Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The three best-described genetic polymorphisms of drug metabolism--the debrisoquin/sparteine type of oxidative polymorphism (hereafter referred to as the debrisoquin polymorphism), the polymorphism of N-acetylation, and the mephenytoin type of oxidative polymorphism--are reviewed. For all three polymorphisms, the poor-metabolizer phenotype is inherited as an autosomal recessive trait. The debrisoquin and mephenytoin oxidative polymorphisms involve defects in two separate cytochrome P450 enzymes. The prevalence of the poor-metabolizer phenotype for debrisoquin ranges between 2% and 10% for groups of various ethnic origins. The poor-metabolizer phenotype for mephenytoin comprises about 5% of the Caucasian population and about 20% of the Japanese population. N-acetyltransferase is a cytosolic enzyme whose clinical polymorphism was discovered using isoniazid as the substrate probe. The prevalence of the slow-acetylator phenotype among American and European Caucasian and American black groups is about 50%; among the Japanese it is about 10%. More than 20 agents are substrates for debrisoquin hydroxylase, about 15 for N-acetyltransferase, and 3-5 for mephenytoin. In poor metabolizers, debrisoquin can cause hypotension, and sparteine can cause blurred vision, headache, and dizziness. Clinical consequences of the slow-acetylator phenotype include increased susceptibility to systemic lupus erythematosus induced by procainamide and hydralazine, peripheral neuropathy induced by isoniazid, hydralazine, and dapsone, and sulfasalazine-induced dose-related leukopenia, nausea, vomiting, headache, and vertigo. After administration of mephenytoin, poor metabolizers have increased somnolence and intellectual impairment. Awareness of genetic polymorphisms of drug metabolism should improve understanding of interindividual variability in drug disposition and response.
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PMID:Polymorphic drug metabolism. 268 60

Hepatic cytochrome P450-dependent oxidation is deficient in 5% to 10% of the Caucasian population. A similar percentage seems to suffer from migraine. The hypothesis was tested that an oxidation deficiency possibly relevant to potential dietary triggers plays a role in the pathogenesis of migraine. In 37 migraine sufferers and 26 controls age- and sex-matched to 26 of these patients, debrisoquine hydroxylation following an oral dose of 10 mg was employed as a marker of oxidation status, determined by calculating the metabolic ratio (MR): urinary debrisoquine/urinary 4-hydroxydebrisoquine. MR was similarly distributed in migraineurs and controls. Three subjects in each group were poor metabolizers (MR greater than 30, versus normal range, 0.1-12). MR in patients did not depend on type of migraine (common versus classic), attack frequency, the presence of trigger factors, smoking or a history of adverse reactions or sensitivity to medicines.
Cephalalgia 1988 Jun
PMID:Hepatic cytochrome P450-mediated oxidation function in migraine. 340 19

During the past 2 decades, great advances have been made in the treatment of ulcer disease. This has involved the development of new drugs that are not only well tolerated, but are relatively inexpensive. The lack of significant adverse effects has revealed a degree of tolerability that, to write a review of the adverse effects, poses a difficult task. Most of the adverse effects are related to an excessive reaction to the relevant pharmacological characteristic that mediates the therapeutic response. The drug dosage can be reduced, freeing the patient of the adverse reaction, but leaving behind a background activity adequate to produce a therapeutically beneficial effect. The adverse effects of H2-antagonists fall into 2 groups. Firstly, there are poorly defined symptoms that have a prevalence similar to that in the community; these include headache, giddiness, dizziness, fatigue, constipation and diarrhoea. Secondly, they may delay the metabolism of drugs metabolised by the the cytochrome P450 system, and rarely be androgenic. Many antacids and the site-protective agent sucralfate contain aluminium, which can be absorbed, producing elevation of serum aluminium levels. In view of the possible association of aluminium with Alzheimer's disease, anxiety has arisen as to whether aluminium from these sources may, in those on prolonged treatment, cause Alzheimer's disease. However, the evidence so far indicates that aluminium is not a risk factor for Alzheimer's disease. The association of gastric cancer with achlorhydria has led to the fear that long term use of potent acid inhibitors may cause cancer. This fear has been accentuated by the observation that some rats, given omeprazole over their lifetime, developed carcinoid tumours of the stomach. However, enthusiastic research, both clinical and epidemiological, indicates that drug-induced achlorhydria is unlikely to be a problem in humans. Site protective agents have a role in certain conditions such as pregnancy where the systemic effect of a drug may produce adverse effects.
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PMID:A comparative overview of the adverse effects of antiulcer drugs. 776 37

