HLA-A, -B, -DR and -DQ antigens in black patients with infective endocarditis.

In order to determine if genetically determined immune response factors could play a role in the pathogenesis of infective endocarditis in black patients, we performed HLA-A and HLA-B typing in 38 patients with this disease and HLA-DR and HLA-DQ typing in 33 and 27 of these individuals, respectively. HLA typing was also carried out in a control group of normal black adults. The HLA typing was done by means of a standard microlymphocytotoxicity test. No difference in HLA-A, HLA-B, HLA-DR and HLA-DQ antigen frequencies between patients and controls were noted. This study did not provide any evidence that genetic factors could contribute to a disposition to infective endocarditis.

HLA-A, B, DR, and DQ antigens in Indian patients with severe chronic rheumatic heart disease.

To determine whether genetic factors could be involved in the pathogenesis of rheumatic heart disease, we performed HLA-A and HLA-B typing in 59 Indian patients with severe chronic rheumatic heart disease requiring cardiac surgery, and HLA-DR and HLA-DQ typing in 58 of these patients. The HLA typing was done by a standard microlymphocytotoxicity method. Patients were 12 to 59 years old (mean 32.9 years). No significant differences in HLA-A, HLA-B, HLA-DR and HLA-DQ frequencies between patients and controls were noted. The role of genetically determined immune-response factors in the pathogenesis of chronic rheumatic heart disease was not evident in this study.

Intravenous isradipine in the management of severe hypertension in pregnant and nonpregnant patients. A pilot study.

To determine the appropriate dosage regimen of isradipine in black patients with severe hypertension of pregnancy, 10 patients (gestational age, 30 to 38 weeks; diastolic blood pressure [DBP], 110 to 148 mm Hg; no hypertensive crises; and normal central venous pressure) were given an isradipine infusion while the fetal heart rate was continuously recorded using a cardiotocograph. The infusion rate of isradipine was adjusted at regular intervals until control (DBP < 95 mm Hg) was achieved. The optimal dosage regimen in black patients was found to be an initial dose of 0.15 micrograms/kg/min, with increments of 0.0025 micrograms/kg/min every 15 min until control is achieved. Thereafter, a maintenance infusion of 0.15 micrograms/kg/min can be commenced. This dosage regimen is associated with neither maternal hypotension nor fetal heart rate deceleration. A second group of 10 patients (9 men and 1 woman) with DBP > 115 mm Hg (range, 117 to 135 mm Hg) and no features of hypertensive crises were also studied. The optimal dosage regimen in this patient group differed from the other in two respects: dosage increments could be made more rapidly (at 10-min intervals); and the dosage that produced blood pressure control needed to be continued for 30 min before the maintenance infusion was commenced. This regimen was not associated with hypotension.

Intravenous isradipine in the management of severe hypertension of pregnancy in black patients: a pilot study.

The ideal antihypertensive agent for lowering very high blood pressure levels rapidly in severe hypertension of pregnancy still eludes researchers. This pilot study was conducted to determine the appropriate dosage regimen for isradipine in black patients with severe hypertensive disorders of pregnancy. Ten black patients with gestational age > or = 30 (range 30-38) weeks and diastolic blood pressure (DBP) > or = 110 (range 110-148) mmHg following 2 h of bed rest were recruited following informed consent. None of the patients had symptoms or signs of hypertensive crisis. After correction of hypovolaemia (using central venous pressure monitoring) with Ringer's lactate, high blood pressure was lowered by an isradipine infusion. Fetal heart rate was continuously recorded using a cardiotocograph. All blood pressure measurements were made using the same mercury sphygmomanometer by a single observer. The infusion rate of isradipine was adjusted at regular intervals until blood pressure control (DBP < 95 mmHg) was achieved. The optimal dosage regimen in black patients was found to be an initial dose of 0.15 microgram kg-1 min-1 with increments of 0.0025 micrograms kg-1 min-1 every 15 min until blood pressure control is achieved. Thereafter, a maintenance infusion of 0.15 microgram kg-1 min-1 can be initiated. This dosage regimen is associated with neither maternal hypotension nor fetal heart rate deceleration.

