摘要:

We designed a clinical trial to obtain dose‐ranging, efficacy, and aspirin‐withdrawal data on tiopinac in patients with rheumatoid arthritis. To accomplish this without exposing the patients to risk of disease exacerbation and avoiding type II error, we used a 3‐phase protocol adding tiopinac to current therapy. The 3 phases–open‐label dose ranging, double‐blind tiopinac versus placebo, and aspirin withdrawal–began after a single‐blind run‐in period. The manufacturer withdrew tiopinac from investigation because of toxicity at higher doses, but with only 13 patients we found that tiopinac (up to 300 mg/day) decreased walking time, painful joints, and morning stiffness and increased grip strength (p<0.05). Both the global evaluation by the investigators and patient ratings of their activity showed superiority of tiopinac (tiopinac: 5 better, 1 worse: placebo: 1 better, 6 worse; p = 0.028 by Fisher's exact test). Complete aspirin withdrawal could be accomplished in only 3 patients, although in 10 of 13 the dose could be reduced 50% of baseline or less. The 3‐phase protocol indicated effectiveness, a dose range, and partial aspirin replacement with minimal patient risk.Clinical Pharmacology and Therapeutics(1980)27,579–585; do

ISSN:0009-9236    

DOI:10.1038/clpt.1980.82

年代:1980

数据来源: WILEY

摘要:

In a double‐blind crossover study, it has been shown that the hypotensive response to propranolol in 24 patients with essential hypertension was no greater at doses of 80, 160, or 240 mg twice daily than at 40 mg twice daily. A relationship was observed between dose and response as defined by the ability to achieve a standing diastolic blood pressure of 95 mm Hg. Four patients with low plasma renin activity (PRA) had no fall in blood pressure even at highest dose levels. Plasma propranolol levels in the groups were related to dose, and up to a concentration of 300 ng/ml, with degree of β‐adrenoceptor blockade; there was, however, no correlation with hypotensive response.Clinical Pharmacology and Therapeutics(1980)27,586–592; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.83

年代:1980

数据来源: WILEY

摘要:

Three randomized, placebo‐controlled, crossover experimental designs were used to define a suitable interdose interval and to study the adequacy of once‐daily administration for applications in preventive trials on manifest or latent ischemic patients. Suppression of exercise tachycardia was used as the major effect variable. All measurements were made at different intervals after the last dose when the healthy subjects had been treated for at least 1 wk. Reductions of exercise tachycardia were found 24 hr after the last dose for atenolol, metoprolol, Penbutolol, pindolol, propranolol, Sotalol, and timolol. Penbutolol and propranolol induced equal reduction of exercise tachycardia at the end of the dose interval regardless of whether the total daily dose was given once daily or divided in 2 daily doses. Atenolol and Sotalol, both with long half‐lifes (t½s), were not superior to other beta blockers. Neither were slow‐release preparations of metoprolol and propranolol markedly more effective 24 hr after that preparation than after ordinary tablets. Plasma concentration‐time patterns after slow‐release preparations may be important in patients with adverse experiences during peak plasma levels after conventional tablets.Clinical Pharmacology and Therapeutics(1980)27,593–601; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1980.84

年代:1980

数据来源: WILEY

摘要:

The effect of amitriptyline that leads to ventricular tachycardia was evaluated by the repetitive extrasystole threshold (RET) technique in 18 dogs. The RET was 28.8 ± 7.9 mamp before and 8.2 ± 5.3 mamp after amitriptyline, p<0.001. Physostigmine, propranolol, sodium bicarbonate, and left stellate ganglionectomy reversed the effect of amitriptyline on RET. We conclude that amitriptyline overdose predisposes to sudden death by lowering the ventricular fibrillation threshold. This cardiotoxic effect is mediated partly through the central nervous system and can be inhibited by increased plasma binding (bicarbonate), cholinergic stimulation (physostigmine), beta adrenergic blockade (propranolol), and sympathetic denervation (left stellate ganglionectomy).Clinical Pharmacology and Therapeutics(1980)27,602–606; doi:10.1038/clpt.198

ISSN:0009-9236    

DOI:10.1038/clpt.1980.85

年代:1980

数据来源: WILEY

摘要:

The effect of acute methadone withdrawal was studied on PGE1‐sensitive platelet adenylate cyclase of 8 former heroin addicts who had been stabilized with methadone. During acute methadone withdrawal there was a significant increase in PGE1‐sensitive platelet adenylate cyclase activity, which correlated with the severity of withdrawal symptoms. This suggests that PGE1‐sensitive adenylate cyclase and cyclic adenosine monophosphate (cyclic AMP) are involved in the human addictive process.Clinical Pharmacology and Therapeutics(1980)27,607–611; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1980.86

年代:1980

数据来源: WILEY

摘要:

The effects of in vitro carbamylation of plasma with potassium cyanate on drug‐protein binding have been investigated. Potassium cyanate added to samples of normal plasma and incubated for 30 to 150 min induced time‐related plasma protein carbamylation. Carbamylation of plasma did not influence quinidine protein binding, but resulted in decreased salicylate binding. The increased free fraction of salicylate in plasma correlated with the degree of carbamylation of plasma proteins (r = 0.99; p<0.001). Plasma from patients with chronic renal disease showed varying degrees of plasma protein carbamylation, correlating with the values of free plasma salicylate (r = 0.80; p<0.05). Scatchard plots for sulfadiazine binding in plasma from patients with uremia and in normal plasma carbamylated in vitro with potassium cyanate showed changes in the 2 groups when compared with those in normal individuals. If cyanate is produced in vivo from urea in patients with uremia, plasma protein carbamylation may play a role in the decreased plasma protein binding of some acidic drugs.Clinical Pharmacology and Therapeutics(1980)27,612–618; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1980.87