Major depression is a common and disabling disorder with far-reaching social and economic implications. Nonetheless, major depression is treatable by one of the many currently available antidepressants with response rates of approximately 65-70%. Treatment of depression has improved in recent years because of the availability of effective and well-tolerated antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). The currently available antidepressants are generally equally effective and are distinguished primarily by side-effect profiles. The side effects of tricyclic antidepressants (TCAs) are attributed to their nonspecific interaction with cholinergic, histaminergic, serotonergic, and dopaminergic receptors in the central nervous system. The secondary amine TCAs, nortriptyline and desipramine, are preferred among the TCAs because of a more favorable side-effect profile. The TCAs are cardiotoxic, and overdoses are frequently fatal. Adverse effects, including potentially fatal drug and food interactions, limit the use of the monoamine oxidase inhibitors (MAOIs); however, these agents have a role in the treatment of depression with comorbid anxiety, refractory depression, atypical depression, and bulimia. The SSRIs possess a class side-effect profile of headache, nausea, and sexual dysfunction. Individual differences in side effects may distinguish fluoxetine (nervousness, restlessness), sertraline (diarrhea, loose stools), and paroxetine (dry mouth). The SSRIs all inhibit certain cytochrome P450 isoenzymes involved in the metabolism of drugs, such as the TCAs, and each SSRI has been reported to increase plasma concentrations of concomitantly administered TCAs. Bupropion therapy is associated with a risk of seizure development, which can be minimized by multiple daily doses. Trazodone is sedating and can rarely cause priapism. The related compound, nefazodone, does not cause sexual dysfunction or priapism, but is associated with sedation. Venlafaxine, a recently available antidepressant that appears to have efficacy in treatment-refractory depression, may cause nausea that requires gradual upward dosage titration. Higher doses of venlafaxine may also cause elevations in blood pressure, heart rate, and serum cholesterol. As more is learned about the pathophysiology of depression, even more specific and well-tolerated antidepressants will be developed.
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PMID:Contemporary management of depression. 799 23

H2-receptor antagonist therapy is associated with a low incidence of adverse reactions. Adverse events reported in clinical trials of ranitidine in daily doses of up to 1200 mg include headache, tiredness and mild gastrointestinal disturbances, but the incidence is similar to or less than that for placebo. High doses of cimetidine (> 5 g/day) can cause reversible impotence or gynaecomastia. While ranitidine exhibits no clinically significant drug-drug interactions, cimetidine interacts with many drugs metabolized by cytochrome P450. In contrast to ranitidine and cimetidine, where safety data are available for up to 10 years of continuous therapy, experience with famotidine and nizatidine is limited. The safety of long-term H2-receptor antagonist therapy needs to be considered in relation to the potential consequences of prolonged acid suppression, including the risk of proliferation of gastric flora and the risk of developing enterochromaffin-like cell hyperplasia, which could in turn, theoretically, lead to gastric malignancy. Such problems have not been observed in patients during long-term therapy at low or full doses of H2-receptor antagonists. Standard doses of currently available H2-receptor antagonists permit acid secretion in response to food and other stimuli, and this daily acid tide prevents persistent bacterial colonization.
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PMID:Safety issues relating to long-term treatment with histamine H2-receptor antagonists. 810 74

Drug-induced achlorhydria in experimental animals results in excessive hypergastrinaemia, ECL-cell hyperplasia and ECL-cell carcinoidosis. However, these events have not been observed in long-term studies in patients receiving proton pump inhibitors. Serum gastrin levels increase only modestly during acute and long-term treatment. It is concluded that monitoring of serum gastrin levels and of fundic ECL cells is of no clinical relevance even during long-term therapy with proton pump inhibitors. The clinically available proton pump inhibitors such as pantoprazole, omeprazole and lansoprazole are well tolerated, with a low incidence of side-effects. Minor and serious side-effects classified as possibly related to proton pump therapy have been described in up to 2.5% of patients. This is the same order of magnitude as that found in patients treated with H2-receptor blockers and in placebo-treated controls. In most cases, therefore, the observed side-effects are unrelated to the intake of proton pump inhibitors. Minor adverse events include headache, diarrhoea, dizziness, pruritus and rash. Proton pump inhibitors are metabolized mainly in the liver via the cytochrome P450 system and interactions with drugs metabolized by the same system are possible. Evidence is becoming available which suggests that pantoprazole may have less potential to interact with the cytochrome P450 system than the other proton pump inhibitors. In the case of diazepam metabolism, pantoprazole had the least effect on prolongation of the diazepam effect. This may well be an advantage in the clinical use of the drug.
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PMID:Safety of proton pump inhibitors--an overview. 818 Feb 97

