Overexpression of the multidrug resistance gene product in adult rat hepatocytes during primary culture.
(57/363)
Expression of P-glycoprotein (P-gp), the product of multidrug resistance gene(s), was investigated in primary cultures of normal adult rat hepatocytes. Levels of P-gp mRNAs determined by Northern blotting and of P-gp measured by immunoblotting increased in parallel with time in culture. As in normal liver, P-gp was found to be localized on the membrane of bile canaliculus-like structures. This increased expression of P-gp was associated with decreased intracellular retention of doxorubicin, which could be restored by compounds such as verapamil and cyclosporin; doxorubicin (and also vincristine) was more cytotoxic to early than to late cultures. As in preneoplastic and neoplastic liver, overexpression of P-gp in cultured hepatocytes was associated with differential changes in drug-metabolizing enzymes, including increased glutathione S-transferase 7-7. Functional P-gp over-expression was observed in the absence of xenobiotic exposure or cell division; it could be linked to cellular stress occurring during cell isolation and plating. Increased expression of P-gp was blocked by actinomycin D, indicating its dependence on increased transcription, while cycloheximide led to a superinduction suggesting negative regulation by a protein factor. (+info)
The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects.
(58/363)
1. The pharmacokinetics and metabolism of oxycodone were studied in nine healthy young volunteers in a cross-over study. Each subject received oxycodone chloride once intramuscularly (0.14 mg kg-1) and twice orally (0.28 mg kg-1) at intervals of 2 weeks. A double-blind randomized pretreatment with amitriptyline (10-50 mg a day) or placebo was given prior to oral oxycodone. 2. The concentrations of oxycodone, noroxycodone and oxymorphone in plasma and the 24 h urine recoveries of their conjugated and unconjugated forms were measured by gas chromatography. 3. No differences were found between treatments in mean Cmax and AUC values of oxycodone which varied from 34 to 38 ng ml-1 and from 208 to 245 ng ml-1 h, respectively. The median tmax of oxycodone was 1 h in all groups. The bioavailability of oral relative to i.m. oxycodone was 60%. The mean renal clearance of oxycodone was 0.07-0.08 l min-1. The kinetics of oxycodone were unaffected by amitriptyline. 4. The mean ratio of the AUC(0.24 h) values of unconjugated noroxycodone to oxycodone was 0.45 after i.m. oxycodone and 0.6-0.8 after oral oxycodone. Plasma oxymorphone concentrations were below the limit of the assay. Eight to 14% of the dose of oxycodone was excreted in the urine as unconjugated and conjugated oxycodone over 24 h. Oxymorphone was excreted mainly as a conjugate whereas noroxycodone was recovered mostly in an unconjugated form. (+info)
Edinburgh primary care depression study: treatment outcome, patient satisfaction, and cost after 16 weeks.
(59/363)
OBJECTIVE: To compare the clinical efficacy, patient satisfaction, and cost of three specialist treatments for depressive illness with routine care by general practitioners in primary care. DESIGN: Prospective, randomised allocation to amitriptyline prescribed by a psychiatrist, cognitive behaviour therapy from a clinical psychologist, counselling and case work by a social worker, or routine care by a general practitioner. SUBJECTS AND SETTING: 121 patients aged between 18 and 65 years suffering depressive illness (without psychotic features) meeting the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition for major depressive episode in 14 primary care practices in southern Edinburgh. MAIN OUTCOME MEASURES: Standard observer rating of depression at outset and after four and 16 weeks. Numbers of patients recovered at four and 16 weeks. Total length and cost of therapist contact. Structured evaluation of treatment by patients at 16 weeks. RESULTS: Marked improvement in depressive symptoms occurred in all treatment groups over 16 weeks. Any clinical advantages of specialist treatments over routine general practitioner care were small, but specialist treatment involved at least four times as much therapist contact and cost at least twice as much as routine general practitioner care. Psychological treatments, especially social work counselling, were most positively evaluated by patients. CONCLUSIONS: The additional costs associated with specialist treatments of new episodes of mild to moderate depressive illness presenting in primary care were not commensurate with their clinical superiority over routine general practitioner care. A proper cost-benefit analysis requires information about the ability of specialist treatment to prevent future episodes of depression. (+info)
THE INCREASE IN THE TOXICITY OF YOHIMBINE INDUCED BY IMIPRAMINE AND OTHER DRUGS IN MICE.