Randomised double-blind comparative study of efficacy and safety of hydroflumethiazide and reserpine and chlortalidone and atenolol in the treatment of mild to moderate hypertension in black patients.

This randomised, double-blind study compared the efficacy and safety of a fixed combination of hydroflumethiazide 50 mg and reserpine 0.125 mg (H-R) and chlortalidone 12.5 mg and atenolol 50 mg (C-A) in adult black patients with mild to moderate hypertension (a resting supine diastolic blood pressure (DBP) between 95 and 115 mmHg after a two week placebo washout period). If the DBP did not reach 90 mmHg after four weeks, the dosage was doubled. There were 27 patients in the H-R group and 22 in the C-A group who completed the study. In the H-R group, supine systolic and diastolic BP were reduced from 156.5 (95% confidence intervals 150.1-162.9) and 102.0 (97.5-106.5) mmHg to 137.0 (130.6-143.4) and 87.4 (83.0-91.9) mmHg, respectively. The corresponding values in the C-A group were 154.1 (147.0-161.2) and 103.4 (98.5-108.4) mmHg to 136.4 (129.3-143.5) and 91.2 (86.2-96.1) mmHg, respectively. Normalisation, response and control of DBP was achieved in 88.9, 92.6 and 100% of patients, respectively, in the H-R group, and in 81.8, 95.5 and 95.5% of patients in the C-A group, respectively. The dose was doubled in 14.8% of patients on H-R and 40.1% on C-A. No clinically significant abnormalities in laboratory variables and no serious adverse effects were encountered. Both drugs have been shown to be efficacious and safe in the treatment of mild to moderate hypertension in black patients.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparative study of isradipine SRO and enalapril in black patients with mild-to-moderate hypertension.

Fifty-two black men who had supine diastolic blood pressures (DBP) above 95 mm Hg at the end of a 2-week placebo wash-out period were randomized to receive either isradipine SRO at 2.5 mg/day or enalapril at 10 mg/day for 8 weeks. After 4 weeks, the dosages were doubled if DBP remained above 90 mm Hg. Reductions in blood pressure were comparable in both groups. Mean supine DBP was reduced from 100.6 to 93.9 mm Hg in the isradipine-treated group, and from 103.9 to 98.2 mm Hg in the enalapril-treated group. At the end of the study, 24/27 patients were taking 5 mg isradipine SRO once daily, and 20/25 patients were taking 20 mg enalapril once daily. There were no serious adverse events. The results of this study indicated that monotherapy with isradipine SRO at the recommended initial dosage of 5 mg once daily is appropriate in black patients with hypertension. This was, however, not the case with enalapril at 10 mg once daily. The concurrent administration of a diuretic with enalapril may be more appropriate.

A comparison of the acute hypotensive effects of two different doses of nifedipine.

To determine whether a dose of 5 mg of nifedipine would be useful in the treatment of hypertensive emergencies, we compared the acute hypotensive effects of two different doses of nifedipine, 5 mg and 10 mg, in patients with severe hypertension. In this prospective, randomized, double-blind study, 30 consecutive black patients with diastolic blood pressure that was equal to or greater than 115 mm Hg received either a 5 mg or 10 mg nifedipine capsule and a placebo capsule, which matched that of the alternative strength. Patients were asked to bite the capsules and swallow the contents. Blood pressure response over 4 hours and adverse effects were monitored. Mean systolic blood pressure was reduced from 191.7 mm Hg (95% confidence interval 170.8 to 212.7 mm Hg) to 157.9 mm Hg (137.0 to 178.9 mm Hg) and 206.1 mm Hg (185.1 to 227.0 mm Hg) to 153.7 mm Hg (132.8 to 174.7 mm Hg) in patients who were given 5 mg and 10 mg doses of nifedipine, respectively. Mean diastolic blood pressure in the group of patients that received 5 mg doses of nifedipine decreased from 128.2 mm Hg (115.6 to 140.7 mm Hg) to 105.2 mm Hg (92.7 to 117.7 mm Hg); the corresponding values in the group that received 10 mg doses of nifedipine were 129.9 mm Hg (117.4 to 142.5 mm Hg) and 97.5 mm Hg (85.0 to 110.1 mm Hg), respectively. The minimum mean systolic blood pressures occurred 20 and 25 minutes after administration of the 5 mg and 10 mg capsules, respectively; the minimum diastolic blood pressures were reached after 20 and 30 minutes, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of angiotensin-converting enzyme inhibitors on urinary excretions: interactions with diuretics.

