%. Also the severity of the arthritis in rats selected in that manner was higher than in non-selected rats. Treatment of arthritic rats of either source with phenylbutazone resulted in a comparable dose-related reduction of the diameters of the hind-limbs. Mating of rats with various degrees of arthritic response showed that sensitivity transmission to the F1-descendants was optimal with the most sensitive parents. Although the exact nature of the transmission has not been defined, the uniform and higher sensitivity of thus selected rats is of great value for quantitative pharmacological studies.


A new inflammation model.

The UV-edema in the hairless mouse is a suitable inflammation model as the degree of edema can be quantified - the degree of edema being a function of the irradiation time. The UV-edema may also be employed in the testing of antiphlogistics using oral administration as well as cutaneous application.


[The influence of haloperidol on the blood pressure lowering effect of theophylline in the dog (author's transl].

Theophylline in a dose of 12 mg/kg i.v. causes a slight decrease in arterial pressure. This acute dose was not influenced by pretreatment with a dopaminergic receptor inhibitor (haloperidol 0.2 mg/kg i.v.). The chronotropic action of theophylline remained also unchanged.


Inhibition of lactation in rabbits by 2-Br-alpha-Ergokryptine-mesilate (CB154).

The lactating rabbit responds to single injections of the inhibitor of prolactin secretion 2-Br-alpha-ergokryptine-mesilate (CB 154) by a reversible reduction in milk yield, which is dose-dependent. Inhibition of galactopoiesis by CB 154 is also observed in rats, dogs, pigs and in woman, but not in goats and cattle. This points to a difference in prolactin dependence of galactopoiesis in the two groups.


[The effect of clotrimazole on the pathogen of toxoplasmosis, Toxoplasma gondii].

By means of a toxoplasma infection in the mouse it was tested whether the antimycotic agent bis-phenyl-(2-chlorophenyl)-1-imidazolyl-methane (clotrimazol, Canesten¿) is also effective against the asexual stages of replication of T. gondii as they occur in man. Canesten did not influence the forms of the proliferative phase of replication of T. gondii (trophozoites, pseudocysts = tachyzoites) either in vivo in infected mice or in vitro in the tissue culture.


The effect of solasodine on the body temperature.

The action of solasodine, the steroid-structure alcaloid of Solanum laciniatum Ait., was studied on normal and pyretic body temperature of rats and mice. In rats a single dosage of 3 mg/kg depressed by an average of --1.5+/-0.3 degrees C the normal temperature for 24 h. With larger dosages or longer treatment the effect could not be intensified and tolerance was also not observed. In mice the temperature decrease was even more explicit, --2.0+/-0.2 degrees C lasting 48 h. The effect was reproducible by repeated treatment. In mice fever provoked by a suspension of killed bacteria, Pyrago¿, or by 2,4-dinitrophenol (DNP) could be counteracted with 1 mmole/kg solasodine. Body temperature depressed with solasodine was not raised by Pyrago but became higher after administration of DNP, in part of the animals even comparable to normal initial averages. Following solasodine treatment the body temperature of normothermic rats and mice decreased to subnormal values. Pyrexia produced either with centrally acting Pyrago or with the peripherally acting DNP was depressed with small solasodine dosages. Previous administration of the alcaloid counteracted Pyrago effect but could not inhibit the development of DNP action. These data are pertaining to the possible central effect of solasodine.


[The effect of cytostatic therapy with vincristin sulphate on disaccarchidases of rat intestinal mucosa (author's transl)].

This report shows that appropriate doses of vincristin sulphate may decrease disaccharidase activities of intestinal mucosa. With the higher doses of the cytostatic drug, the drastic drop of enzyme activities is associated with morphological alterations of the mucosa; disacchardiase activities remain depressed at least for a couple of days even after full morphological restoration of the mucosa. Studies in man should reveal whether similar intestinal lesions occur due to therapeutic doses of vincristin sulphate.


Role of histidine-decarboxylase inhibitors on gastric acid secretion in the rat.

The comparison between DL-alpha-(hydrazino)-beta-4(5)imidazolyl-propionic acid (alpha-HH) and DL-gamma-N(1,2,3,4-tetrahydroisoquinolyl)-alpha-hydrazino-butyric acid (AIS 48), a new inhibitor of histidine-decarboxylase shows that both compounds inhibit enzyme activity in vitro and lower gastric histamine content and acid secretion in vivo. The potency of AIS 48 is of the same order as that of alpha-HH while its toxicity is lower. Although AIS 48 is not a selective histidine-decarboxylase inhibitor, it does not affect tissue cathecholamine levels.


[Disturbances in the regulation of phospholipid metabolism of the whole liver, mitochondria and microsomes in acute thioacetamide poisoning and the influcence of silymarin].

