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Biomedical subjects

O M Bakke

Publications and source records attributed to O M Bakke.

At least 19 recordsLinked to original sources
PubMed1995

Drug safety discontinuations in the United Kingdom, the United States, and Spain from 1974 through 1993: a regulatory perspective.

The objective of the present study was to compare the number of new chemical entities (NCEs) and new biologicals entities (NBEs) approved for marketing during the period 1974 through 1993 in the United Kingdom, the United States, and Spain that were subsequently discontinued (removed from the market, withdrawn, or whose license was allowed to lapse) while a question of safety existed. Of the products approved during the two decades of the study period, a total of 29 drugs were subsequently discontinued for safety reasons in at least one of the three countries (United Kingdom: 20 safety discontinuations; United States: 10; and Spain: 16). These represent 3% to 4% of all drugs introduced in these countries, an increase compared to the period from 1964 through 1983, when approximately 2% of all NCEs were discontinued for safety reasons. The therapeutic classes most commonly associated with safety discontinuations were the nonsteroidal anti-inflammatory drugs (nine drugs), vasodilators (four drugs), and antidepressants (three drugs). U.S. companies or their foreign subsidiaries were involved as originators (patent-holders and/or developers) of approximately 40% of the drugs discontinued for safety reasons.

Animals↗
PubMed1985

Tissue distribution of penicillin during constant rate infusion in rats at 71 ATA.

Benzyl[14C]penicillin was infused at a constant rate of 100 mg X kg-1 X h-1 for 90 min in rats at 1 ATA air for the control group (n = 10) and at 71 ATA He-O2 for the pressure group (n = 11). The radioactivity was measured in the arterial blood, brain, liver, kidney, muscle, and fat. The mean brain penicillin concentration after 90 min infusion was approximately 20% increased at 71 ATA (P less than 0.05), but the brain: blood concentration ratio was not significantly affected. The mean blood, liver, and muscle penicillin content was slightly higher and the mean kidney content was slightly lower at pressure, but no statistically significant changes were observed.

Adipose Tissue↗
PubMed1984

Induction of peroxisomal enzymes and palmitoyl-CoA hydrolase in rats treated with cholestyramine and nicotinic acid.

Male Wistar rats were given 200 mg/kg/day nicotinic acid or 1000 mg/kg/day cholestyramine by stomach tube for ten days. Peroxisomal palmitoyl-CoA oxidation (cyanide-insensitive) and the activities of palmitoyl-CoA hydrolase and urate oxidase were significantly increased in the total liver homogenate. Subcellular fractionation showed enhanced enzyme activities after drug treatment mainly in the peroxisome-containing fractions. The increase in urate oxidase activity and its subcellular distribution suggest that the tested drugs induce core-containing peroxisomes. The findings are similar to those previously reported with low doses of peroxisome-proliferating hypolipidemic drugs and with acetylsalicylic acid, a drug which is structurally similar to nicotinic acid. Since cholestyramine is not absorbed, its influence on hepatic enzymes probably occurs indirectly as a consequence of enhanced catabolism of cholesterol.

Animals↗
PubMed1984

Enzymatic changes in rat liver associated with low and high doses of a peroxisome proliferator.

The activities of a number of lipid-metabolizing and subcellular marker enzymes were measured in total homogenates and subcellular fractions prepared from the livers of male rats fed diets containing 0.05, 0.1, 0.3, and 0.5% of the hypolipidemic drug tiadenol, resulting in mean drug intake of 45, 90, 330, and 530 mg/day/kg body wt, respectively. In the total homogenates, a massive induction of palmitoyl-CoA hydrolase and peroxisomal palmitoyl-CoA oxidation accompanied by increased free CoASH and long-chain acyl-CoA content was observed at the highest dose levels whereas little change occurred up to 90 mg/day/kg/body wt. The palmitoyl-CoA synthetase activity increased slightly up to 90 mg/day/kg body wt, but higher doses resulted in decreased enzyme activity. Catalase activity increased with the dose to be elevated by a factor of approximately 1.6 at 330 mg/day/kg, whereas the activities of urate oxidase decreased. The specific activities of palmitoyl-CoA hydrolase and peroxisomal palmitoyl-CoA oxidation increased in all fractions, but most markedly in the cytosol. The changes in the activities and the distribution of subcellular marker enzymes and the increase of the peroxisome-associated polypeptide (PPA-80) are in keeping with a peroxisome proliferating effect resulting in formation of premature organelles with altered properties. Since high doses of many hypolipidemic drugs produce hepatic tumors and peroxisomal proliferation in rodents and since no increase in peroxisomes is found in human liver after therapeutic use of lower doses, the dose-response relationship is of interest for the evaluation of the toxicology of this class of agents.

