摘要:

Since the modern era of drug regulation began in the early 1960s, fewer new drugs have been approved for marketing in the United States than in the United Kingdom. We examined whether information can be obtained about the relative safety of higher and lower introductory rate policies by comparing each country's record of drugs that have been discontinued (removed from the market, withdrawn, or whose licenses were allowed to lapse) while a question of safety existed. We have compiled a list of both older (approved before 1964) and newer (approved in 1964 or later) chemical entities discontinued in the last two decades. With the aforementioned broad criteria to define “discontinuation,” and to assess whether a question of safety was involved, our study showed that a total of 24 chemical entities have been discontinued in the United States or the United Kingdom. Nearly half (10 drugs) were products that had been approved in both countries, while the remainder (drugs that had been exclusively available in one country or the other) consisted of four drugs in the United States and 10 in the United Kingdom. Among the drugs introduced during the last two decades, five have been discontinued in the United States and eight in the United Kingdom. Each country's record of discontinuations has been remarkably similar for drugs introduced after 1974: Four have been discontinued in the United States and three in the United Kingdom. Since drugs discontinued while a safety question existed represent only 2% of the new chemical entities introduced, it appears that drugs that reach the market under the prevailing regulatory systems are seldom associated with unacceptable toxicity.Clinical Pharmacology and Therapeutics(1984)35,559–567; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.78

年代:1984

数据来源: WILEY

摘要:

In 15 normal men, Cimetidine taken orally in a dose of 300 mg twice a day for 3 days reduced to similar extents the rate constants for formation (ki) of the three principal metabolites of antipyrine (AP): 29.9% ± 8.5% (X̄± SD) for 4‐hydroxyantipyrine (4‐OH‐AP); 28.3% ± 6.3% for 3‐hydroxymethylantipyrine (3‐OHM‐AP); and 22.4% ± 5.6% for N‐demethylantipyrine (NDM‐AP). AP clearance declined 24.3%; AP salivary t½ rose 33%; and corrected AP apparent volume of distribution was unchanged. In one apparently normal subject, however, kis for formation of 3‐OHM‐AP and NDM‐AP rose after Cimetidine even though AP clearance declined 19.7%. This surprising result, which suggests that Cimetidine can exert an inductive effect on the hepatic mixed‐function oxidases of some subjects, was checked by restudying the individual. Very similar values occurred on repetition. The average increase in kis for NDM‐AP and 3‐OHM‐AP was 172.2% and 34.0%. These unusual results in this subject indicate that at least two distinguishable forms of cytochrome P‐450 participate in AP metabolism in man. Cimetidine appeared to reduce the amount of AP absorbed from the gut in 10 of our 15 normal subjects.Clinical Pharmacology and Therapeutics(198

ISSN:0009-9236    

DOI:10.1038/clpt.1984.79

年代:1984

数据来源: WILEY

摘要:

Tricyclic antidepressants (TADs) are known to antagonize the hypotensive and sedative actions of Clonidine. We compared the effects of bupropion and Imipramine pretreatment on the acute hypotensive and sedative actions of Clonidine in eight normotensive male subjects in a randomized, double‐blind crossover study. Pretreatment with bupropion, 100 mg by mouth three times a day for 9 days, had no effect on baseline supine blood pressure (BP) and heart rate (HR) and did not modify the hypotensive, bradycardic, and sedative actions of Clonidine. Imipramine, 25 mg by mouth three times a day for 9 days, increased supine and standing HR and decreased standing systolic BP. In half the subjects the hypotensive action of Clonidine was reduced 40% to 50% by Imipramine. The specific binding of3H‐yohimbine to α2‐receptors of platelet membranes was not affected by pretreatment with either antidepressant. In spontaneously hypertensive rats, 16 days of bupropion, 25 mg/kg subcutaneously, had no effect on baseline BP and HR and did not antagonize the hypotensive and bradycardic effects of Clonidine, 5 mg/kg iv. Pretreatment with desipramine, 5 mg/kg subcutaneously for 16 days, accelerated baseline HR and reduced cardiovascular actions of Clonidine. These observations suggest that not all antidepressants antagonize the effects of Clonidine. If the negative interaction between TADs and Clonidine is a result of sensitivity of α2‐receptors, these receptor changes are not the common denominator of antidepressant activity and may only be seen with TADs.Clinical Pharmacology and Therapeutics(1984)35,576–584; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1984.80

年代:1984

数据来源: WILEY

摘要:

The disposition of salicylic acid (SA) and its metabolites and the clinical response to long‐term aspirin treatment at varying doses were assessed in patients with rheumatoid disease. Steady‐state kinetics of SA (total and unbound), salicyluric acid (SUA), gentisic acid (GA), and clinical status were estimated weekly in 10 patients with rheumatoid arthritis. Eight received a soluble aspirin form and two received an enteric‐coated form. The starting dose of aspirin in each patient was 1.8 gm (soluble) or 1.95 gm (enteric‐coated) daily. Weekly increments in dose were made until a satisfactory clinical outcome was achieved. The final aspirin dose range was 3.6 to 8.1 gm daily, which resulted in mean steady‐state plasma SA concentrations (CpSA) from 56 to 375 mg/l. Since the mean total CpSAincreased approximately proportionately over the dose range, there was little change in total SA clearance. By contrast, increasing aspirin dosage resulted in decreased clearance and disproportionate increases in unbound SA (CpuSA). The maximum velocity of conversion of SA to SUA (Vm) increased significantly, from 57.3 ± 11.7 mg/hr at an aspirin dose of 1.8 gm/day to 71.4 ± 19.4 mg/hr at the next highest dose (2.7 to 3.6 gm/day), with no further change with increasing dosage. Km ranged from 0.4 to 1.2 mg/l for CpuSAand from 5.5 to 17.2 for total CpSA. Renal clearance of SUA (CISUA) ranged from 124 to 893 ml/min and correlated with creatinine clearance. ClGAranged from 23 to 164 ml/min, and ClSAranged from 0.1 to 17.1 ml/min; neither correlated with creatinine clearance. The fraction of CpuSUAranged from 20% to 75% and correlated with the fraction of CpuSA. There was a significant improvement in the patients' clinical status with rising CpSA. Disposition of salicylate and metabolites does not appear to differ in patients with rheumatoid disease from that in healthy subjects.Clinical Pharmacology and Therapeutics(1984)35,585–593; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1984.81

年代:1984

数据来源: WILEY

摘要:

Xamoterol is a new orally active partial β‐adrenoceptor agonist. Its kinetics, hemodynamic and metabolic effects, and cardioselectivity were investigated in eight normal subjects. Plasma xamoterol concentrations after 100 µg/kg iv declined biexponentially over 8 hr and t½β averaged 2.6 hr. Resting heart rate (HR) increased slightly in the supine position but was unchanged on sitting. Systolic blood pressure (SBP) rose by 5 to 10 mm Hg and cardiac index (CI) rose 15% to 20%. Both parameters were above control values 6 hr after dosing, when plasma xamoterol concentrations had fallen to about 10 ng/ml. There were no changes in diastolic or mean arterial pressure (MAP). During graded exercise the effects of xamoterol on HR and SBP were the reverse of those at rest, with lowering of exercise HR and SBP at higher work loads. CI during exercise was not altered by xamoterol. Doses of xamoterol were calculated from the kinetic data to give plasma concentrations of 100, 200, 400, and 800 ng/ml. HR and blood pressure effects at each xamoterol level were compared before and after inhibition of cardiovascular reflexes with prazosin, atropine, and Clonidine. Hemodynamic effects of xamoterol and isoproterenol were compared. Before autonomic block xamoterol increased HR by 10 bpm and MAP by 7 mm Hg at the highest dose. After autonomie block there was a 200% to 300% rise in HR at each dose and MAP still rose. The rise in MAP after block could be entirely accounted for by a 23% increase in CI because total peripheral resistance did not change. The effects of isoproterenol after autonomic block were a rise in HR and a fall in MAP. Metabolic responses to xamoterol were measured at the four dose levels. There was a dose‐related increase in nonesterified fatty acids and a fall in plasma lactate levels but no changes in plasma renin activity or blood glucose. Results suggest that xamoterol is a cardio selective partial β‐adrenoceptor agonist in man.Clinical Pharmacology and Therapeutics(1984)35,594–603; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1984.82

年代:1984

数据来源: WILEY

摘要:

The antihypertensive effects of guanfacine (0.5 to 4 mg daily) were investigated for 1 yr in 13 patients with essential hypertension. Blood pressure (BP) and heart rate (HR) response was measured during isometric exercise (handgrip) before starting the therapy, after 1 yr of treatment, and 2 wk after withdrawal. Guanfacine in once‐daily dosage reduced BP during rest (supine BP: control, 175 ± 6/103 ± 4 mm Hg; 1 yr guanfacine, 161 ± 5/91 ± 3 mm Hg). Steady‐state plasma concentrations after 1 yr were 4.1 ± 0.59 ng/ml. Resting plasma norepinephrine (NE) and epinephrine (E) levels were lower during active therapy than 2 wk after withdrawal (guanfacine and control: plasma NE, 0.27 ± 0.03/0.64 ± 0.13 ng/ml; plasma E, 0.09 ± 0.02/0.17 ± 0.05 ng/ml). The relative reduction of plasma catecholamines (guanfacine and withdrawal) was of the same order during handgrip exercise as during supine rest. During isometric handgrip exercise, BP was lower during guanfacine therapy than before treatment and 2 wk after withdrawal, but the increment in BP during handgrip exercise was not affected by the drug despite the lower BP values on therapy. Our data indicate that the central α2‐agonist action of guanfacine reduces sympathoadrenal function equally during rest and isometric exercise.Clinical Pharmacology and Therapeutics(1984)35,604–609; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1984.83

年代:1984

数据来源: WILEY

摘要:

The efficacy and safety of a new dosage regimen of intravenous disopyramide in ventricular arrhythmias were evaluated in 10 patients. Each had at least four premature ventricular contractions (PVCs)/min during a 30‐min period before dosing. By the classification of Lown et al.,18grade III arrhythmia was present in four patients, grade IVA in three patients, and grade IVB in three patients. Disopyramide was injected intravenously as a bolus of 0.5 mg/kg over 5 min. Each patient received two to three additional boluses of same strength with 5‐min intervals between each dosing during the first hour. Continuous intravenous infusion was started with the first bolus and continued at a rate of 1 mg/kg/hr for 3 hr and at 0.4 mg/kg/hrfor 15 hr. All patients had continuous Hoher monitoring throughout the 18‐hr treatment period and for 30 to 60 min before treatment. In eight patients the grade of arrhythmia after drug decreased and the frequency of PVCs fell by 70% to 100% (>85% in six patients and2 µg/ml) were reached after the first or second bolus and were maintained during the continuous infusion period. There were no side effects necessitating termination of disopyramide infusion. The dosage regimen of intravenous disopyramide evaluated was effective in 60% of patients with ventricular arrhythmia, induced no severe toxic effects, and rapidly achieved therapeutic serum levels that were maintained during continuous infusion.Clinical Pharmacology and Therapeutics(1984)35,610–616; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1984.84

年代:1984

数据来源: WILEY

摘要:

We investigated lidocaine kinetics after cardiac surgery to elucidate the effects of cardiopulmonary bypass (CPB) and major surgery on its disposition. In five patients lidocaine kinetics were unchanged 15 min and 1 day after CPB, but lidocaine clearance decreased 42% and volume of distribution was reduced by 40% in eight patients 3 days after surgery. Seven days after surgery lidocaine kinetics had returned to baseline in five patients. These changes correlated with a doubling of the α1‐acid glycoprotein concentration and a 46% decrease in lidocaine free fraction on day 3, effects that persisted on day 7. Our results suggest that the use of lidocaine need not be altered in the first day after uncomplicated coronary artery surgery, but, in light of our findings the use of lidocaine and the interpretation of measured total lidocaine concentrations 3 to 7 days thereafter should be reexamined.Clinical Pharmacology and Therapeutics(1984)35,617–626; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1984.85

年代:1984

数据来源: WILEY

摘要:

Gold sodium thiomalate has been shown to inhibit serine esterase enzymes isolated from the lysosomes of white cells. We demonstrate for the first time to our knowledge that gold sodium thiomalate is inhibitory to the serine esterase thrombin in its interaction with washed human platelets, human platelet‐rich plasma, and human platelet‐poor plasma. Since thrombin is a serine esterase phylogenetically related to the serine esterases elastase and cathepsin G, the most likely mechanism of action is an interaction of the gold thiol complex with one or all of the four cysteine–cysteine disulfide bridges of the thrombin molecule.Clinical Pharmacology and Therapeutics(1984)35,627–632; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1984.86

年代:1984

数据来源: WILEY

摘要:

Thromboxane A2, the predominant cyclooxygenase product of arachidonic acid in the platelet, is a potent vasoconstrictor and stimulus of platelet aggregation. Prostacyclin, the principal cyclooxygenase metabolite formed in the vascular endothelium, inhibits platelet aggregation and dilates blood vessels. A therapeutic objective in the treatment of human vascular occlusive disease has been the inhibition of thromboxane formation without coincident reduction in prostacyclin biosynthesis. We compared the biochemical selectivity and platelet inhibitory actions of single doses of aspirin, a cyclooxygenase inhibitor, with imidazo(1,5‐2)pyridine‐5‐hexanoic acid (CGS 13080), an inhibitor of thromboxane synthase. Aspirin, 325 mg, prolonged the bleeding time markedly, inhibited aggregation and nucleotide release in whole blood and platelet‐rich plasma, and maximally inhibited thromboxane generation in serum. The effects of aspirin, 20 mg, were considerably less marked but, as with the higher dose, persisted throughout the study period (24 hr after dosing). CGS 13080 also prolonged bleeding time and inhibited thromboxane formation. In contrast to aspirin, these effects were reversible and inhibition of aggregation was less marked. Endogenous prostacyclin biosynthesis was measured by excretion of the major urinary metabolite 2,3‐dinor‐6‐keto‐PGF1α(PGI‐M). Whereas aspirin, 325 mg, reduced PGI‐M excretion a mean 29%, excretion increased 48% and 100% after CGS 13080, 100 mg and 200 mg. Aspirin, 20 mg, did not alter prostacyclin biosynthesis. Inhibition of thromboxane synthase permits selective inhibition of thromboxane formation in man. Although drugs of greater potency and longer duration of action are desirable, enhanced prostacyclin synthesis may be an important component of the platelet inhibitory actions of thromboxane synthase inhibitors in man.Clinical Pharmacology and Therapeutics(1984)35,633–640; d

ISSN:0009-9236    

DOI:10.1038/clpt.1984.87

年代:1984

数据来源: WILEY