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Biomedical subjects

J Koch-Weser

Publications and source records attributed to J Koch-Weser.

At least 19 recordsLinked to original sources
PubMed1986

Differing attitudes of industry and academia towards controlled clinical trials.

A consensus conference was held in 1984 on controversial issues concerning controlled clinical trials. Thirty-six individuals working in academic institutions, forty-six in industry and twelve in regulatory authorities participated. Academics accepted and industrial representatives rejected the following: existing regulations cannot cope with the rate at which new treatments develop; drug companies may be reluctant to undertake surveillance programmes because sales will fall if adverse reactions are detected; novel remedies should not be promoted before extensive post-marketing surveillance; third parties should finance trials promising to reduce the costs of illness and trialists should be separated from sponsors in data analysis and interpretation, the investigator owning the data unless stated otherwise. Industrial representatives supported and academics rejected the following: government price control inhibits drug development and a multicentre trial can be justified simply by the wish to speed drug registration.

Attitude↗
PubMed1983

Kinetics of medroxalol, a beta- and alpha-adrenoceptor antagonist.

Eight healthy men received single oral doses of 400, 800, and 1200 mg medroxalol and a single intravenous dose of 1 mg per kg body weight on four occasions separated by at least 2 wk. Plasma medroxalol concentrations were assayed up to 24 hr after each dose by a specific high-pressure liquid chromatographic assay. Urinary excretion of parent compound was determined as well. Following oral doses medroxalol reached peak plasma concentrations within 2.5 to 3 hr. The t 1/2 of the terminal decay phase was 11.1 hr. Mean apparent volume of distribution (aVD) was between 11.2 and 16.4 l/kg, and mean total body clearance (ClT) was between 0.73 and 0.99 l hr-1 kg-1. Mean urinary recovery of parent drug within 48 hr was 2.3%, 3.9%, and 3.6% after the oral doses compared to 8.2% after the intravenous dose. Bioavailability estimated from AUC was 27.2% after 400 mg, 31.3% after 800 mg, and 37.4% after 1200 mg by mouth. Since aVD, t 1/2, ClT, and urinary excretion did not differ significantly after the three oral doses, medroxalol kinetics appear to follow a dose-linear model.

Administration, Oral↗
PubMed1982

Effect on prostatic growth of 2-difluoromethylornithine, an effective inhibitor of ornithine decarboxylase.

2-Difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, causes marked changes in the polyamine metabolism of ventral prostate when given to adult rats in drinking water (20 g/l) for 3 consecutive days. A 90% inhibition of ornithine decarboxylase activity is accompanied by approx. 80% decreases of the concentrations of putrescine and spermidine and by a 36% decrease in spermine. Concomitantly, S-adenosylmethionine decarboxylase activity increases 7-fold and the concentration of decarboxylated S-adenosylmethionine 450-fold. When DFMO is given to immature rats for 12 consecutive days the above described changes are accompanied by a marked reduction in the age-dependent increases of the wet weight and RNA and DNA contents of the ventral prostate. In adult rats DFMO decreases the weight and RNA content of the ventral prostate within 4 days by 32% and 24% respectively and maintains them constant for the next 19 days. After 23 days of treatment, the prostatic weight is 46% of that of control animals of the same age, whereas the weights of other organs are only slightly decreased. Cytological studies carried out at this time show that DFMO reduces the size of both prostatic acini and the epithelial cells lining the acini.

Animals↗
PubMed1982

Concentration gradients of free and total gamma-aminobutyric acid and homocarnosine in human CSF: comparison of suboccipital and lumbar sampling.

Concentrations of free and total gamma-aminobutyric acid (GABA) and homocarnosine were determined in sequential aliquots of the first 30 ml of CSF obtained by lumbar puncture in five patients. Rostrocaudal gradients were calculated and compared to gradients estimated by determining concentrations of these substances in CSF obtained by simultaneous suboccipital and lumbar punctures in four more patients. In the lumbar fractions study, rostrocaudal mean gradients of 0.36, 36, and 21 pmol/ml for free GABA, total GABA, and homocarnosine, respectively, were calculated. In the suboccipital/lumbar study, gradients of 0.33, 30, and 24 pmol/ml for free GABA, total GABA, and homocarnosine, respectively, were estimated. These results indicate that valid comparison of CSF concentrations of these substances is restricted to similar fractions and suggest that in CSF the substances originate largely from brain rather than from peripheral sources.