The excretions of urinary sodium, potassium, magnesium, urate, and water after dosing with diuretics or the angiotensin-converting enzyme inhibitor perindopril are reported, as well as the results of other recent studies. Perindopril in low dose had no significant effect on any of these 24-hour urinary excretions and in high dose, in contrast to captopril and enalapril, does not increase magnesium loss. These effects were studied in healthy volunteers, which may not reflect urinary excretions in hypertensive patients.

Isradipine in the treatment of mild to moderate essential hypertension.

Male patients with supine diastolic blood pressures above 95 mmHg after placebo therapy received twice daily isradipine (Dynacirc; Sandoz) 1.25, 2.5 or 5.0 mg for 12 weeks. Blood pressures were measured every 14 days. Doses of 2.5 or 5 mg isradipine twice daily significantly reduced supine and erect mean systolic, mean diastolic and mean arterial pressures. Isradipine 1.25 mg twice daily reduced supine mean diastolic and mean arterial pressures only. A dose of 5 mg twice daily was accompanied by an increase in adverse reactions. The recommended dose of isradipine is 2.5 mg twice daily.

Time course of the blood pressure response to oral isradipine in uncomplicated mild-to-moderate essential hypertension.

Forty-five patients with supine diastolic blood pressures (DBPs) above 95 mm Hg at the end of a four-week placebo run-in period were randomized to receive either 1.25 mg, 2.5 mg, or 5 mg isradipine twice daily as monotherapy for 12 weeks. Blood pressures (BP) were measured every 14 days, always by the same observer and using standard techniques. The Montevideo Mathematical Model was used to determine the time course of the response to treatment in each dosage group. Of the 33 patients who completed the study, four of the 12 patients receiving 1.25 mg isradipine twice daily had their BP controlled by weeks 10 or 12 (supine DBP less than or equal to 90 mm Hg), seven of 11 by 2.5 mg twice daily, and five of 10 by 5 mg twice daily. Mean DBPs for each dosage group were significantly reduced by week 12 (P less than .015 in all groups). The Montevideo Model allows estimation of the time after onset of treatment by which BP is reduced by a given amount. This model indicated that, with 2.5 mg isradipine twice daily, a fall in mean arterial pressure of 10 mm Hg is to be expected within three weeks of initiating drug administration.

Renal excretory actions of furosemide, of hydrochlorothiazide and of the vasodilator flosequinan in healthy subjects.

The responses of urine and urinary solute outputs and flows to single doses of 80 mg furosemide, 25 mg hydrochlorothiazide, and 100 or 200 mg flosequinan were investigated in healthy subjects using a double-blind, randomized, crossover design. Treatment days were separated by 7 days. Volumes of urine passed between 0 and 3, 3 and 6, 6 and 9, 9 and 12, and 12 and 24 h after drug administration were determined and urinary concentrations of chloride, sodium, potassium, calcium, magnesium, phosphate, zinc, urate, urea and creatinine were measured. Venous blood was taken before and 6 and 24 h after dosing and the serum was analysed for the same solutes as urine. Excretions of urine and urinary solutes accumulated at the end of each collection period after each formulation were fitted by the UY function, whose derivative provided corresponding flows as functions of time. Instantaneous renal clearances of solutes 6 and 24 h after dosing were evaluated from the flows. This approach showed that 80 mg furosemide and 25 mg hydrochlorothiazide were equipotent 24-h natriuretics. Rapid urinary responses which then rebounded compared with the control responses were produced by 80 mg furosemide, whereas changes after 25 mg hydrochlorothiazide were smooth. Neither 100 or 200 mg flosequinan showed any important effect on urinary excretion.

Diltiazem compared with hydrochlorothiazide in the treatment of mild-to-moderate essential hypertension.

