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Biomedical subjects

N Gerber

Publications and source records attributed to N Gerber.

At least 109 records · Page 6Linked to original sources
PubMed1979

Evidence for the epoxide-diol pathway in the biotransformation of mephenytoin.

A dihydrodiol metabolite of mephenytoin (5-dihydroxycyclohexadienyl)-5-ethyl-3-methylhydantoin and other mono- and dihydroxylated and N-demethylated metabolites were identified in urine from a male epileptic patient receiving therapy with mephenytoin (300 mg/day). Metabolites, extracted from urine before and after enzymatic hydrolysis, were derivatized with a trimethylsilyl reagent and analyzed by combined gas chromatography and mass spectrometry. Two previously unreported metabolites were characterized: 5-ethyl-5-(di-hydroxyphenyl)-3-methylhydantoin and 5-ethyl-5-(hydroxy-methoxy-phenyl)-3-methylhydantoin. The structures of several other metabolites were confirmed: N-demethylmephenytoin, 5-ethyl-5-hydroxyphenylhydantoin, 5-ethyl-5-hydroxyphenyl-3-methylhydantoin and mephenytoin dihyrodiol. The dihydrodiol metabolite was of special interest since it was probably produced via an epoxide intermediate, 5-(epoxy-cyclohexadienyl)-5-ethyl-3-methylhydantoin. Previous reports have demonstrated that epoxides of this structural class are extremely reactive compounds, capable of alkylating biologic macromolecules. Covalent binding of the mephenytoin epoxide to macromolecules may be an important factor in the production of adverse and sometimes fatal side effects observed in patients receiving long-term therapy with mephenytoin.

Adult↗
PubMed1979

Disposition of valproic acid in the rat: dose-dependent metabolism, distribution, enterohepatic recirculation and choleretic effect.

A specific gas chromatographic assay has been developed for measurement of valproic acid (VPA) and its major conjugated metabolites. In rats given single intravenous doses, the decline in blood concentration of VPA was dose-dependent and followed first-order kinetics only at the lowest dose. The time required for the maximum concentration of VPA, after completion of the brief distribution phase, to decline by 50% was 11.7, 41 and 125 min at doses of 15, 150 and 600 mg of NaVPA per kg, respectively. A secondary increase in drug concentration, abolished by exteriorization of the bile, was observed in all intact rats with all doses. Some 45 to 55% of the dose appeared in the bile in 5 hr as VPA glucuronide. Urinary excretion of VPA glucuronide in intact animals accounted for 23 and 51% of the 15 and 150 mg/kg doses, respectively. Tissue distribution studies in rats sacrificed 20 and 90 min after dosage with [14C] NaVPA (150 mg/kg) showed that the drug concentration was highest in blood, moderate in liver, kidney, heart and lung and low in brain, fat, testis and skeletal muscle. During this interval the drug concentration declined in all tissues, whereas the total conjugated metabolites in the small intestine increased from 7 to 28% of the administered dose. The large intestine contained 30 times as much free drug as conjugate. Reabsorption of free VPA, released by hydrolysis of conjugate in the large bowel, accounted for the secondary rise in concentration of VPA observed in blood after single doses. The major urinary metabolites, VPA-glucuronide and 2-n-propylgutaric acid, were identified by gas chromatography/chemical ionization mass spectrometry. Sodium VPA caused a dose-dependent stimulation of bile flow, the magnitude and duration of which closely followed the blood concentration of VPA.

Animals↗
PubMed1978

Excretion of valproic acid into semen of rabbits and man.

Dipropylacetic acid (VPA, valproic acid) has been quantified in plasma and semen from rabbits and man using a new gas-liquid chromatographic assay. The drug assay is rapid, sensitive and free from interference by VPA metabolites. The beta phase half-life of VPA in rabbits after an i.v. dose (50 mg/kg) was 56 +/- 6 min. The concentration of VPA in rabbit plasma was 17 to 30 times the concentration in rabbit semen. In man, 500 mg doses of the free acid, p.o., resulted in VPA concentrations in plasma that were 11 to 17 times the concurrent levels in semen. VPA, in concentrations up to 10(-3) M, did not influence the motility of rabbit spermatozoa in vitro.