In the whole liver of rats, pretreated with 4% polyvinylpyrrolidone solution, 24 h after i.p. application of 300 mg thioacetamide/kg body weight, an increase of total lipids, triglycerides and phospholipids is observed, in the mitochondrial fraction phospholipid concentrations are decreased. At the same time, phosphatidylcholine/phosphatidyl-ethanolamine ratio is diminished in mitochondrial and microsomal fraction. After administration of [l-14C]-palmitate, in comparison with non-intoxicated animals, a statistically significant reduction of specific radioactivity of phosphatidylethanolamine could be observed in microsomal and mitochondrial fraction; specific radioactivities of total lipids, total phospholipids and phosphatidyl choline trend to diminution in the whole liver and in subcellular fractions. By prophylactic i.p. application of silymarin-N-methylglucamine salt (400 mg/kg body weight), dissolved in 4% polyvinylpyrrolidone solution, there is a normalization of altered microsomal phosphatidylcholine/phosphatidylethanolamine ratio as well as an enhancement of diminished mitochondrial phosphatidylcholine concentration, while the reduction of specific radioactivities of phosphatidylethanolamine is partially abolished in the mitochondrial fraction.


Liver protection by silymarin: in vitro effect on dissociated rat hepatocytes.

The liver-protective effects of silymarin have been investigated in isolated hepatocytes suspended in vitro in sucrose solutions of graded hypotonicity. Cells preincubated with the drug at the concentration of 10(-4) M were found to be entirely resistant or relatively little affected when exposed to hypotonic solutions which have a lethal effect on a considerable proportion of the control liver cells, as shown by the determination in the cell preparations (1) of the proportion trypan blue-positive (broken) cells, (2) of the protein synthesizing capacity. The protection was reduced but not abolished upon removal of the drug and cell washing. A smaller effect was observed with a drug concentration of 10(-5) M. At 10(-6) M the effect was no longer detectable. Chlorpromazine, a drug which belongs to the group of the so called "unspecific membrane stabilizers", was without effect in this test.


Effect of pregnenolone-16alpha-carbonitrile on the rat liver.

In female rats, pregnenolone-16alpha-carbonitrile [PCN (a known microsomal enzyme inducer)] augmented liver weight and significantly increased hepatic protein, total lipid, phospholipid and ATP concentrations. These changes were correlated with hepatic drug-metabolizing enzyme induction. PCN did not alter body weight, or water, ash, triglyceride and cholesterol levels in the liver, but caused a mild reduction of hepatic glycogen.


[Direct Quantitative Evaluation of Thin-Layer Chromatograms by Measuring Remission and Fluorescence (author's transl)].

A highly specific method for the estimation of free serotonin in urine is described. The technique is based on the separation of the serotonin from urine by an ion exchange resin, acetylation of the separated serotonin with subsequent extraction into an organic solvent followed by a thin-layer chromatographic separation. After t.l.c. the plates are sprayed with o-phthaldialdehyde (OPT), whereupon serotonin forms intense fluorescent spots, which can be measured directly. The reproducibily of this method is about +/- 7%.


Topical anesthesia and topical toxicity of bupivacaine combined with hydroxypolyethoxydodecane.

The biological effects of adding hydroxypolyethoxydodecane (HPED) to N-butylpipecolic acid 2,6-xyiidide (bupivacaine) has been studied in animals and in man. The topical toxicity of bupivacaine was somewhat aggravated by HPED 0.25-1.0%, and the topical anesthetic effect was strongly potentiated both in animals and in man. It was concluded that HPED increased the absorption of bupivacaine after topical application. It was also found that D(+)-bupivacaine was more potent as a topical anesthetic than L(-)-bupivacaine.


Urinary metabolites of amixetrine in man and in the dog.

The urinary metabolites of N-(2-phenyl-2-isoamyloxy) ethyl-pyrrolidine-hydrochloride (amixetrine) studied in man and in the dog demonstrated a comparable mode of transformation of the drugs for both species. The principal metabolites of amixetrine isolated from urine and purified with the aid of chromatographic techniques were identified by IR, NMR and mass spectrometry. Untransformed amixetrine and (1,2-phenyl-1-hydroxy)ethylpyrrolidine were found in small quantities. In man, as in the dog, the principal metabolite coming from an omega-1-oxidation of the isoamyl chain corresponded to 2-phenyl-2-butoxy-(3-methyl-3-ol)ethyl-pyrrolidine.


The effect of oxyfedrine on the phases of the cardiac cycle of normal persons.

With non-invasive techniques we have studied the effects of oxyfedrine given i.v. in a dose of 8 mg on the systolic phase of cardiac cycle in 10 cardiologically healthy persons. We have found a strongly positive inotropic result and an augmentation of the stroke volume.


[Clinical questions on bioavailability and proff of efficacy (author's transl)].