The combination of caffeine with acetaminophen (APAP) is used widely in the treatment of headache. The effects of caffeine on APAP-induced hepatotoxicity and APAP bioactivation by liver microsomes from uninduced mice and from mice pretreated with various agents that induce cytochrome P450 were studied. When 1 mM caffeine was included, the rate of glutathione-APAP conjugate (GS-APAP) formation was increased significantly by 33 and 39% in microsomes from phenobarbital (PB)- and dexamethasone (DEX)-treated mice, respectively, whereas this parameter was decreased 39 and 12% by caffeine in microsomes from beta-naphthoflavone (beta NF)- and acetone-treated mice, respectively. A 5 mM concentration of caffeine increased GS-APAP formation by 47, 107 and 117% in microsomes from control, PB-, and DEX-treated mice, respectively, and decreased it 39 and 25% in microsomes from beta NF- and acetone-treated mice, respectively. Caffeine was a competitive inhibitor of APAP bioactivation in microsomes from beta NF- and acetone-treated mice. While caffeine increased APAP bioactivation in microsomes from uninduced, PB-, and DEX-treated mice, the apparent Km values for APAP were increased by caffeine, indicating that this enhancement was not due to a direct effect of caffeine on APAP binding to cytochrome P450 but may be due to an effect of caffeine on the substrate-enzyme complex. The variable effect of caffeine on APAP hepatotoxicity correlated with the effect of caffeine on APAP bioactivation by liver microsomes, regardless of pretreatment. Lack of correlation of aminopyrine N-demethylase, but good correlation of erythromycin N-demethylase activity with the extent of caffeine enhancement of APAP bioactivation following PB or DEX treatment suggests that a murine P450 subfamily similar to the rat P450 3A subfamily may be the candidate in mediating the stimulatory effect of caffeine on APAP bioactivation and APAP-induced hepatotoxicity.
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PMID:Interaction of caffeine with acetaminophen. 1. Correlation of the effect of caffeine on acetaminophen hepatotoxicity and acetaminophen bioactivation following treatment of mice with various cytochrome P450 inducing agents. 834 73

The question of whether the pharmacokinetics of ethinyl estradiol (EE2) is affected differently by the progestins in low-dose combined oral contraceptives containing gestodene or desogestrel was revisited. 80 randomly allocated women took 30 mcg EE2 and either 75 mcg gestodene or 150 mcg desogestrel for the first 21 days of each cycle for 6 months. Blood samples taken on days 1, 10, and 21 of the 1st, 3rd and 6th cycle, at frequent times for 24 hours after pill intake, were analyzed for EE2, corticosteroid binding globulin, cortisol and 6beta-hydroxycortisol. 31 women in each group completed the study. Minor side effects such as headache, breast tension, acne, and nausea occurred in each group; 1 subject dropped out because of headache, nausea, and hypermenorrhea and 1 because of a hematoma. No significant differences were seen in serum EE2 levels including the rise in mean EE2 on days 1-10, or the smaller rise between days 10-21, or the pharmacokinetic parameters Cmax, tmax, area under the curve (AUC) at 0-4 hours, or AUC at 0-24 hours. There was a maximal variation of 11% in intracyclical increases in serum EE2, but no change in intercyclical variations. There were also no significant differences between groups in the expected estrogen-induced increase in corticosteroid binding globulin. Urinary hydroxycortisol increased slightly over each cycle, somewhat more in the 1st cycle, and a bit more in the desogestrel cycles than in gestodene cycles, but not significantly. This study was contrasted in detail with the reports that prompted the controversy over pharmacokinetics of estradiol during intake of the involved combined pills. The import of the assays for cortisol metabolites is the fact that estradiol and cortisol are metabolized by the same liver cytochrome P450 isoenzyme.
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PMID:Influence of gestodene and desogestrel as components of low-dose oral contraceptives on the pharmacokinetics of ethinyl estradiol (EE2), on serum CBG and on urinary cortisol and 6 beta-hydroxycortisol. 846 17