The efficacy of diltiazem (DTZ) (Tilazem; Parke-Davis) 90-180 mg twice daily was compared with that of hydrochlorothiazide (HCT) 25-50 mg once daily in the monotherapy of mild-to-moderate essential hypertension using a double-blind, double-dummy technique. Twenty-nine patients were randomly assigned to two groups and after a 4-week placebo period treated with HCT 25 mg once daily or DTZ 90 mg twice daily for 12 weeks. Dosage was doubled at week 8 in non-responders. Cross-over of therapy took place after a 4-week placebo washout. Both drugs effectively reduced raised arterial pressures with little change in pulse rate. HCT caused a slight elevation of the mean serum urate level. The study confirms that diltiazem offers an effective well-tolerated monotherapy for essential hypertension.

Comparative antihypertensive effects of ketanserin and a ketanserin-hydrochlorothiazide combination administered once daily.

The effects of monotherapy with once-daily ketanserin (40 mg) were compared to those of ketanserin (40 mg) plus hydrochlorothiazide (25 mg) once daily in 21 patients with mild essential hypertension. After a placebo run-in period of 4 weeks, medication was randomly allocated. The study was double-blind and the double-dummy technique was used. The measurements of blood pressure during the 3-month treatment period showed a tendency for progressive decreases of the variable. Supine and erect blood pressure mean values were significantly reduced, between pretreatment and the end of week 12, by 17 and 12 mm Hg with ketanserin therapy and by 19 and 16 mm Hg with combination treatment, respectively. A mathematical model used for studying the evolution of erect diastolic blood pressure over time revealed that the combination lowered blood pressure at a higher rate than did ketanserin alone in the first week of treatment, but that thereafter the velocity of change was higher for ketanserin alone. Both treatments had equally effective antihypertensive effects after 12 weeks, although differences existed in the time courses of blood pressure changes. More prolonged studies are required in order to distinguish further between the medications used.

Effects of single doses of two antihypertensive rauwolfia-diuretic combinations on urinary excretion.

In a double-blind placebo-controlled investigation, 14 healthy adult male volunteers were studied to assess and compare the urinary effects of acute single doses of two antihypertensive formulations containing: hydroflumethiazide 50 mg, Rauwolfia serpentina 50 mg and potassium chloride 625 mg (HFRK) (Rautrax-50; Squibb Laboratories); and clopamide 5 mg, reserpine 0.1 mg and dihydroergocristine 0.5 mg (CRE) (Brinerdin; Sandoz Products). Both significantly increased mean 24-hour urinary outputs of fluid, Cl-, Na+, K+ and Mg2+. CRE increased creatinine and decreased Ca2+ output. After dosing, times to maximal urinary flow of fluid, Cl-, Na+, Ca2+ and creatinine were shortened by HFRK and CRE and those corresponding to K+, Mg2+, phosphate and urate were unaffected. Both formulations thus acted mainly through their diuretic constituents.

Antihypertensive effects of acebutolol plus hydrochlorothiazide and hydrochlorothiazide alone in black patients.

Fifty black (Zulu) men, aged 20-60 years, with mild-to-moderate essential hypertension participated in a double-blind randomized parallel-group study lasting 12 weeks. Study drugs were acebutolol 200 mg plus hydrochlorothiazide 12.5 mg (Secadrex; Maybaker) (SDX) or hydrochlorothiazide 25 mg (HCT) given as a single tablet once daily under supervision. Following a 4-week washout period and after protocol exclusions and withdrawals, a total of 37 patients took the active preparations for 6 weeks, 33 for 7 weeks and 32 for 8 weeks. Of 17 patients treated with SDX, 16 responded satisfactorily; 20 patients were treated with HCT and 18 responded satisfactorily. No important biochemical or haematological changes occurred and no serious adverse reactions were noted. Mild-to-moderate essential hypertension was effectively controlled in a significant proportion of both treatment groups.

Effects of an acebutolol-hydrochlorothiazide combination on urinary solute excretion in healthy adults.