Adult↗
PubMed1978

[Acute iridocyclitis, ankylosing spondylitis (Bechterew) and congenital tissue antigens (author's transl)].

The tiysue antigen HLA-B27 was present in 92.6% of 95 Swiss patients with classical ankylosing spondylitis. This tissue antigen is present in only 7.7% of healthy Swiss blood donors. 36% of all patients had one or several acute attacks of anterior uveitis. This usually follows the onset of joint symptoms. In 4% of the 95 patients the iritis was the first symptom. The combination of acute uveitis and ankylosing spondylitis with the tissue antigen HLA-B27 indicates that not only the spondylitis, but also the uveitis is in many cases genetically determined.

Acute Disease↗
PubMed1978

Seminal excretion, vaginal absorption, distribution and whole blood kinetics of d-methadone in the rabbit.

The disposition of 40 mg of d-methadone HCl was studied in New Zealand White rabbits. After an intravenous infusion to male rabbits, the beta phase half-life was 106 +/- 21 min and the apparent volume of distribution was 12.6 liters/kg b.w. After an i.m. injection, the peak drug concentration in arterial blood (1.02 microgram/ml) occurred 10 min after the injection, whereas the peak concentration in semen (2.58 microgram/ml) occurred 140 min later. The semen/blood drug concentration ratio was 6.8 at 150 min after the injection. The concentration of d-methadone was measured in blood, spleen, liver, lung, prostate, seminal vesicle, testis and heart 130 minutes after an i.m. dose. All tissues had drug levels that exceeded the concentration in blood (0.42 microgram/ml). The concentrations in lung (33.5 microgram/g), kidney (15.2 microgram/g) and spleen (30.6 microgram/g) were particularly elevated. After intravaginal implantation, d-methadone was rapidly absorbed into the systemic circulation of female rabbits; the peak drug level in blood (0.94 microgram/ml) occurred 60 min after drug administration.

Absorption↗
PubMed1977

[Arthritis in thalassemia minor].

Seven cases with the syndrome of thalassemia minor and pauciarticular, non-erosive, seronegative arthritis are described. Other known causes of seronegative arthritis had been excluded. There was a predilection for middlesized joints such as ankles, wrists and elbows. Usually the synovitis was asymmetrical from onset, with one to eight joints affected. Finger or toe joint were usually spared. Extraarticular synovitis such as tenosynovitis or bursitis were not observed, nor were nodules, signs of vasculitis or visceral involvement. The course of this arthritis showed chronicity and mild, persistent, non-erosive synovitis without joint effusions. X-ray revealed juxtaarticular osteoporosis of the affected joints, characterized by a diminution of the number of trabeculae (hypertrophic atrophy) combined with broadening of the singular trabeculae; this picture is typical of hemoglobinopathies. - Computed tomography showed a probable slight deficit of bone mineralization. Laboratory investigations including ESR, routine immunological tests, blood chemistry, and HLA-tissue typing were all normal. - The combination of this peculiar arthropathy with thalassemia minor would appear to be worthy of note and requires a further search among the forms of arthritis of unknown origin.

Adult↗
PubMed1977

[Vasculitis in hepatitis B infection].

Personal observations have confirmed the frequent association of HB-infection with certain forms of vasculitis. 4 of 11 patients with polyarteritis nodosa were repeatedly found to be HBs-Ag positive and had chronic hepatitis of varying severity. In patients with giant cell arteritis (polymyalgia rheumatica and temporal arteritis) anti-HBs was found more frequently than in controls, especially when examined within 6 months after onset of symptoms (7 of 20 equal 35% had anti-HBs, versus 6% of controls). Several lines of evidence point to the important role played by circulating HBs-Ag/anti-HBs complexes in the development of HB-associated vasculitis.

Arteritis↗
PubMed1977

New gas chromatogrphic assay for the quantification of methadone. Application in human and animal studies.