The problems referring to bioavailability may be considered as follows: up to now extact informations on bioavailability as to the determined substances to meet the requirements of therapy are not obtainable. Obvious is the lack of precise investigations about what kind of bioavailability is desirable in respect to rate of rise of the drug, its course of time and its quantity under consideration for the different groups of disease. For this reason and excluding special cases, only common suggestions can be given at present. Difficulties are also presented by the entitled demand for the proof of efficiency. Test of new substances in man are confined to compromises either on the significance of the tests or the security of the patient.


An overview of the analysis and interpretation of bioavailability studies in man.

Bioavailability is defined and types of bioavailability studies are classified. The point is made that the validity or interpretation of comparative bioavailability data does not rest on any correlation between pharmacological or clinical response and blood levels of the drug. Equations used to assess the "first pass" effect, absolute absorption efficiency and relative absorption efficiencies are given. Methods for assessing intrinsic and relative rates of absorption are discussed. Various pitfalls in bioavailability assessment and some of the problems in interpreting bioavailability data are discussed.


[The role of biopharmaceutical parameters in drug development (author's transl)].

The biopharmaceutical factors, which influence the interaction between dosage form and drug activity, extend from the mode of application, through chemical and physical properties of the active constituent, to the final product, including the excipients and manufacturing processes involved. In recent years, important strides have been made in this field, which improve drug safety. This has consequently influenced and enlarged the present scope of pharmaceutical technology drug research.


[Clinical problems of optimum bioavailability, in particular in cytostatic therapy (author's transl)].

The clinical application of cytostatic drugs requires knowledge of their biochemistry, pharmacology, pharmacokinetics as well as their action at the cellular level within the generation cycle. The principles apply to tumor cells as well as to normal, rapidly proliferating tissues. The intensive research on cancer treatment all over the world is leading to a rapid accumulation of experimental data about the action of single cytostatic drugs in tissue culture and on transplantable animal tumor systems, especially in rodents. Clinical chemotherapy in human malignancies today preferentially uses combinations of different cytostatics. Inumerable combinations of drugs are available, especially if variations in respect to drug dose and intervals of drug application are taken into consideration. The experimental basis for such combinations of drugs and drug interactions is scanty. Using the pyrimidine analog cytosine arabinoside and the two antibiotics daunorubicin and doxyrubicin (adriamycin) as examples, it is demonstrated that information on the pharmacolinetic behaviour of cytostatic drugs is a prerequisite for their success in clinical application, but is on its own insufficient to predict the tumor response.


[Therapeutic equivalence and inequivalence of chemically identical substances using cardiac glycosides for an example (author's transpl)].

The problem of therapeutic equivalence or inequivalence cannot be solved by "ignoring facts and proclaiming opinions". The entire problem is multifarious and is not even clearly arranged although heart glycosides have been used for 200 years in the therapy of cardiac insufficiency. It comprises the physico-chemical properties of the drugs, its preparation and its pharmacolinetic behaviour in the organism. Therapeutic equivalence or inequivalence can primarily only be evaluated in connection with the disease and the symptoms of disease, respectively. Thus, manufacturers, pharmacists and physicians likewise are confronted with the problem. The differences in bioavailability of the individual cardiac glycosides show the necessity for: 1. The number of fixed combinations of heart glycosides should be limited in the interest of drug safety. 2. Only such drugs should be approved whose quantitative and qualitative equivalence has been demonstrated with regard to the monoglycoside. 3. When prescribing digoxin derivatives one should not only observe the bioavailability but take also into account the chemical stability and the pharmacolinetic behaviour.


Importance of biopharmaceutics and pharmacokinetics in clinical medicine.

Despite the paucity of biopharmaceutic and pharmacokinetic data for many old drugs, these areas of scientific research have demonstrated an immense value in clinical medicine, and can be expected to expand man's knowledge of drug action and the influence of physiological function of drug disposition. Illustrated in this report are four major areas where biopharmaceutics and pharmaco-kinetics have contributed significantly to the field of medicine. Foremost among these contributions are: 1. the assessment of bioavailability and bioequivalence of new drugs and generic marketed drugs, respectively; 2. the pharmacolinetic characterization of new drugs and new drug delivery systems; 3. adjustment of dosing regimen; 4. assessment of kinetic profile of drugs in diseases state and dose adjustment thereof. Patient-drug pharmacokinetic profile designed to avoid toxicity is illustrated.


[Bioavailability, proof of efficacy and their consequences for drug legislation (author's transl)].

Drugs should be effective for the indicatons stated, they should not involve risks which would not be justified in relation to their benefit and they should be of the necessary quality. It is the objective of drug legislation to warrant these requirements in its area of jurisdiction. It has become a necessity to revise current legislation; it is going to be replaced by a new law. A corresponding bill is being considered by Parliament at present. The present and the future legal situation with regards to proof and safeguarding of the bioavailability of pharmacologically active substances and the necessary prerequisites and rules for the procedure of clinical testing of drugs to prove their efficacy and safety is described.