Adult↗
PubMed1982

Artifactual increases in the concentration of free GABA in samples of human cerebrospinal fluid are due to degradation of homocarnosine.

Samples of untreated human cerebrospinal fluid (CSF) were kept at room temperature (20 +/- 1 degree C) up to 72 h, and changes in gamma-aminobutyric acid (GABA) and homocarnosine contents were measured. The concentration of free GABA increased with time, and concomitantly a similar decrease occurred in the concentration of homocarnosine. Total GABA after hydrolysis (present in human CSF at concentrations of 40-100 times that of free GABA) did not change. After 2 h the increase in CSF GABA for seven subjects ranged from 42 to 244 pmol/ml. The rate of increase in CSF GABA was positively correlated with the initial homocarnosine concentration. Approximately 5% per h of the initial homocarnosine content was degraded during the first 7 h at room temperature; thereafter the rate gradually decreased. No free GABA was formed in CSF frozen at -70 degrees C for 10 days. When this CSF was restored to room temperature, the formation of free GABA from homocarnosine occurred at essentially the same rate as that observed in fresh CSF. These results demonstrate that the well-known artifactual increase in GABA concentration of untreated human CSF depends on the concentration of homocarnosine. The rapidity of this increase (up to 2 pmol/ml/min) could account for disparities among CSF free GABA concentrations previously reported from normal subjects. It is suggested that measurement of concentrations of total GABA in the CSF would provide a better index of human brain GABA concentration than determination of CSF free GABA.

Carnosine↗
PubMed1982

[Therapeutic trial of gamma-vinyl GABA, an inhibitor of GABA transaminase, in tardive dyskinesias induced by neuroleptics].

Oral gamma-vinyl GABA, an irreversible inhibitor of GABA-transaminase, was given to 10 patients with neuroleptic-induced tardive dyskinesia (7 chronic simple schizophrenics and 3 chronic paranoid schizophrenics). Dyskinesia was reduced in 8 of 10 cases. Aggravation of dyskinesia and major psychomotor sedation was observed in two elderly patients with senile dementia. In addition, with regard to schizophrenic symptoms, gamma-vinyl GABA appeared to have beneficial effects on affective withdrawal and retardation, while hallucinations seemed to be aggravated.

4-Aminobutyrate Transaminase↗
PubMed1981

Kinetics of alpha-difluoromethylornithine: an irreversible inhibitor of ornithine decarboxylase.

We gave alpha-difluoromethylornithine (DFMO), a selective, irreversible inhibitor of ornithine decarboxylase, to six health men in single intravenous doses of 5 and 10 mg/kg body weight and oral doses of 10 and 20 mg/kg. Plasma concentrations were monitored during the 24 hr after each dose. Urine was collected from 0 to 24 hr after drug and amount of unchanged drug excreted was determined. Peak plasma concentrations were reached within 6 hr after oral doses. The decay of the plasma concentrations followed first-order kinetics with a mean half-life (t 1/2) for all four doses studied of 199 +/- 6 min (+/- SD). Mean total body clearance (ClT) for the four doses was 1.20 +/- 0.06 ml . min-1 . kg-1. Mean renal clearance was determined as 0.99 +/- 0.03 ml . min-1 . kg-1, accounting for 83% of drug elimination. Mean apparent volume of distribution (aVD) was 0.337 +/- 0.031 l/kg-1, corresponding to 24 l for 70 kg of body weight. The amount of unchanged drug in 24-hr urine samples was 47 +/- 7% and 40 +/- 11% after 10 and 20 mg/kg orally, and 78% and 81 +/- 8% after 5 and 10 mg/kg intravenously. Bioavailability of the 10 mg/kg dose was estimated as 58% from the urinary recoveries and as 54% from the areas under the plasma concentration curves (AUC 0 leads to infinity). Since doubling of the dose resulted in a doubling of the mean AUC 0 leads to infinity and since other kinetic parameters, such as aVD, t 1/2, ClT, and the urinary recovery of unchanged drug, were essentially the same at all doses, DFMO kinetics follow a dose-linear model.