年代:1980

数据来源: WILEY

摘要:

Our purpose was to determine the feasibility of using salicylate (SA) concentrations in saliva as an indirect measure of SA concentrations in serum of children with juvenile rheumatoid arthritis. Sixty‐four paired blood and saliva samples were obtained from 17 children, 4 to 17 yr of age (average, 9 yr), who were receiving aspirin every 8 hr. Serum total (free and bound) SA concentrations ranged from 5 to 36 mg/100 ml. The fraction of free (unbound) SA in serum, determined by equilibrium dialysis against an equal volume of buffer, rose with increasing total SA concentration. SA concentrations in saliva correlated strongly with both free and total SA concentrations in serum. The ratio of SA concentration in saliva to total SA concentration in serum rose with increasing total SA concentration in serum, whereas the relationship between SA concentration in saliva and free SA concentration in serum was essentially linear. However, there was considerable intrasubject variation of the saliva SA to serum free SA concentration ratio that could not be related to fluctuations of saliva pH. Therefore another analysis of the relationship was performed, using areas under the concentration–time curve during a dosing interval (AUCτ), which were determined from 0‐, 2‐, 4‐, and 8‐hr saliva SA and serum free SA concentrations of 12 children. These patients had serum SA concentrations at or near steady state and had provided all 4 pairs of blood and saliva samples during 1 dosing interval. The time‐average saliva SA and serum free SA concentrations calculated from the AUCτvalues are strongly correlated (r = 0.944, p<0.001). The mean saliva SA to serum free SA concentration ratio determined from these data is 0.637. This ratio varied appreciably between patients (coefficient of variation, 24%; range of ratio values, 0.358 to 0.892), which limits the usefulness of salivary SA determinations as a noninvasive indirect method for monitoring serum free SA concentrations in children with juvenile rheumatoid arthritis.Clinical Pharmacology and Therapeutics(1980)27,619–627; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1980.88

年代:1980

数据来源: WILEY

摘要:

Diflunisal protein binding was studied by equilibrium dialysis at 37° in plasma from healthy, uremic, and geriatric subjects. Binding data were computer analyzed assuming 2 classes of independent binding sites (Scatchard model). K1, the primary association constant for the diflunisal‐albumin interaction, was substantially lower in uremic plasma (2.39 ± 0.29 × 105M−1) than in normal plasma (6.86 ± 0.59 × 105M−1). No difference was found between the number of primary diflunisal binding sites (N1) in uremic and normal plasma. In geriatric plasma neither K1nor N1differed from the normal values, indicating that decreased diflunisal plasma protein binding in the elderly is a result of lower plasma albumin concentration. Binding studies with plasma from uremic patients during hemodialysis revealed that free diflunisal rose from 0.46 ± 0.04% at the start to 0.61 ± 0.06% at the end of dialysis. Plasma free fatty acid concentrations rose similarly. In vitro displacement studies showed that oleic acid is a competitive inhibitor for the binding of diflunisal to human serum albumin. This may explain the decrease in diflunisal plasma binding at the end of hemodialysis treatment.Clinical Pharmacology and Therapeutics(1980)27,628–635; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1980.89

年代:1980

数据来源: WILEY

摘要:

The disposition of Captopril, an angiotensin‐converting enzyme inhibitor with antihypertensive properties, was studied in 10 normal male subjects after a single 100‐mg tablet of35S‐labeled drug. Average absorption parameters for unchanged Captopril in blood were Tmax0.93 ± 0.08 hr and Cmax800 ± 76 ng/ml. For total radioactivity in blood the values were Tmax1.05 ± 0.08 hr and Cmax1,580 ± 90 ng/ml (as Captopril equivalents). Because of the curvilinearity of the semilogarithmic plots of blood concentrations of Captopril: time, elimination half‐life (t½) of unchanged drug could not be determined. At 1 hr unchanged Captopril accounted for about 52% of total radioactivity in blood, and the dimeric disulfide metabolite of Captopril accounted for about 10%. In the first 5 days after dosing, an average of about 68% of the radioactive dose was recovered in urine and 18% in feces. The distribution of radioactivity in the first 24‐hr urine sample (66% of the dose) was 58% Captopril (38% of dose), 2% Captopril disulfide (1.5% of dose), and 40% unidentified polar metabolites (26% of dose).Clinical Pharmacology and Therapeutics(1980)27,636–641; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.90

年代:1980

数据来源: WILEY

摘要:

After single doses (100 to 400 µg orally), pergolide, a synthetic ergot, reduced basal plasma prolactin levels in normal subjects in a dose‐related manner. This effect persisted for more than 24 hr. Multiple doses of pergolide (150 to 250 µg daily for 7 days) resulted in a plasma prolactin decrease of more than 80%. A single dose of pergolide (150 µg orally) suppressed plasma prolactin and abolished the plasma prolactin diurnal rhythm, i.e., suppression of sleep‐induced elevation in plasma prolactin during a 40‐hr period. Perphenazine (5 mg intramuscularly)–induced plasma prolactin elevation was inhibited by pergolide; the effect was dose dependent. After single or multiple doses, pergolide had no effect on plasma follicle‐stimulating hormone, luteinizing hormone, Cortisol, growth hormone, and thyroid‐stimulating hormone. Pergolide appears to have specificity at the pituitary level for the dopamine receptors that mediate prolactin secretion.Clinical Pharmacology and Therapeutics(1980)27,642–651; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.91

年代:1980

数据来源: WILEY