Genetic variation in the alpha1B-adrenergic receptor and vascular response.

The alpha1B (α1B)-adrenergic receptors contribute to vasoconstriction in humans. We tested the hypothesis that variation in the ADRA1B gene contributes to interindividual variability and ethnic differences in adrenergic vasoconstriction. We measured dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 41 African Americans and genotyped 34 ADRA1B variants. We validated findings in another model of catecholamine-induced vasoconstriction, the increase in mean arterial pressure (ΔMAP) during a cold pressor test (CPT). One ADRA1B variant, rs10070745, present in 14 African-American heterozygotes but not in Caucasians, was associated with a lower phenylephrine ED50 (geometric mean (95% confidence interval), 144 (69-299) ng ml-1) compared with 27 African-American non-carriers (208 (130-334) ng ml-1; P=0.015) and contributed to the ethnic differences in ED50. The same variant was also associated with a greater ΔMAP during CPT (P=0.008). In conclusion, ADRA1B rs10070745 was significantly associated with vasoconstrictor responses after adrenergic stimulation and contributed to the ethnic difference in phenylephrine sensitivity.

Genetic variation in the α1A-adrenergic receptor and phenylephrine-mediated venoconstriction.

There is large interindividual variability and ethnic differences in phenylephrine-mediated vasoconstriction. We tested the hypothesis that genetic variation in ADRA1A, the α1A adrenergic receptor gene, contributes to the variability and ethnic differences. We measured local dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 42 African-Americans and genotyped for 32 ADRA1A single nucleotide polymorphisms. The ED50 ranged from 11 to 5442 ng min(-1), and the Emax ranged from 13.5-100%. The rs574647 variant was associated with a trend towards lower logED50 in each race and in the combined cohort (P=0.008). In addition, rs1079078 was associated with a trend to higher logED50 in each race and in the combined cohort (P=0.011). Neither variant accounted for the ethnic differences in response. None of the ADRA1A haplotypes was associated with the outcomes. In conclusion, ADRA1A variants do not contribute substantially to the marked interindividual variability or ethnic differences in phenylephrine-mediated venoconstriction.

A common beta1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to beta-blockade.

BACKGROUND: A common polymorphism of the beta(1)-adrenergic receptor Arg389Gly markedly affects function in vitro, but little is known about its in vivo significance. METHODS AND RESULTS: Resting and exercise hemodynamic responses were measured in subjects homozygous for Arg389 (n = 21) or Gly389 (n = 13) alleles before and 3 hours after administration of a beta-blocker, atenolol. Demographic characteristics and atenolol concentrations were similar in the two genotypic groups. Genotype had a marked effect on resting hemodynamic responses to atenolol, with Arg389-homozygous subjects having a larger decrease in resting systolic blood pressure (8.7 +/- 1.3 mm Hg versus 0.2 +/- 1.7 mm Hg, P < .001) and mean arterial blood pressure (7.2 +/- 1.0 mm Hg versus 2.0 +/- 1.7 mm Hg, P = .009). Attenuation of exercise-induced hemodynamic responses by atenolol was not affected by genotype. CONCLUSIONS: There is reduced sensitivity of Gly389 homozygotes to a beta-adrenergic receptor antagonist, and this polymorphism may be an important determinant of variability in response to beta-blockade.

The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization.