Animals↗
PubMed1984

Effect of aminoglutethimide on antipyrine, theophylline, and digitoxin disposition in breast cancer.

The influence of aminoglutethimide (AG) on antipyrine, theophylline, and digitoxin kinetics was examined. Antipyrine was given as a single test dose before and after 3 mo of AG treatment, whereas theophylline and digitoxin kinetics were investigated at steady state in patients receiving these drugs therapeutically before and after AG therapy. During AG treatment, mean clearance rates for antipyrine, theophylline, and digitoxin increased by 81%, 32%, and 109%. Together with earlier reports of effects of AG on warfarin and dexamethasone disposition and on its own metabolism, these findings indicate that AG is a potent inducer of drug metabolizing microsomal monooxygenases of the liver. Since many drugs known to be metabolized by this enzyme system are frequently used for concomitant conditions in patients with breast cancer, interactions with AG are to be expected.

Adult↗
PubMed1984

Drug discontinuations in the United Kingdom and the United States, 1964 to 1983: issues of safety.

Since the modern era of drug regulation began in the early 1960s, fewer new drugs have been approved for marketing in the United States than in the United Kingdom. We examined whether information can be obtained about the relative safety of higher and lower introductory rate policies by comparing each country's record of drugs that have been discontinued (removed from the market, withdrawn, or whose licenses were allowed to lapse) while a question of safety existed. We have compiled a list of both older (approved before 1964) and newer (approved in 1964 or later) chemical entities discontinued in the last two decades. With the aforementioned broad criteria to define "discontinuation," and to assess whether a question of safety was involved, our study showed that a total of 24 chemical entities have been discontinued in the United States or the United Kingdom. Nearly half (10 drugs) were products that had been approved in both countries, while the remainder (drugs that had been exclusively available in one country or the other) consisted of four drugs in the United States and 10 in the United Kingdom. Among the drugs introduced during the last two decades, five have been discontinued in the United States and eight in the United Kingdom. Each country's record of discontinuations has been remarkably similar for drugs introduced after 1974: Four have been discontinued in the United States and three in the United Kingdom. Since drugs discontinued while a safety question existed represent only 2% of the new chemical entities introduced, it appears that drugs that reach the market under the prevailing regulatory systems are seldom associated with unacceptable toxicity.

Animals↗
PubMed1984

Drug selection in a regulated society: the Norwegian experience.

Norway has strictly regulated the introduction and marketing of drugs for more than 50 years. The system is a state owned whole-sale monopoly with nationwide distribution. Marketing approvals must satisfy a medical "need" clause and are granted and reviewed every 5 years by the " Specialties ' Committee." Although clinical trials are not mandatory for drug approval, relative efficacy and benefit/risk considerations make them desirable. Assessment of clinical data is based on reviews by outside consultants. Because of such strict regulation, the total number of drug products available is smaller than other Western European countries, however, only a few therapeutic classes are not represented. The impact of regulation on the drug market and the therapeutic armamentarium available for health care in Norway are discussed.

Drug Industry↗
PubMed1983

Hepatic enzymes, CoASH and long-chain acyl-CoA in subcellular fractions as affected by drugs inducing peroxisomes and smooth endoplasmic reticulum.

