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A HPLC method for a rapid determination of ethosuximide in plasma is described. A sample is extracted with ethyl ether from acidic medium with glutethimide as internal standard and injected onto analytical RP-18 column with spectrophotometric monitoring at 244 nm.
Cytochromes P-450IIB1 and P-450IIB2 were recently shown to be inducible in rat hepatocyte cultures maintained on a reconstituted extracellular tumor matrix (Matrigel) as indicated by increases in P-450IIB1 and -IIB2 mRNAs and immunoreactive proteins (J. Cell. Physiol., 134: 309-323, 1988). Here we show that treatment of cultured rat hepatocytes with phenobarbital and other compounds known to induce P-450IIB1/2 in vivo increased spectral cytochrome P-450, immunoreactive proteins, and benzyloxy- and pentoxy-resorufin dealkylases, activities known to be specific for cytochrome P-450IIB1/2. These increases were observed when cells were cultured on either Matrigel or collagen matrix in Williams E medium. Cytochrome P-450III was also increased by phenobarbital and dexamethasone on either matrix. Propoxycoumarin depropylase activity, which has been proposed as a specific activity catalyzed by cytochrome P-450III, was increased 3-4-fold more by treatment with 3-methylcholanthrene than by phenobarbital or dexamethasone. The activity catalyzed by P-450III could be distinguished from that catalyzed by other P-450 forms using the specific inhibitor triacetyloleandomycin. Benzoyloxyresorufin dealkylase was also increased in these cells by treatment with 2,4,5,2',4',5'-hexachlorobiphenyl, glutethimide, or mephenytoin. Treatment with phenobarbital or 2-allyl-2-isopropylacetamide slightly induced 5-aminolevulinate synthase activity. 5-Aminolevulinate synthase activity was slightly increased in cells treated with phenobarbital or 2-allyl-2-isopropylacetamide. Succinyl acetone also induced 5-aminolevulinate synthase activity and, in combination with either of the other two drugs, synergistically increased the enzyme activity regardless of whether cells were cultured on collagen or Matrigel. These results indicate that with simple and economical enzyme assays for holocytochrome P-450 and 5-aminolevulinate synthase, the rat hepatocyte culture system can be used for studies of the interrelationships between phenobarbital induction of cytochrome P-450 and heme metabolism.
Cigarette smoking-induced alterations in drug absorption, distribution, metabolism, excretion, and effectiveness are reviewed. Drug therapy can be affected pharmacokinetically by polyaromatic hydrocarbons and pharmacodynamically by nicotine. Pentazocine and phenylbutazone show increased metabolism in smokers and may have to be given in higher dosages. Smokers experience less pain relief with propoxyphene than do nonsmokers. Codeine, meperidine, and morphine are unaffected pharmacokinetically, and the effect on acetaminophen is probably not clinically important. Carbamazepine, phenytoin, and phenobarbital are not influenced. Heparin metabolism is elevated in smokers; this effect may necessitate modest increases in dosage. Warfarin clearance is increased, but this is not associated with a change in prothrombin time. Pindolol and propranolol are unaffected pharmacokinetically, but direct effects of nicotine may interfere with blood pressure control. Smoking transiently diminishes the diuretic effect of furosemide, inconsistently affects protein binding of lidocaine, and has no effect on prednisone, prednisolone, or dexamethasone. The metabolism of estrogens to less active metabolites is increased. Smoking is associated with decreased subcutaneous absorption of insulin and increased dosage requirements. Healing of GI ulcers with histamine H2-receptor antagonists may be compromised in smokers; sucralfate is probably more useful. Imipramine, benzodiazepines, chlorpromazine, and glutethimide may be influenced, and theophylline metabolism is accelerated. Cigarette smoking can affect the pharmacokinetic and pharmacodynamic properties of many drugs.
We present a method for simultaneously determining 12 hypnotics and sedatives (primidone, methyprylon, phenobarbital, butabarbital, butalbital, ethchlorvynol, pentobarbital, amobarbital, phenytoin, glutethimide, secobarbital and methaqualone) in 200 microliter of serum. Serum proteins are precipitated with an acetonitrile solution containing 5-(4-methylphenyl)-5-phenylhydantoin, the internal standard. The drugs are eluted from a reversed-phase column with a mobile phase consisting of an acetonitrile/phosphate buffer, at a flow rate of 3.0 ml/min. The eluted drugs are detected by their absorption at 195 nm; their quantities are estimated from their peak heights. Each analysis requires no longer than 30 min at the optimum column temperature of 50 degrees C. The lower limit of detection for all of these drugs is less than 10 ng/sample for drug standard. A sensitivity of 1.0 mg/liter of serum is attained routinely for each of the drugs. Analytical recoveries for the 12 drugs varied from 94 to 112%, with good day-to-day precision (CV between 3.8 and 10.4%). Of more than 35 drugs tested for possible interference, only ethotoin interferes with the analysis of phenobarbital.
