Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Depression is a common, life-disrupting, potentially lethal illness that can affect both sexes and all ages. Its peak onset is in the early adult years. It is more common than hypertension in primary care practice. Recent studies show that fewer than 1 in 20 depressed patients are correctly diagnosed and adequately treated. Depression periodically destroys the productivity of those with the condition, and depressed patients have a worse quality of life than patients with debilitating, chronic conditions such as arthritis, hypertension, diabetes mellitus and back pain. Suicide occurs in as many as 15% of patients with depression, especially those with recurrent episodes and hospitalisations, and may even occur in those with in subsyndromal depression. Suicide is one of the leading causes of death, and individuals who complete suicide have usually experienced mood disorders, mainly depression. Current data support a decreased frequency of suicidal ideation with all antidepressants, including selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs). Modern pharmacotherapy is the cornerstone for effective treatment of depression. As they are well tolerated, even in the presence of comorbid medical illness, and easier to manage, SSRIs enhance compliance. A fully adequate antidepressant dosage is suitable for patients of all ages and can be used by non-psychiatrist physicians for the treatment of the acute episode, as well as the frequent recurrences that often require long term maintenance antidepressant medication. SSRIs have fewer drug interactions than older antidepressants, and even the SSRI inhibition of hepatic cytochrome P450 enzymes has proven only very infrequently to be of clinical importance. SSRIs also effectively treat anxious depression, dysthymia and atypical depression. Fluoxetine may provide more rapid onset of therapeutic effect because it can be started at closer to its usual full therapeutic dosage than other SSRIs or older antidepressants. SSRIs, in particular fluoxetine, are more suitable for use as long-term maintenance therapy in these chronic relapsing diseases. These factors and the high efficacy rate, increased safety in overdose, reduced incidence of adverse effects (mostly decreasing with time) and superiority in ease of maintaining patients in adequate treatment plans provides fluoxetine with an overall superior therapeutic profile.
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PMID:Risks and benefits of selective serotonin reuptake inhibitors in the treatment of depression. 946 88

Angiotensin II in proximal tubule epithelium is known to stimulate the release of arachidonic acid after stimulation of phospholipase A2 (PLA2) independent of phospholipase C-mediated signaling. Furthermore, an angiotensin II type 2 receptor subtype has been linked to this signaling cascade. We investigated the regulation and differential stimulation of PLA2s by comparing the PLA2 activities associated with the membranes and cytosol of rabbit renal proximal tubular epithelial cells after stimulation with angiotensin II, epidermal growth factor, and bradykinin. Both fractions demonstrated PLA2 activity that was dithiothreitol insensitive, required micromolar concentrations of Ca2+ for optimal activity, and was inhibited in a dose-dependent manner by an antiserum to a cytosolic PLA2 with a molecular mass of 85 kD. However, membrane-associated PLA2 did not demonstrate significant substrate specificity, whereas 1-steroyl-2-[14C]arachidonylphosphatidyl choline was the preferred substrate for cPLA2. An antiserum generated against mastoparan, a known PLA2 activator, inhibited membrane- but not cytosol-associated PLA2 activity. Membrane fractions showed a broad pH range (7.5 to 8.5) for optimal PLA2 activity, whereas cytosol was maximum at pH 9.5. Angiotensin II stimulated membrane-associated PLA2 activity by 88%, whereas bradykinin and epidermal growth factor inhibited activity by 54% and 41%, respectively. The three agonists stimulated cPLA2. Moreover, angiotensin II-induced activation of membrane-associated PLA2 preceded the activation of cPLA2. These results demonstrate differential localization and regulation of proximal tubular epithelial PLA2 isozymes, which may determine the pattern of subsequent arachidonic acid metabolism by the cytochrome P450 system.
Hypertension 1998 Mar
PMID:Role of phospholipase A2 isozymes in agonist-mediated signaling in proximal tubular epithelium. 949 65