Dry polyacrylamide batch method for determining the binding of various compounds by plasma proteins.

A new modification of the gel diffusion method has been developed using dry polyacrylamide gel. The theoretical background is explained and the mathematical formulas are presented. The properties of the gel are studied, concerning the absorbing capacities and changes in ion equilibria. As a model compound the freely diffusible calcium is assayed and the result obtained (52.4 +/- 2.9%) agrees well with the results from previous methods by other authors. The accuracy of the method is discussed and the theoretical explanation to the sensitivity in determinations is calculated.


[The effect of pemolin on the mitotic activity of Vicia faba L (author's transl)].

The effect of diverse concentrations of 5-phenyl-2-imino-4-oxazolidone (PIO, pemolin, Tradon) on the mitotic activity in lateral roots of Vicia faba L. was studied by aerated and non-aerated hydrocultivation with and without mineral nutrition, respectively. With optimal conditions (aerated nutrient solution) weak PIO-concentrations, most significantly 10(-6) g/ml, effected a marked increase of the mitotic index. Contrarily, strong PIO-concentrations (10(-4) and 3 X 10(-4) g/ml = saturated solution) significantly decreased the mitotic index though simultaneously preserving the mitotic activity in long-term experiments, when on account of nutrient deficiency it had already collapsed in weak PIO-concentrations and the controls. The activating effect of weak PIO-concentrations compared with the controls is more significant in stress situations (nutrient deficiency, O2-deficiency) than under optimal conditions. Furthermore a slight acceleration of mid-mitotic phases (metaphase--anaphase) recognized by a marked decrease in percentage of these phases, can be stated with weak PIO-concentrations, again particularly so with 10(-6) g/ml. In total, dependent on concentration, pemolin presumably may either activate or suppress cell metabolism and particularly the mitotic cycle. The exact site of action of the substance is still unknown.


[The effect of pentobarbital sodium on mouse fibroblasts in vitro].

In mouse fibroblasts grown during a period of 48 h in a medium containing between 0.3 and 4.8 mMoles of sodium pentobarbital, there appeared diminished replication, some stathmokinesia, and plain toxicity. In further cells of this kind, taken from fetuses which had been treated with sodium pentobarbital via the dam, cell multiplication, lethality, and mitotic rate did not differ from those of control cells.


[Regulation of lipid and carbohydrate metabolism of the heart by carbocromen (author's transl)].

The influence of 3-(2-diethylaminoethyl)-4-methyl-7-(carbethoxy-methoxy)-2-oxo-1,2-chromene-hydrochloride (carbocromen, Intensain) on lipid and carbohydrate metabolism of the heart was investigated. Carbocromen inhibits the incorporation of 14C-palmitate in heart slices of the rat. The degree of inhibition is dose-dependent and can reach a maximum of 30%. However, the relative concentrations of the various lipid components do not vary significantly. In the heart tissue of the mouse carbocromen increases the uptake of 14C-3-O-methyl-D-glucose by about 30% which might be due to an increased influx of glucose into the heart. The metabolic degradation of 14C-palmitate to 14CO2 decreases up to 40% in the presence of carbocromen with a parallel reduction in oxygen consumption.


[Studies on inhibition of platelet aggregation by carbocromen (author's transl)].

3-(2-Diethylaminoethyl)4-methyl-7-(carbethoxy-methoxy)-2-oxo-1,2-chromene-hydrochloride (carbocromen; Intensaïn) shows dose dependent platelet aggregation inhibitory activity in vitro according to the methods of Born (following ADP, epinephrine and collagen) and of Breddin (platelet agglutination test--PAT--, adhesively). The effect was found to be more pronounced than that of acetylsalicylic acid. Furthermore, in vivo carbocromen inhibited the increased spontaneous platelet aggregation in man.


[The pharmacokinetics of 14C-zolimidine in rats].

The blood levels and urinary and fecal excretion of 14C-zolimidine [2-(p-methylsulfonyl)-imidazo(1,2-a)pyridine-2-14Ci1 were studied following oral and intravenous application. The elimination from the blood after i.v. administration can be described by a 3-compartment model. Male rats eliminate the radioactivity more rapidly than do females. Although radioactivity is detectable for several days in the blood an accumulation of the drug or its metabolites can be excluded on the basis of the calculated values. 14C-Zolimidine is rapidly absorbed in rats after oral administration of 10 mg/kg and reaches peak blood levels within 45 to 60 min. In the first phase the elimination is rapid but trace activity can be measured for several days. Based on the amount of urinary excretion the rate of absorption is estimated to between 80 and 90%. Biliary excretion amounted to about 15% of the i.v. administered dose. It is assumed that the difference of 25% between fecal and biliary excretion is sequestered through the gastrointestinal mucosa.