We describe a simple liquid-chromatographic system for simultaneously measuring bronchodilators, anticonvulsants, hypnotics, and chloramphenicol. Use in therapeutic drug monitoring includes determination of theophylline, caffeine, chloramphenicol, ethosuximide, primidone, phenobarbital, phenacemide, phenytoin, mephenytoin, nirvanol, and carbamazepine and its bioactive metabolites within 13 min. In the "toxicology mode" theophylline, caffeine, barbital, butabarbital, pentobarbital, amobarbital, secobarbital, primidone, phenobarbital, methylprylon, glutethimide, methaqualone, phenytoin, mephenytoin, nirvanol, and carbamazepine and its bioactive metabolites are resolved within 17 min. A reversed-phase C8 column (5-microns particles) is used, with acetonitrile/water (20/80 by vol) as mobile phase. The drugs are extracted from 50 microL of serum with use of a Chromosorb P microcolumn and chloroform/isopropanol (6/1 by vol). The drugs are quantified by absorbance at 208 nm, with tolylphenobarbital as internal standard. Lower limits of detection varied from 0.05 to 0.1 mg/L, analytical recovery from 94% to 106%; CVs were less than 5.6% within run, less than 6.9% between runs.
Pharmacological activities of N-allyl, N-benzyl and N-o-xylyl derivatives of both 2,6-dioxopiperidine (DOP = glutarimide) and 4-ethyl-4-methyl-2,6-dioxopiperidine [bemegride(BG)] were studied in mice. Convulsant activity, hypnotic activity, anticonvulsant activity, acute toxicity and interactions with some hypnotics were used as pharmacological indexes. N-Benzyl-2,6-dioxopiperidine (ByDOP) and N-o-xylyl-2,6-dioxopiperidine (o-XyDOP) exhibited some hypnotic activity. N-Allyl-2,6-dioxopiperidine (ADOP), ByDOP and o-XyDOP prolonged the pentobarbital (PB)-induced sleep by 2.5-, 9- and 4-fold, respectively, as compared with the control at a dose of 80 mg/kg, i.p. On the other hand, N-allylbemegride (ABG) exhibited convulsant activity at a high dose. N-Benzylbemegride (ByBG) and N-o-xylylbemegride (o-XyBG) also showed some hypnotic and anticonvulsant activities. BG (20 mg/kg, i.p.) shortened the amobarbital (AB)- and thiopental (TP)-induced sleep, whereas ABG (80 mg/kg, i.p.) significantly shortened only the barbital (B)-induced sleep, in spite of showing with 20 and 80 mg/kg, i.p. the prolonging effect on the AB- and PB-induced sleep. At a dose of 80 mg/kg, i.p., ByBG significantly prolonged the phenobarbital (PheB)-, AB-, PB-, TP- and glutethimide (GI)-induced sleep, and o-XyBG also showed the prolonging effect on the PheB-, AB-, TP- and GI-induced sleep. These results indicate that ByDOP and o-XyDOP possess some central depressant effect, ABG has antagonistic effect on the B-induced sleep and that substitution of aromatic groups on the N position of BG reduces the convulsant activity but increases the depressant activity.
To examine current models for the co-ordinate regulation of 5-aminolaevulinate (ALA) synthase and cytochrome P-450 we have determined the effect of drugs, inhibitors of haem biosynthesis, haem and cycloheximide on the steady-state expression of mRNAs for ALA synthase and a phenobarbital-inducible cytochrome P-450 (PB1 P-450), in chick embryo hepatocytes in vivo and in primary culture. We found that the mRNAs for ALA synthase and PB1 P-450 were rapidly and simultaneously induced by the porphyrinogenic drugs glutethimide and 2-propyl-2-isopropylacetamide. Inhibitors of haem biosynthesis when administered alone had a small effect on ALA synthase mRNA induction, but in combination with the drugs synergistically increased induction of both ALA synthase mRNA and enzyme activity. However, there were concentrations of inhibitors that increased induction of enzyme activity without increasing mRNA induction. Haem suppressed ALA synthase mRNA induction by drugs by only 50%, whereas induction of ALA synthase enzyme activity was completely suppressed. This suppression of ALA synthase mRNA by haem was blocked by cycloheximide treatment which did not block the induction of ALA synthase mRNA by drugs. In fact, cycloheximide synergistically increased the drug induction of ALA synthase mRNA, suggesting the presence of a labile protein factor which may interact with a haem-responsive element of the ALA synthase gene. Cycloheximide treatment alone did not significantly affect ALA synthase mRNA expression, but induced PB1 P-450 mRNA to a similar extent to that caused by porphyrinogenic drugs, suggesting the presence of a labile repressor which modulates PB1 P-450 gene expression. Basal and drug-inducible PB1 P-450 mRNA levels were unaffected by haem or by inhibitors of haem biosynthesis, indicating that the PB1 P-450 gene is not regulated by haem in chick embryo hepatocytes. Our results indicate that drugs simultaneously induce ALA synthase and PB1 P-450 mRNA expression, and that ALA synthase activity is regulated by haem principally at a post-transcriptional site rather than at the transcriptional level.
