摘要:

Desipramine has the least anticholinergic and sedative effects of the first generation tricyclic antidepressant agents, but its pain‐relieving potential has received little study. Other antidepressant agents—notably amitriptyline—are known to ameliorate postherpetic neuralgia, but those agents are often toxic. In a randomized double‐blind crossover design, we gave 26 postherpetic neuralgia patients 6 weeks of treatment with desipramine (mean dose, 167 mg/day) and placebo. Nineteen patients completed both treatments; 12 reported at least moderate relief with desipramine and two reported relief with placebo. Pain relief with desipramine was statistically significant from weeks 3 to 6. Psychiatric interview at entry into the study produced a diagnosis of depression for 4 patients; pain relief was similar in depressed and nondepressed patients and was statistically significant in the nondepressed group alone. We conclude that desipramine administration relieves postherpetic neuralgia and that pain relief is not mediated by mood elevation. Blockade of norepinephrine reuptake, an action shared by desipramine, amitriptyline, and other antidepressant agents that have relieved neuropathic pain, may be involved in relief of postherpetic neuralgia.Clinical Pharmacology and Therapeutics(1990)47,305–312; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1990.33

年代:1990

数据来源: WILEY

摘要:

Stereoselective 4′‐hydroxylations of R‐(−)‐mephenytoin and S‐(+)‐mephenytoin and 3′‐hydroxylation of R‐(‐)‐hexobarbital and S‐(+)‐hexobarbital were determined in liver microsomes of 14 Japanese subjects who were extensive metabolizers of mephenytoin and in five Japanese subjects who were poor metabolizers of mephenytoin. Content of P‐450 human‐2 assessed by Western blots was correlated to microsomal S‐(+)‐mephenytoin 4′‐hydroxylation, R‐(−)‐hexobarbital 3′ α‐hydroxylation, and S‐(+)‐hexobarbital 3′ ß‐hydroxylation, and was less correlated to R‐(−)‐mephenytoin 4′‐hydroxylation, R‐(−)‐hexobarbital 3′ ß‐hydroxylation, and S‐(+)‐hexobarbital 3′ α‐hydroxylation. Antibodies raised against P‐450 human‐2 inhibited microsomal S‐(+)‐mephenytoin 4′‐hydroxylation efficiently but was less efficient on R‐(−) ‐mephenytoin 4′‐hydroxylation in extensive metabolizers and on 4′‐hydroxylation of mephenytoin enantiomers in poor metabolizers. The antibodies also inhibited R‐(−)‐hexobarbital 3′ α‐hydroxylation and S‐(+)‐hexobarbital 3′ ß‐hydroxylation but did not effectively inhibit the hydroxylation of the two other optical isomers of hexobarbital in extensive metabolizers and of four stereoisomers in poor metabolizers. These findings indicate the close relationship between polymorphic mephenytoin 4′‐hydroxylation and two stereospecific hexobarbital hydroxylations, and they suggest that P‐450 human‐2 is a typical S‐(+)‐mephenytoin 4′‐hydroxylase and a major hexobarbital 3′‐hydroxylase in the livers of extensive metabolizers. The findings were further supported by the experiments that used P‐450 hum

ISSN:0009-9236    

DOI:10.1038/clpt.1990.34

年代:1990

数据来源: WILEY

摘要:

The efficacy of a transdermal nicotine patch in facilitation of smoking cessation was evaluated in a randomized double‐blind trial. Sixty‐five smokers who were highly dependent on cigarettes participated in the study, which included a behavioral smoking‐cessation program. The rates of continuous abstinence were significantly higher in the nicotine group both initially (55% versus 34%) and at 3 weeks (18% versus 6%). Certain smoking withdrawal symptoms, including negative affect and hypoarousal, were effectively relieved by the nicotine patch. There was a trend toward a reduction in cigarette craving, whereas hunger and habit withdrawal symptoms were not affected. The main side effect associated with the nicotine patch was skin irritation. These findings suggest that a nicotine skin patch may be a useful aid to smoking cessation; however, the combination of other techniques with nicotine replacement may provide a more effective treatment for symptoms such as craving for cigarettes.Clinical Pharmacology and Therapeutics(1990)47, 323–330; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1990.35

年代:1990

数据来源: WILEY

摘要:

We examined the pharmacokinetics of a transdermal nicotine patch and evaluated the usefulness of such a patch in a pilot smoking‐cessation program. Use of the patch was associated with plasma nicotine concentrations that were comparable to smoking or to the use of other smoking‐cessation devices. However, these plasma concentrations were maintained for 24 hours, and the patch appeared to be suitable for use once a day. Its use in a 6‐week placebo‐controlled double‐blind study resulted in a significant degree of smoking cessation or in reduction of smoking activity. The findings suggest that it may be valuable to extend investigations to a larger population and that transdermal nicotine may have a useful role in smoking‐cessation therapy.Clinical Pharmacology and Therapeutics(1990)47,331–337; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1990.36