Cisapride, a cytochrome P450 3A4 (CYP3A4) substrate, is widely prescribed for the treatment of gastrointestinal motility disorders. Prolongation of QT interval, torsades de pointes, and sudden cardiac death have been reported after concomitant administration with erythromycin or azole antifungal agents, but not with other CYP3A4 inhibitors. A possible drug interaction occurred in a 45-year-old woman who was taking cisapride for gastroesophageal reflux disorder and diltiazem, an agent that has inhibitory effect on CYP3A4, for hypertension. The patient was in near syncope and had QT-interval prolongation. After discontinuing cisapride, the QT interval returned to normal and symptoms did not recur. We suggest that caution be taken when cisapride is prescribed with any potent inhibitor of CYP3A4, including diltiazem.
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PMID:Prolongation of the QT interval related to cisapride-diltiazem interaction. 954 59

Eprosartan is a nonpeptide angiotensin II receptor antagonist which has a high affinity for the AT1 receptor subtype. When administered at dosages of 400 to 800 mg/day (once or twice daily) for 13 weeks to patients with mild to moderate essential hypertension, eprosartan significantly reduced blood pressure compared with placebo. Eprosartan was at least as effective as enalapril 10 to 40 mg/day in a dose-titration study in patients with severe hypertension. Eprosartan is generally well tolerated; clinical trials have shown the drug to have a tolerability profile similar to that of placebo. As with other angiotensin II receptor antagonists, it does not cause cough. Eprosartan is not metabolised by the cytochrome P450 system and therefore has a low potential for drug interactions.
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PMID:Eprosartan. 958 67

L- and T-type voltage-dependent transmembrane calcium channels are important for normal functioning of the cardiovascular system. T-type channels are a heterogeneous group, and have physiologic and pathophysiologic relevance in a number of organ systems, including the heart and central nervous system. They appear to be involved in the control of blood pressure in patients with essential hypertension and in protection from ischemic damage. Alterations of both L- and T-type calcium channels are involved in the development of hypertension. Pharmacologic modulation of T-type calcium channels appears to reduce membrane calcium flux and ameliorate hypertension. During early ischemic damage, T-type calcium channels appear to remain functional whereas L-type channels are already inactivated. T-type calcium channels also appear to be involved in the development of supraventricular arrhythmias, some forms of arrhythmias in cardiomyopathy, and cardiac hypertrophy. The heterogeneity of T-type calcium channels should make it possible to target drugs to specific subgroups of T-type calcium channels. A new class of calcium antagonist, the benzimidazolyl-substituted tetraline derivatives, has been shown to block both L- and T-type calcium channels. The first member of this class approved for clinical use is mibefradil. Clinical studies have demonstrated the efficacy of mibefradil in lowering blood pressure and as an antianginal and antiischemic agent. At clinically recommended doses, mibefradil has a heart rate lowering effect without a negative inotropic effect, and a favorable side effect profile. Because it is metabolized by the cytochrome P450 pathway, it should be used cautiously with other agents similarly metabolized.
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PMID:The relevance of T-type calcium antagonists: a profile of mibefradil. 972 40

Cyclosporine (CsA) is an immunosuppressor widely used in all postoperative transplantation protocols. Nephrotoxicity and hypertension are the major secondary effects of cyclosporine. The CsA acts on two essential regulatory mechanisms of the blood pressure: the extracellular volume and the systemic vascular resistances. The incidence of hypertension in patients treated with CsA varies from 10% to 80% in the literature. In view of two main mechanismes implicated in CsA-induced hypertension the most logical therapeutic approach would be to use diuretics and calcium inhibitors. The major drawback of diuretic therapy is the risk of hyperuricaemia and attacks of gout, the predisposition to which is already increase by treatment with CsA. In addition, renal failure may rarely be observed. The calcium channel blockers are the drugs of choice in the treatment of CsA-induced hypertension. Not only are they effective in decreasing the blood pressure, but they also have a major advantage of having a nephroprotective effect against CsA. Cyclosporine is metabolised in the liver by cytochrome P450 3A4 dependant enzymes. Many pharmacological interferences have been described with this drug and other pharmacological agents. This type of interaction has been described with certain calcium inhibitors which inhibit hepatic and digestive degradation of cyclosporine and therefore increase its plasma concentrations. The choice of calcium inhibitors should be based on criteria of efficacy and tolerance and on the drug's pharmacokinetics. The interaction between cyclosporine and some calcium inhibitors exposes the patients to the risk of overdosage when treatments is instituted and of underdosage when the treatment is withdrawn.
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PMID:[Calcium inhibitors in the management of hypertensive patients on cyclosporine]. 974 27