New trends in drug use in the United States of America have usually started in populations of young users in California. The use of hallucinogenic drugs (psychedelics), phencyclidine (PCP) and the smoking of cocaine free base were all first detected in populations of young Californian users. Five patterns of youthful drug use are described: experimental, social-recreational, circumstantial-situational, intensified and compulsive. These patterns are supported by several myths whereby users tend to trust the appearance and folklore surrounding specific drugs. New trends in drug use detected in a sample population of young users in California include increased use of cocaine, psilocybin mushrooms, psycho-active phenylisophropylamines, PCP, fentanyl, and codeine combined with glutethimide. Other evidence suggests that future trends are likely to include increased use of cathinone, yohimbine, fentanyl analogues and ephedrine.
The term addictive as used by the popular press frequently confuses the more precise concepts of acute and chronic tolerance, physical dependence and withdrawal, and psychologic dependence. Serious physical dependence on psychoactive drugs is rare and is easily managed. In contrast, psychologic dependence, the most important reason for persistent drug use, is much more common and is difficult to treat. Some tactics are available - for example, confrontation and discussion with the patient about how a drug is not going to be effective over long periods. Treating the symptom of a complex problem should, of course, not be expected to solve the problem. The most important tactic is to prescribe dependence-associated drugs only when clearly indicated, when the problem is responsive to drug therapy and for the shortest period necessary, without the option for renewing the prescription. Many problems related to drug use long after the period of expected benefit is past can be avoided by far more restrictive drug prescribing. Barbiturates and nonbarbiturate sedative hypnotics (e.g., ethchlorvynol, glutethimide, meprobamate, methaqualone and methyprylon) should not be prescribed for insomnia, acute reactive anxiety, chronic anxiety neurosis or depressive illnesses, since the safer and equally effective benzodiazepines, which are less associated with dependence, are available.
Intensity and duration of action of several compounds which are metabolized in the liver, are reduced in rats following pretreatment with 3-trifluoromethyl-alpha-ethylbenzhydrol (RGH-3332, Zixoryn), e.g., hexobarbital, methohexitone, glutethimide, hydroxymephenesine, chlorzoxazone, zoxazolamine, ketamine, chlordiazepoxide, diphenylhydantoin, ethylmorphine and pentylenetetrazol, hydroquinone, acenocumarol, respectively. Hypnotic effect of barbital is not altered by RGH-3332. Hexobarbital, meprobamate, mephenesine, nikethamide, canrenone, metyrapone, antipyrine, bromsulphophthalein, inocyanin green, bilirubin disappearance are enhanced, excretion of ascorbic acid is increased after RGH-3332 treatment. The effect of RGH=3332 is inhibited by D,L-ethionine. Hepatic cytochrome P450 concentration is increased following treatment with RGH-3332. Results of in vivo studies proved that 3-trifluoromethyl-alpha-ethylbenzhydrol has enzyme inducing activity.
The clinical profile of aminoglutethimide (AG), an amino derivative of the hypnotic agent glutethimide, is described. AG suppresses estrogen formation in postmenopausal women by its inhibitory effect on steroid synthesis in the adrenal glands as well as in the peripheral tissues. The results of treatment of 959 breast cancer patients by AG and glucocorticoids in several studies are reviewed. The treatment of these patients, who were not selected according to the hormonal receptor status in their tumors, resulted in about 30% objective responses. About 50% of the patients with estrogen receptor positive tumors responded with an objective regression. The favorable effect of medical adrenalectomy is comparable to that of hypophysectomy or surgical adrenalectomy; the advantage of medical adrenalectomy compared to ablative endocrine surgery is reversibility of the inhibitory effect on the production of adrenal hormones and estrogens after cessation of treatment. The AG-glucocorticoid regimen appears to exert a greater effect on skeletal metastases than tamoxifen. Patients who fail on tamoxifen and other endocrine regimens can still benefit from AG-glucocorticoid treatment. The value of medical adrenalectomy as adjuvant treatment is not yet known. At present, several agents with a selective effect on androgen-to-estrogen conversion in the peripheral tissues are under study. Their potential as inhibitors of the estrogen production in breast cancer patients is considerable.