BACKGROUND: With continuous exposure to beta2-adrenergic agonists, vascular tissue becomes desensitized to agonist-mediated vasodilatation. We studied the effects of two common polymorphisms of the beta2-adrenergic receptor, one at codon 16 and one at codon 27, on agonist-mediated vasodilatation and desensitization in the vascular bed. METHODS: We studied 26 healthy subjects who were selected to represent three genotypes: 7 were homozygous for the alleles encoding Arg16 and Gln27, 8 were homozygous for the alleles encoding Gly16 and Gln27, and 11 were homozygous for the alleles encoding Gly16 and Glu27. Vascular responses were assessed by measuring changes in the diameter of a dorsal hand vein. A dose-response curve of the effect of the beta2-adrenergic-receptor agonist isoproterenol was constructed (dose range, 4 to 480 ng per minute). Desensitization was then induced by a 2-hour continuous infusion of isoproterenol, and venodilatation was measured 30, 60, 90, and 120 minutes after the start of the infusion. RESULTS: Subjects who were homozygous for Arg16 had almost complete desensitization; venodilatation in response to isoproterenol in this group decreased from a mean (+/-SE) of 44+/-11 percent to 8+/-4 percent (P=0.006). In contrast, subjects who were homozygous for Gly16 did not have significant desensitization, irrespective of the amino acid encoded by codon 27. Subjects who were homozygous for Glu27 had higher maximal venodilatation in response to isoproterenol than those who were homozygous for Gln27 (86+/-13 percent vs. 54+/-8 percent, P=0.03). CONCLUSIONS: The Arg16 polymorphism of the beta2-adrenergic receptor is associated with enhanced agonist-mediated desensitization in the vasculature, and the Glu27 polymorphism is associated with increased agonist-mediated responsiveness. Therefore, polymorphisms of the beta2-adrenergic receptor are potentially important determinants of the vascular response to stress.

In vivo inhibition of human CYP1A2 activity by oltipraz.

PURPOSE: Oltipraz is currently undergoing clinical evaluation as a cancer chemopreventive agent, especially with respect to aflatoxin-associated hepatocarcinogenesis. The agent's ability to induce phase II xenobiotic enzymes that detoxify the ultimate carcinogen formed in vivo is thought to be an important mechanism by which disease risk may be attenuated. However, an additional mechanism could be a reduction in the activation of environmental procarcinogens by certain cytochrome P450 (CYP) isoforms. This hypothesis was tested with respect to CYP1A2, by using the clearance of caffeine by N-demethylation as a phenotypic trait measurement of the isoform's catalytic activity. METHODS: Subjects received a single oral dose of caffeine (200 mg) on five separate occasions: on the day prior to oltipraz administration (day 0), 2 h after the first (day 1) of eight daily oral doses of oltipraz (125 mg) and 2 h after the last dose (day 8). In addition, CYP1A2 activity was also measured 2 and 14 days (days 10 and 22, respectively) after discontinuation of oltipraz administration. Plasma concentrations of caffeine and its N-demethylated metabolite, paraxanthine, over 24 h after drug administration, were determined by HPLC. RESULTS: A single 125-mg dose of oltipraz markedly reduced CYP1A2 activity by 75 +/- 13% in nine healthy subjects, resulting in a higher caffeine plasma level and prolongation of the in vivo probe's elimination half-life. Daily administration of 125 mg oltipraz for 8 days resulted in further inhibition so that only 19 +/- 13% of the original baseline level of activity was present. However, 2 days after discontinuation of oltipraz treatment, CYP1A2 activity had returned to 66 +/- 33% of its original level and complete recovery was achieved within 14 days of the chemopreventive agent being stopped. CONCLUSIONS: These results demonstrate that oltipraz is a potent, in vivo inhibitor of CYP1A2 in humans and, because this isoform is importantly involved in procarcinogen activation, they also indicate that such inhibition probably contributes to oltipraz's cancer-chemopreventive effect. In addition, the findings also suggest the likelihood of significant drug interactions between oltipraz and drugs whose metabolism is mediated by CYP1A2.

Chronotropic dose response of atropine in Nigerians with congestive heart failure: assessment of ethnic variation and reversibility of parasympathetic dysfunction.