Mibefradil is a single-enantiomer calcium antagonist belonging to a new class, the tetralol derivatives. The recommended doses for treatment of hypertension and chronic stable angina pectoris are 50 or 100 mg. Mibefradil is metabolized via parallel pathways of esterase-catalysed hydrolysis and cytochrome P450 3A4-mediated oxidation. Mibefradil also inhibits cytochrome P450 3A4 and consequently inhibits its own metabolism, a property illustrated by three studies performed early in the drug's development. After single intravenous doses of 2.5 to 80 mg to healthy male subjects, pharmacokinetics are linear. At the representative 40 mg intravenous dose mean pharmacokinetic parameters were clearance 241 +/- 76 mL min(-1), terminal exponential half-life 15.0 h and volume of distribution at steady state 213 L. After single oral doses of 10 to 320 mg, reduced first-pass metabolism occurs with increasing dose. This effect is accompanied by increasing absolute bioavailability as the dose is increased. In an oral multiple-dose study of healthy male volunteers mibefradil doses of 100, 150 or 250 mg (from tablets) were administered once daily for 28 days. Reduction of the first-pass effect was noted, although the data suggested that a maximum was reached for doses of 150 mg or more. In a study of the effect of hypertension on mibefradil pharmacokinetics, 12 patients received oral mibefradil once daily at doses of 50, 100, 150, or 200 mg in 100 mL orange juice for 8 days. Steady state was reached within 3 days and accumulation generally ranged from three- to sevenfold. Single-dose non-linearity was observed in the first-pass effect, although for multiple dosing oral clearance values were dose-independent and lower than for single doses. After multiple dosing at the recommended dosage of 50 and 100 mg once daily, oral clearance of mibefradil stabilizes to approximately the same value for both doses. Hence, the single-dose non-linearity has little clinical relevance but demonstrates the self-inhibition of metabolism seen with mibefradil. Studies so far suggest that self-inhibition of its oxidative metabolic pathway leads to a low clearance and long half-life, enabling once-daily dosing and conferring low intra- and inter-patient variability in pharmacokinetics.
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PMID:Single- and multiple-dose mibefradil pharmacokinetics in normal and hypertensive subjects. 981 Nov 58

Mibefradil, a tetralol derivative, is a new long-acting calcium antagonist used for the treatment of patients with hypertension and chronic stable angina pectoris. The drug is virtually completely metabolised, with less than 3% of an oral dose excreted unchanged in urine. Its metabolism occurs via parallel pathways, which fall into 2 broad categories: esterase-catalysed hydrolysis (producing the major plasma metabolite) and cytochrome P450 (CYP) 3A4-mediated oxidation. Plasma protein binding is greater than 99.5%, predominantly to alpha 1-acid glycoprotein. Oral multiple dose administration of mibefradil 50 or 100 mg once daily is associated with inhibition of the CYP3A4 pathway of metabolism, increasing the half-life and bioavailability of the parent compound. The intensity of the inhibition of CYP similarly results in numerous clinically relevant drug interactions which ultimately motivated the voluntary withdrawal of mibefradil from the market. With multiple oral doses of 50 to 100 mg once daily, the time to maximum plasma concentration was approximately 2.4 hours, absolute bioavailability was around 80%, clearance was 5.7 to 7.5 L/h, oral terminal exponential volume of distribution was 180 L, and terminal exponential half-life was 22 hours (ranging between 17 and 25 hours). A NONMEM sparse data analysis indicated that apparent clearance is not affected by race, gender, age or bodyweight. Renal function does not affect the pharmacokinetics of mibefradil.
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PMID:Clinical pharmacokinetics of mibefradil. 988 14

