摘要:

The combination of hydrochlorothiazide (50 mg daily) and metoprolol (100 to 400 mg daily) reduced erect systolic blood pressure by 23.8 ± 4.0 (SE) mm Hg and erect diastolic pressure by 15.6 ± 2.2 mm Hg in 20 patients with essential hypertension. These decreases were of at least the same magnitude as the sum of the decrements induced by these drugs given separately. The rise in plasma renin activity (PRA) of 5.9 ± 1.2 ng/ml/hr induced by hydrochlorothiazide alone was reversed (p<0.01) by the addition of metoprolol to control levels. Since hypokalemia can stimulate renin release, the absence of decreases in plasma potassium during combination treatment may have enhanced this renin‐lowering effect. These findings appear to emphasize the importance of using relatively small doses of diuretics in combination treatment of hypertension; this approach avoided the countervailing effects of hyperstimulation of the renin‐angiotensin system reported previously, which are not adequately controlled by concurrent β‐blocker treatment. The control PRA tended to be predictive of the response to monotherapy, for it correlated directly (r = 0.52) with changes in diastolic blood pressure induced by hydrochlorothiazide alone and indirectly (r = −0.48) with those induced by metoprolol alone. The algebraic difference between the diastolic pressure decrements induced by metoprolol and hydrochlorothiazide within each patient also correlated with control renin (r = 0.61, p<0.01), suggesting that the β‐blocker is more effective in high‐renin patients and that diuretics work best when renin is low. Black patients had larger decreases in blood pressure than whites on diuretic‐alone.Clinical Pharmacology and Therapeutics(1980)28,149–158; doi:

ISSN:0009-9236    

DOI:10.1038/clpt.1980.144

年代:1980

数据来源: WILEY

摘要:

The β‐blocking potency of timolol was compared with that of propranolol under steady‐state conditions in eight healthy subjects. The effects on systolic time intervals in healthy subjects and patients (n = 6) with coronary artery disease were evaluated in relation to varying timolol dose schedules and plasma concentrations. The β‐blocking potency was assessed by the inhibition of exercise‐induced tachycardia. Timolol was eight times as potent as propranolol. There was wide between‐patient variation (2.6 to 13.8) in timolol plasma concentration, and correlation between dose and peak (r = 0.61, p<0.01) or nadir (r = 0.5, p<0.01). There was a relatively weak correlation between timolol plasma concentration and degree of β‐blockade (r = 0.45, p<0.05) and a linear correlation with dose (r = 0.98, p<0.001). In healthy subjects timolol and propranolol had variable effects on systolic time intervals but in patients with coronary artery disease equipotent doses prolonged the preejection period, isovolumetric contraction time, and the ratio of the preejection period over the left ventricular ejection time. In patients as well as in normal subjects, the data indicated considerable β‐blocking effects for both drugs at the end of a 12‐hourly dosing schedule, suggesting that twice‐daily timolol and propranolol may be clinically practical.Clinical Pharmacology and Therapeutics(1980)28,159–166; d

ISSN:0009-9236    

DOI:10.1038/clpt.1980.145

年代:1980

数据来源: WILEY

摘要:

Five healthy male subjects, aged 26 to 35 yr, received single oral doses of clonidine 0.3 mg, nitrazepam 20 mg, or placebo double‐blind with an interval of at least 1 wk between each treatment. Clonidine induced a maximal fall in systolic blood pressure from 104.2 ± 1.6 to 84.7 ± 1.4 mm Hg (x̄ ± SEM) after 3.5 hr and nitrazepam from 102.9 ± 1.9 to 90.3 ± 2.6 mm Hg after 1.0 hr while after placebo blood pressure rose steadily from 102.5 ± 2.9 to 109.6 ± 3.5 mm Hg at the end of the 8‐hr study. Total sleep time increased from 90.3 ± 25.5 min after placebo to 256.2 ± 21.0 min after clonidine (p<0.001) and 281.0 ± 40.3 min after nitrazepam (p<0.001). Stage I sleep increased from 49.7 ± 11.2 to 76.9 ± 10.2 min after clonidine and to 76.3 ± 25.2 min after nitrazepam (p<0.05), while the greatest increase was observed in stage II: 230.7 ± 25.6 min after clonidine and 236.6 ± 35.4 min after nitrazepam compared with only 48.5 ± 15.8 min after placebo (p<0.001). Plasma norepinephrine did not change after placebo but fell after nitrazepam from 0.28 ± 0.04 to 0.14 ± 0.02 ng/ml after 3 hr (p<0.05) and after clonidine from 0.23 ± 0.07 to 0.07 ± 0.02 ng/ml after 2 hr (p<0.01). clonidine and nitrazepam both induced similar hypnotic and hypotensive effects with some evidence that this might be due to a reduction in sympathetic tone.Clinical Pharmacology and Therapeutics(1980)28,167–176