1. The activities of acyl-CoA hydrolase, catalase, urate oxidase and peroxisomal palmitoyl-CoA oxidation as well as the protein content and the level of CoASH and long-chain acyl-CoA were measured in subcellular fractions of liver from rats fed diets containing phenobarbital (0.1% w/w) or clofibrate (0.3% w/w). 2. Whereas phenobarbital administration resulted in increased microsomal protein, the clofibrate-induced increase was almost entirely attributed to the mitochondrial fraction with minor contribution from the light mitochondrial fraction. 3. The specific activity of palmitoyl-CoA hydrolase in the microsomal fraction was only slightly affected while the mitochondrial enzyme was increased to a marked extent (3-4-fold) by clofibrate. 4. Phenobarbital administration mainly enhanced the microsomal palmitoyl-CoA hydrolase. 5. The increased long-chain acyl-CoA and CoASH level observed after clofibrate treatment was mainly associated with the mitochondrial, light mitochondrial and cytosolic fractions, while the slight increase in the levels of these compounds found after phenobarbital feeding was largely of microsomal origin. 6. The findings suggest that there is an intraperoxisomal CoASH and long-chain acyl-CoA pool. 7. The specific activity of palmitoyl-CoA hydrolase, catalase and peroxisomal palmitoyl-CoA oxidation was increased in the lipid-rich floating layer of the cytosol-fraction. 8. The changes distribution of the peroxisomal marker enzymes and microsomal palmitoyl-CoA hydrolase after treatment with hypolipidemic drugs may be related to the origin of peroxisomes.

Acyl Coenzyme A↗
PubMed1983

Sustained release disopyramide compared to plain capsules after change-over from intravenous infusion.

The plasma concentration profile of disopyramide was examined in 13 patients with arrhythmias following acute myocardial infarction. Intravenous loading doses of 1.5 mg/kg followed by 0.7 mg/kg and then infusion of 0.3 mg kg-1h-1 resulted in final concentrations between 2.4 and 4.9 mg l. Change-over to oral therapy with disopyramide sustained release (SR) tablets was smooth, and therapeutic plasma concentrations were maintained throughout. Comparison of the plasma concentrations in a subsequent cross-over study with disopyramide plain capsules 150 mg every 6 h and SR tablets 250 mg every 12 h, each being administered for 3 days to attain a steady state, showed that the bioavailability and the variation of the plasma concentration were similar with both regimens. In patients with body weight between 62 and 92 kg disopyramide SR tablets 250 mg every 12 h matched the preceding infusion rate of 0.3 mg kg-1h-1 resulting in plasma concentrations close to steady state already on the first day of oral therapy. The absorption of disopyramide SR tablets is only moderately delayed, and the preparation can be used twice daily in direct succession of intravenous infusion.

Adult↗
PubMed1983

Tissue distribution of thiopental and diazepam in rats at 71 atmospheres pressure.

35S-thiopental 15 mg/kg and 14C-diazepam 5 mg/kg were injected intravenously in separate groups of rats (n = 6) at 1 ATA air and at 71 ATA air-He. Total radioactivity was measured in the brain, liver, kidney, muscle and fat after 1, 3, 5 and 15 min. The thiopental content was significantly reduced at pressure in the brain at 3, 5 and 15 min. The diazepam content of the brain was significantly reduced at pressure at 1, 5 and 15 min. The liver, muscle and kidney tissue generally contained slightly less of either drug at pressure, particularly at the earliest sampling times.

Animals↗
PubMed1983

Pharmacokinetics of antipyrine, paracetamol, and morphine in rat at 71 ATA.

The pharmacokinetics of [14C]antipyrine, [3H]paracetamol, and [3H]morphine were studied in male Wistar rats at 1 ATA and then at 71 ATA, each animal being its own control. Separate control groups were studied at 1 ATA in order to test the validity of the one-way crossover protocol. The drugs were injected through a femoral venous catheter, and blood was sampled from a catheter in the femoral artery. There were no significant differences in the biological half-life (T1/2), the apparent volume of distribution (Vd), and the clearance (C) of antipyrine and paracetamol. Likewise, there was no appreciable effect of high pressure on the blood concentration profile of morphine.

Acetaminophen↗