Multiple-endocrine therapy with combinations of various types of treatment has not been evaluated properly in spite of the success of individual types of hormone treatment. This paper reports the early results of a randomized controlled clinical trial comparing tamoxifen (10 mg 2 times/day)-amino-glutethimide (250 mg 3 times/day)-danazol (100 mg 3 times/day)-hydrocortisone (20 mg 2 times/day) (TAD) with tamoxifen (10 mg 2 times/day). Analysis of the first 107 assessable patients indicates objective response (criteria of the International Union Against Cancer) in 33% of patients receiving tamoxifen versus 50% of patients receiving TAD. Duration of response to TAD is identical to duration of response to tamoxifen alone. TAD is well tolerated, and toxicity, although greater than or tamoxifen, is acceptable.
Human breast neoplasms can be divided into hormone-dependent and hormone-independent subtypes. Estrogen is the major hormonal stimulus for growth of the dependent tumors. Failure to respond to estrogen suppression therapy could reflect either an incomplete lowering of estrogens or the hormonal independence of the tumor. To address this issue, we compared the levels of several estrogens and other hormones in women experiencing objective responses (the responders) and disease progression (the progression group) during therapy with the aromatase-steroidogenesis inhibitor, aminoglutethimide, and replacement hydrocortisone. Pretreatment hormonal profiles of the estrogens, and androgens, ketosteroids, thyroxine, polypeptide hormones, and carcinoembryonic antigen did not differ significantly among response groups. During treatment, the levels of all estrogens were suppressed to a similar degree in the progression group and in the responders. Urinary estrone, for example, fell to 16.7 +/- 3.2% of basal in the responders versus 16.3 +/- 3.8% of basal in the progression group. These data suggested that lack of estrogen suppression did not explain the response to treatment in the patients receiving aminoglutethimide-hydrocortisone. This finding differs from our results in a similarly analyzed control group of patients treated with surgical adrenalectomy. Levels of the weak androgens, dehydroepiandrosterone sulfate and androstenedione, were found to be higher in the progression group compared to the responders. This observation could not be explained by differences in duration of treatment between groups. Analysis at 1 to 12 weeks, 13 to 24 weeks, and 25 to 36 weeks after initiating treatment indicated higher androgen levels at each time point in the progression group. In addition, the results were not attributable to differing serum levels of aminoglutethimide among responder groups. While the finding of higher androgen levels in the responder group remains unexplained, this study indicates that incomplete estrogen suppression is not responsible for lack of tumor response in patients with progressive disease during amino-glutethimide-hydrocortisone therapy.
Seven instances of child abuse due to poisoning are reported; two of the children died. Forty-one cases of this form of poisoning are found in the literature. Of the total of 48 children, eight (17%) died as a result of the incident; and one was mentally retarded. The seven different agents described here are alcohol, glutethimide (Doriden), propoxyphene hydrochloride (Darvon), diazepam, insulin, lye, and pepper, constituting 27 different types of poison used by abusing guardians. The most common cause of abuse reported is excessive salt ingestion with water restriction. Excessive ingestion of water is the second most common cause. Barbiturates and tranquilizers are also frequent agents. In 30% of the cases, poisoning persists even after hospitalization. Child abuse by battering is associated in 20% of the cases. The need for a high index of suspicion of abuse in bizarre presentations of children for medical care when the etiology is obscure is emphasized.
A standardized stirred-batch experiment has been performed to determine the maximum adsorptive capacities of three activated carbons (R4, ASO and walnut coal) produced in the GDR for acetylsalicylic acid, methylsalicylate, phenobarbital, crotylbarbital, hexobarbital, pentobarbital, glutethimide, chlorophenethazine and methaqualone from aqueous and low-percentage ethanolic solutions. The activated carbon ASO and the walnut coal have always been found to be markedly superior to the activeated coal R 4. The maximum adsorptive capacities so far determined compare with data on activated carbons produced abroad, so that further developmental work seems worthwhile.20
Hypnotic action of barbiturates (hexobaribtal, cyclobarbital-Ca, phenobarbital, barbital) chloral hydrate, glutethimide was investigated in spontaneously hypertensive Okamoto-Aoki rats (SHR). Hypnotic effect of investigated drugs was decreased in hypertensive rats comparing with normotensive animals. The decrease in the hypnotic effect was related to the increase of the threshold hypnotic dose. No changes were observed in the pharmacokinetic parameters of hexobarbital and barbital and in the rate of crossing of blood-brain barrier by the latter drug in SHR rats. The results suggested that the decrease of hypnotic activity of investigated drugs did not depend on the hypertension but they were produced by the hyposensitivity of CNS to hypnotic agents. The latter phenomenon appeared as the result of some biochemical changes in the brain tissue.
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