Administration, Oral↗
PubMed1981

Treatment of Huntington disease with gamma-acetylenic GABA an irreversible inhibitor of GABA-transaminase: increased CSF GABA and homocarnosine without clinical amelioration.

gamma-Acetylenic GABA (GAG, RMI 71.645), a potent irreversible inhibitor of gamma-aminobutyric acid transaminase, was given orally in various dosage schedules to 14 patients with Huntington disease. The biochemical effects of the drug on cerebrospinal fluid (CSF) concentrations of gamma-aminobutyric acid (GABA) and the GABA-containing dipeptide, homocarnosine, were measured in 10 of 14 patients. Treatment with GAG increased CSF concentrations of GABA and homocarnosine as compared to pretreatment values, suggesting that the drug increased brain GABA concentration. Despite this neurochemical effect, the clinical state was not improved. Except for single seizure episodes in five patients, GAG therapy was well tolerated. These results do not exclude the possibility that agents that augment CNS GABAergic function may prove useful in therapy of Huntington disease.

4-Aminobutyrate Transaminase↗
PubMed1981

Potentiation of the antitumor therapeutic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea by alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor.

alpha-Difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase, was used alone and in combination with various single doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to treat animals bearing murine glioma 26 and rat 9L gliosarcoma intracerebral tumors. Used as a single agent, DFMO has little or no effect against these tumors. However, in both intracerebral tumor models, pretreatment with DFMO p.o. before i.p. administration of BCNU potentiates the effect of BCNU without increasing toxicity. The effects of DFMO administered p.o. after BCNU or before and after various doses of BCNU indicate that DFMO may also effectively slow the repopulation of these tumors after BCNU therapy.

Animals↗
PubMed1981

Effects of alpha-difluoromethylornithine alone and combined with adriamycin or vindesine on L1210 leukemia in mice, EMT6 solid tumors in mice, and solid tumors induced by injection of hepatoma tissue culture cells in rats.

The effects of alpha-difluoromethylornithine (DFMO; RMI 71782) in combination with vindesine or Adriamycin were investigated in three different animal tumor models. When given in a concentration of 2% in drinking water to C57BL/6 X DBA/2 F1 mice inoculated i.p. with L1210 leukemia cells, DFMO prolonged the survival time 1,2-fold. Treatment with vindesine (0.1 mg/kg/week i.p. or Adriamycin (2.5 mg/kg/week i.p.) increased the mean survival time 1.4- and 2.3-fold, respectively. DFMO with vindesine doubled survival time, while DFMO with Adriamycin increased it 3.5-fold and yielded 30% long-term survivors. The growth of solid tumors induced in Buffalo rats by i.m. injection of hepatoma tissue culture cells was inhibited 65% after 2 weeks of DFMO treatment. Similar inhibition of growth could be achieved by weekly i.p. injections of vindesine (0.2 mg/kg) or Adriamycin (2.5 mg/kg). When the same doses of these drugs were administered in combination with DFMO, the growth of this hepatoma was completely arrested. Combined treatment of BALB/c mice bearing s.c. solid EMT6 tumors with DFMO and adriamycin or vindesine also resulted in enhanced inhibition of tumor growth compared to single-drug therapy. These results indicate that combination of DFMO with vindesine or Adriamycin is an effective approach to the treatment of several animal cancers.

Animals↗
PubMed1981

Serum drug concentrations in clinical perspective.

Determination of serum concentrations of certain drugs is becoming increasingly important for optimal patient care. These drugs include many antibiotics, several antiarrhythmics, cardiac glycosides, lithium, phenytoin, some other anticonvulsants, salicylates, and theophylline. Serum level determinations can also be useful for establishing the best individual dosage of benzodiazepines, phenothiazines, and tricyclic antidepressants. On the other hand, information about serum levels is not necessary or useful for many widely used drugs. In general, measurement of serum concentrations is valuable only for drugs whose dosage should be individualized and whose therapeutic and toxic actions are not adequately quantifiable by clinical endpoints. The serum concentration of the drug and of important active metabolites must be accurately measurable, the relation between their concentrations in the serum and the intensity of therapeutic and toxic effects during clinical use must have been clearly defined, and serum levels must always be knowledgeably interpreted in conjunction with careful clinical observation and judgment. Measurements of serum drug concentrations are most often useful during prophylactic drug therapy, in patients with major pharmacokinetic disturbances, and when patients show unusual and unexplained sensitivity or resistance to therapy with a drug.

Biotransformation↗