Ten healthy adult male volunteers were studied to assess the urinary effects of a single dose of a combination of hydrochlorothiazide 12.5 mg and acebutolol 200 mg (HZAL). The formation induced a significant increase in the 24-hour urinary output of sodium. Outputs of fluid, chloride, potassium, calcium, magnesium, zinc, total inorganic phosphate and creatinine were unaffected. With the exception of Mg2+ flow, times to maximal urinary flows of fluid and solutes were shortened by HZAL. These qualitative changes resemble those induced by hydrochlorothiazide but did not achieve quantitative significance, either because the constituent diuretic dose was too small or because acebutolol compensated for some of its effects.

The effects of single doses of muzolimine upon urinary solute and fluid excretion.

The natriuretic effect of many loop diuretics is followed by an important decrease - rebound undershoot - in renal Na+ excretion, which is accompanied by thirst and fluid reposition. Also most loop diuretics increase K+ and Mg2+ urinary outputs, thus leading to somatic depletion of these cations and subsequent cardiac arrhythmias. The objectives of the present study were to describe the urinary outputs and flows of several solutes after various doses of muzolimine. Experiments were carried out in ten healthy adult volunteers given monodoses of placebo and of muzolimine 20, 30 and 40 mg on separate days and in random order. Urine collected at 3, 6, 9, 12 and 24 h after dosing was analysed for solutes. Muzolimine 20 mg did not increase mean 24 h urinary Na+ output significantly with respect to placebo. Muzolimine 30 mg exerted maximal diuretic, chloriuretic and natriuretic effects, while not affecting the mean 24 h urinary outputs of K+ and Mg2+ significantly. Muzolimine 30 mg caused a small undershoot in urinary Na+ flow after completion of its natriuretic effect. Muzolimine 30 mg should be considered a first choice loop diuretic since it only causes a mild post-natriuretic undershoot and does not increase urinary Mg2+ output significantly.

Effects of captopril, hydrochlorothiazide, and their combination on timed urinary excretions of water and solutes.

The effects of single doses of captopril 100 mg, hydrochlorothiazide 25 mg, and a combination of both on 24-h outputs of fluid and several solutes were compared in healthy volunteers. Thirteen subjects were studied in a metabolic ward under strictly controlled conditions. Single doses of placebo, captopril, hydrochlorothiazide, and a combination of captopril and hydrochlorothiazide were given double-blind in random order on 4 separate days. Urine was collected at regular intervals for 24 h after medication. The combination of captopril and hydrochlorothiazide and hydrochlorothiazide alone significantly increased the 24-h urinary outputs of Cl-, Na+, fluid, and K+ compared with placebo and also accelerated the corresponding urinary flows. Captopril did not change the 24-h urinary excretions of Cl-, Na+, fluid, and K+ significantly, though it advanced the time courses of their urinary flows. All medications significantly increased the 24-h renal outputs of Mg2+ and creatinine. Captopril significantly increased the 24-h urinary output of urate and advanced its urinary flow. Hydrochlorothiazide significantly decreased the output and retarded the flow. The combination of captopril and hydrochlorothiazide did not change the 24-h urinary output and retarded its flow. It is concluded that the renal excretory actions of captopril are more prolonged than the plasma levels of the drug would indicate. Captopril has diuretic effects which may vary in potency with aldosterone concentrations and uricosuric properties unrelated to aldosterone status.

Effects of hydrochlorothiazide plus sotalol on acute urinary electrolyte excretion in normal subjects.

Twenty-four-hour urinary outputs, total volume and urinary chlorine (Cl), sodium (Na), potassium (K), calcium, magnesium (Mg), total inorganic phosphate and creatinine levels were measured in 12 biologically equivalent healthy volunteers given single oral doses of placebo, hydrochlorothiazide (HCTZ) 50 mg and a combination of HCTZ and sotalol (STL) 320 mg in a double-blind, random study. HCTZ and HCTZ + STL increased urinary volume and Na, K, Cl, phosphate and Mg levels significantly and to a similar extent. Since HCTZ causes hyperkaliuresis and hypermagnesiuresis with or without simultaneous administration of STL, the latter does not change the acute effects of HCTZ in healthy subjects.