A new gas chromatographic assay utilizing 2-dimethylamino-4,4-diphenyl-5-nonanone as the internal standard was developed for the quantification of methadone. The method involved extraction of methadone with 1-chlorobutane from tissue at pH 9.8, re-extraction of an aliquot of the organic solvent with 0.5 M sulphuric acid, alkalinization and final extraction into chloroform. The assay was used to determine the concentration of methadone (i) in whole blood samples from a normal volunteer following a single 9.4-mg oral dose of d-methadone hydrochloride, (ii) in whole blood, saliva and gastric juice from a methadone addict maintained on 90 mg of dimethadone hydrochloride per day, (iii) in mouse liver microsomes incubated with methadone, and (iv) in the perfusate of the isolated perfused rat liver.

Animals↗
PubMed1977

Hydantoin ring glucuronidation: characterization of a new metabolite of 5,5-diphenylhydantoin in man and the rat.

A new metabolite of 5,5-diphenylhydantoin has been found in human urine and in rat bile. This new metabolite arises by direct glucuronidation of 5,5-diphenylhydantoin (i.e. no prior aryl hydroxylation occurs) and is characterized as the N-3 glucuronide. This structure assignment is based on (a) study of mass spectra of permethyl, perdeuteriomethyl, N-methyl-per-O-deuteriomethyl and deuteriomethyl ester permethyl derivatives and (b) comparison of the reactions of the new glucuronide metabolite and 5,5-diphenyl-3-methylhydantoin with diazomethane. Prominent ions at m/e 322 and 378 in the mass spectrum of the permethylated derivative of the glucuronide metabolite arise via retro Diels-Alder reactions of the glycone ring.

Animals↗
PubMed1977

Clinical effects and pharmacokinetics of racemic methadone and its optical isomers.

The respiratory and pupillary effects of oral l-, d-, and d,l-methadone were studied in healthy male volunteers 21 to 35 yr of age. The mean half-life of drug in blood was 22 hr for racemic methadone, 24 hr for l-methadone, and 25 hr for d-methadone. The effects of d-methadone were not significantly different from the placebo response at a 7.5 mg dose, whereas a 50 and 100 mg dose slightly depressed respiration in one subject each. Both 7.5 mg of l-methadone and 15 mg of d,l-methadone induced intense and sustained respiratory depression and miosis. The changes induced by l-methadone were of longer duration than those of d,l-methadone, lasting more than 72 hr in some subjects. Whole blood drug concentration correlated well with respiratory depression and miosis for l- and d,,l-methadone. The potency ratio of l-methadone to d,l-methdone, calculated from blood drug concentration data, was found to be 3.0 for respiratory depression and 2.7 for miosis. The antiduretic effect of 15 mg of d,l-methadone was investigated in three subjects and was found to persist for as long as measurements were taken, namely 11 and 12 hr in two subjects. d,l-Methadone administered frequently for pain may have cumulative effects on respiratory control and ability to excrete a water load.

Adult↗
PubMed1977

The metabolism of d-, l- and dl-methadone in the isolated perfused rat liver.

Five-milligram doses of d-, l- and dl-methadone were added to the perfusate of the isolated perfused rat liver and the disposition of each compound was monitored over a period of 120 minutes. There was an initial rapid decline in concentration of each drug in the perfusate, with approximately 70% disappearing in the first 10 minutes of the perfusion. Thereafter, the rate of decline of each compound slowed and the apparent half-life was about 100 minutes. In experiments with d- l- and dl-methadone the mean hepatic extraction from the perfusate at 10 minutes was 72, 66 and 69%, respectively. A comparison of the rate of disappearance of the d- and the l-isomers from the perfusate showed that the concentration of the d-isomer at each sampling time was lower than the concentration of the l-isomer and this concentration ratio ranged between 68 and 79%. A study of the disposition of dl-methadone in the isolated perfused liver indicated that the initial rapid decline of the drug in the perfusate in the first 10 minutes was caused primarily by the uptake of the unchanged drug into the liver. Thereafter, the concentration of methadone in the perfusate and liver declined slowly with time and was paralleled by an increase in the concentration of the primary mono-N-demethylated metabolite, which appeared in the liver, perfusate and bile. Smaller quantities of more polar metabolites, including hydroxylated compounds and conjugates, were also present in the liver and bile. Addition of SKF 525-A retarded the rate of decline of methadone from the perfusate and pretreatment of the rat with phenobarbital increased the rate of biotransformation of methadone in the isolated perfused liver.

Animals↗