Both ethnicity and disease states may influence cardiac parasympathetic tone. We evaluated the cardiac vagal activity in 9 Nigerians aged 57(11) with congestive heart failure, and 9 age- and sex-matched healthy controls aged 51(11) years, using a cumulative low dose atropine response curve. All subjects demonstrated bradycardia at low doses (100 microg-400 microg) and tachycardia at higher doses (600 microg-1,000 microg). However, both the bradycardic and the tachycardic responses were attenuated in heart failure patients compared to controls: bradycardia -1.1(1.5) beats/min in heart failure patients vs -7.1(2.2) beats/min in controls (P<.01) and tachycardia +4(1.5) beats/min in heart failure patients vs +14.3(3) beats/min in healthy controls (P<.01). EC50 values for brachycardia and tachycardia calculated from the dose response curves were significantly higher in healthy controls compared to heart failure patients, for bradycardia 69(39) microg versus 11(1.6) microg (P<.01) and tachycardia 682(61) microg vs 254(84) microg (P<.01). Treatment of heart failure for 4 weeks with furosemide, digoxin and angiotensin converting enzyme inhibitor (enalapril) caused a significant increase in the magnitude of both the bradycardic responses from -1.1(1.5) beats/min to -4.4(0.9) beats/min after treatment, and tachycardic responses from +4(1.5) beats/min to +10.(2.3) beats/min 4 weeks after treatment (P<.05). After 4 weeks of treatment, EC50 was also increased significantly toward normal values. For tachycardia, the values were 254(88) microg before treatment vs 529(78) microg after treatment (P<.05); and for bradycardia, the values were 2.5(1.6) microg before treatment vs 30(13) microg after treatment (P<.05). These findings demonstrate the early bradycardic effect of atropine in Black Africans (both healthy controls and heart failure patients), contradicting earlier reports of its absence in the negroid race. This confirms the reduction in cardiac parasympathetic responsiveness (both maximal heart rate change and EC50) in hypertensive heart failure using a pharmacological assay. It demonstrates the augmentation and amelioration of cardiac vagal tone with enalapril-dixogin-diuretic therapy in non-ischemic heart failure, and the sequential utility of the low dose atropine-chronotropic response in assessing cardiac parasympathetic activity.

Knowledge, attitude and practice of prednisolone prevention of chloroquine induced pruritus among Nigerian health workers.

Severe generalized pruritus is a common drawback in chloroquine therapy of malaria in black Africans. In a cross-sectional study, we evaluated the knowledge, attitude and practice of 117 Nigerian hospital workers, who historically itch to chloroquine, to the use of prednisolone to prevent chloroquine pruritus in malaria. Ninety per cent of respondents had a positive family history of chloroquine induced pruritus. Seventy-five per cent (92) of the subjects were aware of the anti-pruritic action of prednisolone, but only 43% (n = 40) have ever used it during malaria. Among the prednisolone users (n = 40), 25 (62.5%) had total prevention, 25% (n = 10) had marked pruritus attenuation, but no effect was seen in 12.5% (n = 5). The modal prednisolone dose causing inhibition of itching was 10 mg orally given once. Concurrent prednisolone increased compliance with chloroquine in 68% of all who used the combination, and there was no evidence of malaria recurrence.

Vasodilator therapy of hypertensive acute left ventricular failure: comparison of captopril-prazosin with hydralazine-isosorbide dinitrate.

A prospective study to evaluate and compare the cardiorespiratory effects and clinical efficacy of the Neurohormonal inhibitors (Captopril 50 mg+prazosin 1 mg only) and direct arteriolar and venular dilators (Intravenous hydralazine 30 mg+oral isosorbide dinitrate 30 mg) used as vasodilator therapy, was undertaken in a randomized, single blind study in 17 Nigerian patients with hypertensive acute left ventricular failure. Both vasodilator regimes separately and significantly reduced the systolic and diastolic blood pressures (P<0.001 ANOVA), heart rate (P<0.001 ANOVA), and the respiratory rate (P<0.05 ANOVA), the double product, but increased the peak expiratory flow rate (P<0.05 ANOVA). However, the neurohormonal antagonists, captopril and prazosin (n=9) caused a statistically significantly greater reduction in heart rate (P<0.05 ANOVA) respiratory rate (P<0.05 ANOVA) and induced a significantly greater increase in the self-paced exercise capacity, 24 h after initiation of treatment, (P<0.02) compared to the hydralazine and isosorbide dinitrate combination (n=8). Five of the nine patients on the neurohormonal antagonist therapy were ambulant at 24 h, compared to none of the eight patients receiving conventional venular and arteriolar dilators hydralazine and isosorbide dinitrate (chi2=5.84 dfi P<0.05). There was a significant inverse correlation between the systolic blood pressure heart rate product, and the distance covered during symptom limited self paced exercise capacity (r=-0.58, P=0.0146 ANOVA). One of eight patients in the hydralazine+isosorbide nitrate combination died, but there was no mortality in the captopril+prazosin group. These findings collectively suggest that captopril+prazosin combination may be a superior vasodilator therapy compared to hydralazine-isosorbide dinitrate, in hypertensive acute pulmonary oedema.