ISSN:0009-9236    

DOI:10.1038/clpt.1980.146

年代:1980

数据来源: WILEY

摘要:

Lidocaine (L) levels were measured by gas chromatography (GC) and a new technique of direct measurement by enzyme immunoassay (EMIT) in 50 consecutive patients admitted to the Coronary Care Unit who received L. There was no significant difference between the levels by the two techniques. There was eradication of most ventricular arrhythmias in 78% of patients, partial effectiveness in 16%, and no improvement in 6%. Toxicity was mainly mild central nervous system effects, noted in 26 of the 50 patients. All six patients with serum L above 5.9 μg/ml had signs of toxicity. EMIT was found to be accurate and much faster than the traditional GC method.Clinical Pharmacology and Therapeutics(1980)28,177–181; doi:10.1038/clpt.1980.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.147

年代:1980

数据来源: WILEY

摘要:

We studied 10 patients with congestive heart failure to assess the dynamics of their response to 40 mg of furosemide. Patients excreted less sodium than normal controls: 142 ± 36 and 245 ± 16 mEq/4 hr (p<0.05). Patients delivered the same amount of furosemide into the urine—14.9 ± 2.0 and 18.7 ± 2.1 mg/4 hr (p<0.20)—but the time course of delivery differed. Normal subjects had a sigmoid‐shaped curve when furosemide excretion rate was related to response. All patients but one had shifts in this curve and for a number of patients the configuration differed substantially from a sigmoid curve.Clinical Pharmacology and Therapeutics(1980)28,182–186; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1980.148

年代:1980

数据来源: WILEY

摘要:

To evaluate the interaction of secobarbital with racemic warfarin or R,S(±)‐warfarin, S(−)‐warfarin was synthesized with13C‐label in the 2‐position of the coumarin nucleus and added to12C‐R(+)‐warfarin to form a12C‐/13C‐warfarin pseudoracemate. Six normal subjects received 1.5 mg/kg of this “cold‐labeled” pseudoracemate. It was given with and without a daily oral dose of secobarbital, 100 mg, beginning 7 days before the warfarin and continuing throughout the hypoprothrombinemia. Plasma samples were obtained daily and analyzed for warfarin and for one‐stage prothrombin activity. Unchanged warfarin in plasma was fractionated by forward‐phase high‐pressure liquid chromatography, and enantiomorphic ratios were determined by chemical ionization–mass spectrometry with pentadeuterio‐warfarin as the internal standard. There was a reduction of the hypoprothrombinemia of the pseudoracemate during the secobarbital regimen over that on warfarin alone (p<0.001). There was an increase in plasma clearance of R‐warfarin (p<0.05) and an increase in plasma clearance of S‐warfarin (p<0.003) during the secobarbital regimen over that on warfarin alone. It was concluded that secobarbital diminished the hypoprothrombinemia of pseudoracemic warfarin by increasing plasma clearance of the more hypoprothrombinemic S‐warfarin and by increasing plasma clearance of the less hypoprothrombinemic R‐warfarin.Clinical Pharmacology and Therapeutics

ISSN:0009-9236    

DOI:10.1038/clpt.1980.149

年代:1980

数据来源: WILEY

摘要:

Our subjects were 15 young (aged 22 to 42 yr) and 14 elderly (aged 62 to 85 yr) people who took single oral doses of 20 mg prazepam. Plasma desmethyldiazepam (DMDZ) concentrations were determined in venous blood samples drawn up to 9 days after the dose. Appearance in blood of DMDZ was slow, with peak plasma levels reached in an average of 10 to 20 hr. First‐order DMDZ appearance was observed in only 17 subjects. Volume of distribution of total DMDZ (range, 1.33 to 6.30 l/kg) and of unbound DMDZ after correction for protein binding (range, 43 to 243 l/kg) was larger in women than in men of all ages, and in the elderly as opposed to the young. Elimination half‐life (range, 29 to 224 hr) rose with age in men (r = 0.66, p<0.01) but not in women (r = −0.02). Clearance of unbound DMDZ (range, 2.9 to 31.2 ml/min/kg) was greater in women than in men of all ages, and declined with age in men (r = −0.40) but not in women (r = −0.06). As in the case of diazepam, age can influence DMDZ kinetics, but changes in drug disposition with age may differ between sexes.Clinical Pharmacology and Therapeutics(1980)28,196–202; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1980.150

年代:1980

数据来源: WILEY

摘要:

In a randomized crossover study, five normal subjects were given 250‐mg capsules of tetracycline at weekly intervals with cimetidine 300 mg, sodium bicarbonate 2 gm in water, magnesium–aluminium hydroxide gel 30 ml, or water alone. Gastric pH was monitored by radiotelemetry. Antibiotic bioavailability as measured by area under the serum level–time curve, peak serum level, and urinary elimination was not affected by cimetidine or sodium bicarbonate. Magnesium–aluminum hydroxide gel reduced bioavailability by 90%. The data show that gastric pH does not affect absorption of oral tetracycline and that cimetidine can be used in place of antacids to control gastric acid in patients using tetracycline.Clinical Pharmacology and Therapeutics(1980)28,203–207; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1980.151

年代:1980

数据来源: WILEY

摘要:

Kinetics of lidocaine (L) and indocyanine green (ICG), substances with a high hepatic extraction ratio, was studied in 9 normal subjects (4 smokers and 5 nonsmokers) and in 6 patients with chronic type B hepatitis without portal hypertension. L metabolism was studied in each subject after intravenous and oral administration. The data were used to calculate L systemic and oral clearances, L systemic bioavailability, and apparent hepatic blood flow. In smokers, L systemic bioavailability was decreased secondary to a marked increase in oral clearance, reflecting induction of drug‐metabolizing activity. In patients with chronic hepatitis, L systemic and oral clearances were higher than in the normal. These findings indicate that hepatic handling of drugs with a high hepatic extraction ratio, such as L, might be enhanced in patients with chronic type B hepatitis. L disposition approach was validated in 5 patients by comparing results with those using the ICG clearance and extraction method at the time of hepatic vein catheterization. The L systemic bioavailability after oral administration is a reflection of first‐pass clearance by the liver and might be a useful kinetic method for evaluating overall ability of the liver to remove drugs with high hepatic extraction ratios.Clinical Pharmacology and Therapeutics(1980)28,208–215; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1980.152

年代:1980

数据来源: WILEY

摘要:

While severe nephrotoxicity is uncommon during gold therapy of rheumatoid arthritis (RA), the prevalence of mild nephrotoxicity has not been investigated. To study this, levels of leucine aminopeptidase (LAP) andN‐acetyl‐β‐glucosaminidase (NAG) (nmole/hr/mg urinary creatinine), and β2microglobulin (β2M) (μg/mg urinary creatinine) were measured in urine samples from 33 patients with RA receiving gold and 28 patients with various musculoskeletal diseases not receiving gold. Each patient had a normal urinalysis and blood urea nitrogen or serum creatinine. LAP was above 30 in 55% of RA patients and 7% of controls (p<0.01). NAG was above 100 in 70% of RA patients and 14% of controls (p<0.01). In 8 RA patients, NAG was over 200; LAP was over 100 in 4, but in none of the controls. β2M was above 0.32 in 7 of 23 female RA patients and in none of 12 female controls (p = 0.012) and none of the male patients. Patients who excreted high levels of β2M also excreted high levels of NAG and LAP. These data show that gold in therapeutic doses affects renal tubular cells, causing the release of NAG and LAP from lysosomes and brush borders of the cells. This may represent the mildest stage of nephrotoxicity. Elevated β2M in the urine of some patients indicate a degree of nephrotoxicity sufficient to cause renal tubular dysfunction.Clinical Pharmacology and Therapeutics(1980)28,216–222; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1980.153

年代:1980

数据来源: WILEY