The effects of dietary docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, on blood pressure and some pressure-regulating systems were measured in young spontaneously hypertensive rats (SHR). Plasma aldosterone and corticosterone levels, adrenal aldosterone production in vitro, and characteristics of adrenal angiotensin receptors were measured after 6 weeks of diet. Renal cytochrome P450 (CYP) 4A gene expression and arachidonic acid metabolism by renal microsomes were also investigated. Plasma cholesterol, triglycerides, and high-density lipoprotein cholesterol were measured. Diets contained either corn/soybean oil alone (CSO), or oil enriched with DHA. After 6 weeks, rats fed DHA had systolic blood pressures averaging 34 mmHg less than controls (P < 0.001). Plasma aldosterone levels were 33% lower in the DHA-fed animals than in controls (22 +/- 3 vs. 33 +/- 3.7 ng/dl, P < 0.05). Plasma levels of corticosterone were 18% lower in animals fed DHA than in controls, but this difference was not statistically significant. Adrenal glomerulosa cells from DHA-fed rats produced less aldosterone in vitro in response to angiotensin II, ACTH, or potassium. The difference was less marked when aldosterone production was stimulated by supplying exogenous corticosterone, suggesting an effect of DHA on postreceptor steps in signal transduction or the early pathway of aldosteronogenesis. We found no significant differences in angiotensin receptor subtype, number, or affinity. Production of arachidonic epoxides by renal microsomes was 17% lower in DHA-fed animals than in controls (P < 0.05). Renal cortical mRNA levels of CYP4A genes and formation of 19- and 20-hydroxyeicosatetraenoic acid (HETE) did not differ between dietary groups. Plasma total cholesterol and high-density-lipoprotein (HDL) levels were significantly reduced in SHR fed the DHA supplement, but triglyceride levels were not significantly different. The effects of DHA on steroid and eicosanoid metabolism may be part of the mechanism by which this fatty acid prevents some of the hypertension in growing SHR.
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PMID:Docosahexaenoic acid is an antihypertensive nutrient that affects aldosterone production in SHR. 1032 Jun 29

The coexistence of pheochromocytoma and primary adrenal Cushing's syndrome of the same adrenal gland has rarely been reported. We describe here the case of a female patient presenting with mild Cushing's stigmata, hypertension and diabetes mellitus in whom we diagnosed a pheochromocytoma of the left adrenal gland with coexisting non-ACTH-dependent cortisol hypersecretion. While hormonal work-up was still in progress, the patient became pregnant and wanted to carry her pregnancy to full-term. A laparoscopic adrenalectomy in the 17th week of gestation was decided upon and the patient accordingly prepared for surgery by pre-treatment with phenoxybenzamine. Successful surgery--the first ever reported laparoscopic resection of a pheochromocytoma in pregnancy--without perioperative complications was performed under general anesthesia, with the patient receiving peri- and post-operative hydrocortisone substitution. Pathohistological examination revealed a pheochromocytoma with positive immunostaining for interleukin-6 (IL-6) and negative immunostaining for ACTH, vasoactive intestinal polypeptide (VIP) and cytochrome P450, and with no signs of malignancy. A paracrine stimulation of the ipsilateral adrenal cortex by IL-6 produced by the pheochromocytoma, leading to cortical hyperplasia and subclinical Cushing's syndrome, is suggested by the positive immunostaining for IL-6 and the MRI findings. Post-operatively, secondary adrenal insufficiency ensued, necessitating continuing hydrocortisone replacement over 12 months. Hypertension resolved after surgery, and diabetes after the uncomplicated vaginal delivery at term.
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PMID:Pheochromocytoma and sub-clinical Cushing's syndrome during pregnancy: diagnosis, medical pre-treatment and cure by laparoscopic unilateral adrenalectomy. 1047 54


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