Retinoids derived from retinol or beta-carotene are inactivated, among other ways, by enzymes belonging to the P450 cytochrome group. Liarozole, an imidazole-containing compound, is known to be a potent inhibitor of the cytochrome P450-mediated metabolism of all-trans retinoic acid. As a result, increased levels of this retinoid are found in skin and plasma. Therefore, in the treatment of psoriasis, therapeutic effects may be expected with liarozole which are similar to those observed with synthetic retinoids. In an open study, oral liarozole was given at a daily dose of 75 mg b.i.d., for 12 weeks to 31 patients with severe psoriasis. After 1 month, this dosage could be increased to 150 mg b.i.d. if there was no improvement or only moderate improvement. Initially, the effect of liarozole was mainly on scaling. A decrease in the Psoriasis Area and Severity Index (PASI) score of 45% at week 4, of 69% at week 8 and of 77% at week 12 was obtained, compared with baseline. A further decrease in the PASI score of up to 87% was observed in the 16 patients who were allowed to continue treatment for a maximum period of 12 months. An excellent or good improvement was noted in 77% of the patients within 12 weeks of starting treatment. This response rate had increased to 88% by the last follow-up visit. Nearly all patients (29 of 31) experienced adverse reactions, such as dry oral mucosa, headache and itching. These were mostly mild and transient, but four patients dropped out of the study because of an adverse event. Haematological, biochemical and cardiovascular parameters were not significantly influenced by liarozole. Six patients showed an increase in triglycerides, which normalized in three of four patients during further treatment. The results of this pilot study suggest that, at doses of 75-150 mg b.i.d., liarozole is an active antipsoriatic drug, and may be a useful addition to the existing therapeutic armamentarium. Controlled studies should be performed to compare liarozole with standard oral treatments.
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PMID:Inhibition of the metabolism of endogenous retinoic acid as treatment for severe psoriasis: an open study with oral liarozole. 854 99

Pantoprazole is an irreversible proton pump inhibitor which, at the therapeutic dose of 40mg, effectively reduces gastric acid secretion. In controlled clinical trials, pantoprazole (40mg once daily) has proved superior to ranitidine (300mg once daily or 150mg twice daily) and equivalent to omeprazole (20mg once daily) in the short term (< or = 8 weeks) treatment of acute peptic ulcer and reflux oesophagitis. Gastric and duodenal ulcer healing proceeded significantly faster with pantoprazole than with ranitidine, and at similar rates with pantoprazole and omeprazole. The time course of gastric ulcer pain relief was similar with pantoprazole, ranitidine and omeprazole, whereas duodenal ulcer pain was alleviated more rapidly with pantoprazole than ranitidine. Pantoprazole (40mg once daily) showed superior efficacy to famotidine (40mg once daily) in ulcer healing and pain relief after 2 weeks in patients with duodenal ulcer in a large multicentre nonblinded study. In mild to moderate acute reflux oesophagitis, significantly greater healing was obtained with pantoprazole than with ranitidine and famotidine, whereas similar healing rates were seen with pantoprazole and omeprazole. Pantoprazole showed a significant advantage over ranitidine in relieving symptoms of heartburn and acid regurgitation. Reflux symptoms were similarly alleviated by pantoprazole and omeprazole. Preliminary results indicate that triple therapy with pantoprazole, clarithromycin and either metronidazole or tinidazole is effective in the treatment of Helicobacter pylori-associated disease; however, these findings require confirmation in large well-controlled studies. Pantoprazole appears to be well tolerated during short term oral administration, with diarrhoea (1.5%), headache (1.3%), dizziness (0.7%), pruritus (0.5%) and skin rash (0.4%) representing the most frequent adverse events. The drug has lower affinity than omeprazole or lansoprazole for hepatic cytochrome P450 and shows no clinically relevant pharmacokinetic or pharmacodynamic interactions at therapeutic doses with a wide range of drug substrates for this isoenzyme system. In conclusion, pantoprazole is superior to ranitidine and as effective as omeprazole in the short term treatment of peptic ulcer and reflux oesophagitis, has shown efficacy when combined with antibacterial agents in H. pylori eradication, is apparently well tolerated and offers the potential advantage of minimal risk of drug interaction.
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PMID:Pantoprazole. A review of its pharmacological properties and therapeutic use in acid-related disorders. 888 82


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