Chloroquine-induced pruritus in malaria fever: contribution of malaria parasitaemia and the effects of prednisolone, niacin, and their combination, compared with antihistamine.

AIMS: Chloroquine treatment of malaria fever, results in a generalized pruritus of unknown mechanism in up to 60% of adult Africans, by contrast pruritus is unusual in Caucasians following chloroquine use. METHODS: We conducted a double-blind, randomized, parallel group study to examine and compare the antipruritic effects of promethazine, niacin, prednisolone and their combination on pruritus induced by chloroquine, in 28 historical itching patients with parasitologically proven malaria fever. We also evaluated the role of the antecedent malaria parasite density in the severity of chloroquine pruritus intensity. RESULTS: The concurrent administration of chloroquine (2.1 g base total dose) with prednisolone caused a statistically significant reduction in the pruritus AUC (0, 72 h) (P < 0.001 ANOVA) compared with the antihistamine promethazine alone. The areas under the pruritus intensity-time curve were promethazine 105 +/- 28 (units h), niacin 76 +/- 22, prednisolone 28 +/- 24, and prednisolone and niacin 34 +/- 17 (P < 0.001 ANOVA). The 95% confidence interval for the difference in the pruritus AUC between prednisolone and promethazine was 8.4 to 145.6 units h. There was a statistically significant and positive correlation between the pruritus intensity (AUC 0, 72 h) and the malaria parasite load in the itching subjects, not receiving prednisolone (n = 9) (r = 0.73, P = 0.026 ANOVA). CONCLUSION: A single oral dose of prednisolone (10 mg) may be preferable to the antihistamine promethazine (25 mg) as an antipruritic agent for concurrent prescription with chloroquine in individuals predisposed to severe itching. Malaria parasite clearance and clinical amelioration were unaffected by any of the treatments.

Concurrent alpha 1 adrenergic blockade and angiotensin converting enzyme inhibition in the treatment of congestive heart failure.

We tested the hypothesis that concurrent inhibition of the renin angiotensin system by enalapril (5 mg) and the sympathetic nervous system by alpha 1 adrenergic blockade (prazosin 1 mg) will be superior to enalapril alone in 17 patients with heart failure on standard therapy, in a single blind, placebo-controlled, randomized parallel group study for 4 weeks. Enalapril alone induced a significant increase in exercise time from 499 +/- 412 s to 707 +/- 608 s (P < 0.05, ANOVA), but the increase induced by the enalapril + prazosin combination was significantly greater (P < 0.025, MANOVA) from 214 +/- 271 to 1007 +/- 784 s as was the increase in creatinine clearance (P < 0.05).

An open non-comparative pilot study of the safety and efficacy of oral fluconazole in the treatment of dermatophyte infections in Nigeria

In an non-comparative study to assess the efficacy and safety of oral fluconazole in superficial fungal diseases of the skin; 82 adult Nigerian patients (58 males and 24 females) with clinical and mycological diagnosis of dermatomycoses were enrolled for the trial. Sixty-five patients completed the trial and each of them received a daily dose of 50mg fluconazole for a period of 4 weeks. An overall 90 per cent cure rate was observed in patients with other forms of dermatomycoses and 80 per cent for patients with pityriasis versicolor. The drug was well tolerated by all the patients and very few side effects were noticed