年代:1990

数据来源: WILEY

摘要:

The plasma concentrations of α1‐acid glycoprotein (AAG), albumin, triglycerides, cholesterol, and total proteins, as well as the plasma binding of racemic, d‐methadone, and 1‐methadone were measured in 45 healthy subjects. The AAG phenotypes and the concentrations of AAG variants were also determined. The measured free fractions for racemic, d‐methadone, and 1‐methadone were, respectively, 12.7% ± 3.3%, 10.0% ± 2.9%, and 14.2% ± 3.2% (mean ± SD). A significant correlation was obtained between the binding ratio (B/F) for dl‐methadone and the total AAG concentration (r= 0.724;p<0.001). A multiple stepwise regression analysis showed that AAG was the main explanatory variable for the binding of the racemate. When concentrations of AAG variants were considered, a significant correlation was obtained between the binding ratio of dl‐methadone and orosomucoid2 A concentration (r= 0.715;p<0.001), a weak correlation between dl‐methadone and orosomucoidl S concentration (r= 0.494;p<0.001), and no correlation between dl‐methadone and orosomucoidl F1 concentration (r= 0.049; not significant). Similar findings were obtained with the enantiomers. This study shows the importance of considering not only total AAG but also concentrations of AAG variants when measuring the binding of methadone and possibly of other drugs in plasma.Clinical Pharmacology and Therapeutics(1990)47,338–346;

ISSN:0009-9236    

DOI:10.1038/clpt.1990.37

年代:1990

数据来源: WILEY

摘要:

We prospectively studied the effect of albendazole on microsomal reserve and on first‐pass activation to albendazole sulfoxide in patients with hydatid disease. An aminopyrine breath test was performed in 12 patients while they were receiving albendazole treatment and while they were not. Excretion of14CO2in breath averaged 0.70% · kg · mmol−1± 0.20% · kg · mmol−1without treatment and 0.54% · kg · mmol−1± 0.14% · kg · mmol−1with treatment (p<0.005). Plasma levels of albendazole sulfoxide were measured 4 hours after the morning dose during the first and second half of the 4‐week treatment cycles. In nine of the 12 patients albendazole sulfoxide levels decreased during the second half of the cycle by an average of 0.84 ± 0.76 μmol/L (p<0.02). Transaminase levels increased in 10 of the 12 patients during long‐term albendazole treatment, and major side effects, including hepatotoxicity, neutropenia, and alopecia, were observed in three patients. We conclude that albendazole partially inhibits microsomal enzyme function but induces its own metabolism. Hepatotoxicity and other possible severe side effects necessitate close therapeutic monitoring of patients who are given albendazole.Clinical Pharmacology and Therapeutics(1990)47,347–3

ISSN:0009-9236    

DOI:10.1038/clpt.1990.38

年代:1990

数据来源: WILEY

摘要:

The pharmacokinetics of pentoxifylline were investigated in six healthy volunteers and in 10 patients with alcoholic cirrhosis. After a 100 mg intravenous infusion, pentoxifylline elimination half‐life was prolonged in cirrhotic patients (2.12 ± 1.22 hours versus 0.83 ± 0.29 hours,p<0.05) because of a decrease in its plasma clearance (1.44 ± 0.46 L · hr−1· kg−1in patients with cirrhosis versus 3.62 ± 0.75 L · hr−1· kg−1in volunteers,p<0.001). The elimination half‐life of the metabolite (5‐hydroxypentoxifylline) was similar to that of the parent compound. After oral administration of a 400 mg sustained‐released tablet, absolute bioavailability of pentoxifylline increased in cirrhotic patients (0.71 ± 0.24 versus 0.33 ± 0.13,p<0.01). Although plasma concentrations of pentoxifylline and hydroxypentoxifylline were significantly increased in cirrhotic patients, the AUCpentoxifylline/AUChydroxypentoxifyllineratio remained unchanged in both groups after either intravenous or oral administration. These findings show that liver cirrhosis profoundly alters the pharmacokinetics of pentoxifylline. However the formation of hydroxypentoxifylline is not modified in these patients, suggesting an extrahepatic metabolism.Clinical Pharmacology and Therapeutics(1990)47,354–3

ISSN:0009-9236    

DOI:10.1038/clpt.1990.39

年代:1990

数据来源: WILEY

摘要:

Platelet α2‐ and lymphocyte β2‐adrenergic receptor density and responsiveness and platelet responses to prostaglandin E2(PGE2) were measured in black subjects and white subjects. Mean (± SEM) α‐receptor density was greater in white subjects (248 ± 29 versus 392 ±31 fmol/mg protein;p<0.005), whereas β‐reeeptor densities were similar (black subjects, 19.2 ± 2.2 fmol/mg protein; white subjects, 15.2 ± 1.4 fmol/mg protein). Basal platelet cyclic AMP levels (black subjects, 7.8 ± 1.1 pmol/mg protein; white subjects, 14.5 ± 2.4 pmol/mg protein;p<0.05) and PGE2induced increases in platelet cyclic AMP levels were higher in white subjects (black subjects, 47.1 ± 3.3 pmol/mg protein; white subjects, 65.5 ± 3.4 pmol/mg protein;p<0.001). Basal lymphocyte cyclic AMP levels (black subjects, 1.2 ± 0.3 pmol/106cells; white subjects, 2.8 ± 0.6 pmol/106cells;p<0.05) and mean isoproterenol‐induced cyclic AMP increases were also higher in white subjects (black subjects, 6.2 ± 0.6 pmol/106cells; white subjects, 8.5 ± 0.8 pmol/106cells;p<0.05). Responses to isoproterenol as fold stimulation of basal were not significantly higher in black subjects (8.51 ± 0.97 versus 6.16 ± 0.86 fold‐stimulation of basal). Platelet responses to PGE2as fold stimulation of basal (black subjects, 7.9% ± 0.7%; white subjects, 8% ± 1.3%) and α2‐receptor‐mediated inhibition of PGE2responses by UK‐14304 (black subjects, 38.2% ± 1.7%; white subjects, 40.6% ± 2.3%) were also similar in the two groups.Clinical Pharmacology and Therapeutics

ISSN:0009-9236    

DOI:10.1038/clpt.1990.40

年代:1990

数据来源: WILEY

摘要:

The concentration of α1‐acid glycoprotein, the major determinant of the plasma protein binding of basic drugs, and the extent of lidocaine protein binding was related to the severity of liver disease in 30 cirrhotic patients. In comparison with matched control subjects, α1‐acid glycoprotein concentration (77 ± 7 versus 37 ± 3 mg/dl; mean ± SEM;p<0.01) and lidocaine binding (69% ± 2% versus 35% ± 2%;p<0.01) was markedly reduced. There was a significant negative correlation (r= 0.78;p<0.01) between free lidocaine and α1‐acid glycoprotein concentration. Furthermore, both were significantly related to the severity of liver disease, as assessed by use of the Child Turcotte classification.Clinical Pharmacology and Therapeutics(1990)47,366–370; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1990.41

年代:1990

数据来源: WILEY

摘要:

Orthostatic hypotension is a clinical condition that frequently involves abnormal adrenergic control of cardiovascular function. Adrenergic function was studied in six patients with symptomatic orthostatic hypotension and in 11 age‐matched healthy subjects. The patients demonstrated higher supine mean arterial pressures (MAP; 103 ± 8 versus 86 ± 4 mm Hg) and orthostatic hypotension (ΔMAP −70 ± 5 versus +15 ± 2 mm Hg,p<0.001) compared with normal subjects. The ΔMAP in phase II of the Valsalva maneuver was significantly greater (− 31 ± 4 versus −7 ± 4 mm Hg,p<0.002) and phase IV heart rate response was blunted (−5 ± 3 versus −30 ± 8 beats/min,p<0.02) in these patients. More isoproterenol was required to increase heart rate by 25 beats per minute in patients with hypotension (810 ± 670 versus 3.1 ± 1.3 μg,p<0.05), indicating marked chronotropic hyposensitivity. Leukocyte β2‐adrenergic receptor densities were similar in patients and controls. β2‐Adrenergic receptor coupling, however, was elevated in patients with hypotension when compared with control subjects (ratio of the low‐affinity and high‐affinity dissociation constants [KL/KH] 140 ± 7.4 versus 66 ± 4.3,p<0.001). There were negative correlations between the KL/KHvalue and the dose of isoproterenol required to decrease MAP by 20 torr (p<0.02) and between the KL/KHvalue and the product of the hormone receptor and MAP (p<0.01). However, the patients could be subdivided into a group who could mount a nearly normal hormone receptor times MAP response on standing (group 1A), and a group who could not (group 1B). The group 1A patients had elevated plasma norepinephrine responses associated with milder β2‐adrenergic receptor supercoupling, whereas group 1B patients had essentially no orthostatic plasma norepinephrine response and had much higher KL/KHvalues. Thus, though a state of biochemical supersensitivity existed in both patient subgroups, diminished catecholamine exposure was associated, as expected, with β2‐adrenergic hypersensitivity in group 1B, whereas there was no diminution of catecholamine exposure in the β2‐adrenergic hypersensitity observed in group 1A patients.Clinical Pharmacology and Therapeu

ISSN:0009-9236    

DOI:10.1038/clpt.1990.42

年代:1990

数据来源: WILEY