(60/363)
In mice, yohimbine appears to accentuate the normal "alarm" reactions (alerting, flight) to external stimuli. Imipramine increases this effect and at the same time converts a non-lethal dose of yohimbine into a lethal one. The effect of imipramine is greatly reduced by adrenalectomy or by treatment with reserpine, syrosingopine, ganglion-blocking drugs or adrenaline antagonists acting on sympathetic beta-receptors. Hypnotic, anti-convulsant or anaesthetic agents, tetrabenazine or antagonists of 5-hydroxytryptamine do not reduce the imipramine effect. A variety of drugs which, like imipramine, are known to interfere with the tissue binding of noradrenaline also increase the toxicity of yohimbine. Yohimbine significantly reduces brain noradrenaline content; adrenal catechol amines are slightly reduced. The results suggest that yohimbine releases noradrenaline from stores or nerves as a consequence of increased central sympathetic activity. Imipramine increases the actions and toxicity of yohimbine by increasing the effects of the released noradrenaline on beta-receptors. The lethal effects of a high dose of yohimbine alone are not reduced by any of the treatments tested, and appear not to result from activation of sympathetic mechanisms. (+info)
Acute herpes zoster and postherpetic neuralgia: effects of acyclovir and outcome of treatment with amitriptyline.
(61/363)
This retrospective study was designed to assess the effects of acyclovir treatment of acute herpes zoster on subsequent postherpetic neuralgia, and to examine the effects of amitriptyline in the treatment of postherpetic neuralgia. Eighty seven patients with postherpetic neuralgia of three or more months' duration were studied: 24 of them had had their herpes zoster treated with oral acyclovir. At first presentation, only 25% of the 24 patients who had had their herpes zoster treated with acyclovir selected the word group containing burning on the McGill pain questionnaire compared with 76% of the 63 patients who had not received acyclovir. A higher proportion of patients who had had acyclovir than had not selected the word group which contains the word aching (63% versus 49%). Acyclovir thus appears to change the nature of postherpetic neuralgia. Postherpetic neuralgia was treated with amitriptyline, alone or in combination with distigmine and/or sodium valproate. There was a strong correlation between pain relief and the interval between the occurrence of herpes zoster and the initiation of treatment with amitriptyline--early treatment is almost twice as likely to be successful as late. Since conventional analgesics and sympatholytic drugs are of no benefit in the treatment of established postherpetic neuralgia, the sequelae of herpes zoster must, therefore, be recognized and treated with amitriptyline as soon as possible. (+info)
A COMPARISON OF IMIPRAMINE, CHLORPROMAZINE AND RELATED DRUGS IN VARIOUS TESTS INVOLVING AUTONOMIC FUNCTIONS AND ANTAGONISM OF RESERPINE.
(62/363)
Seven structurally-related compounds consisting of three antidepressant drugs (imipramine, desmethylimipramine and amitriptyline), three tranquillizing agents (promazine, chlorpromazine and chlorprothixene) and a hybrid, desmethylpromazine, have been examined in a series of tests involving autonomic functions and antagonism of reserpine. Activities of the compounds in antagonizing reserpine-induced ptosis in rabbits and prolongation of alcohol hypnosis in mice give good correlation with their clinical actions, whilst their activities in augmenting excitation of rats by amphetamine and yohimbine toxicity in mice, and in reversing reserpine-induced bradycardia in rats offer further evidence for drug-induced sensitization to adrenergic or tryptaminic mechanisms, which is not however specific for antidepressant agents. No evidence has been obtained to indicate that a central parasympatholytic action is an important component of the antidepressant activity of imipramine and related drugs. (+info)
THE PHARMACOTHERAPY OF THE DEPRESSIVE SYNDROME.
(63/363)
THREE THERAPEUTIC MODALITIES HAVE PROVED EFFECTIVE IN THE TREATMENT OF DEPRESSIVE SYNDROMES: electroconvulsive therapy (ECT), pharmacotherapy and psychotherapy. ECT gives the most reliable and most rapid results but may be contraindicated in certain cases. Psychotherapy is limited in its application to the reactive aspects of a depression. Pharmacotherapy is currently the most widely applied treatment of depression. Two classes of drugs are available which are effective in about 60% of depressed patients: the monoamine oxidase inhibitors and tricyclic compounds. Their mechanism of action is probably related to the regulation of the biogenic amine balance in the brain. The distinction between antipsychotic and antidepressant drugs is not as sharp as was formerly assumed. Maintenance pharmacotherapy has been shown to have prophylactic value in preventing relapses. (+info)
Treating chronic tension-type headache not responding to amitriptyline hydrochloride with paroxetine hydrochloride: a pilot evaluation.
(64/363)
CONTEXT: In some individuals, chronic tension-type headache fails to respond to tricyclic antidepressant medications that often serve as first-line therapy. OBJECTIVE: To evaluate the clinical efficacy of paroxetine hydrochloride for chronic tension-type headache not responding to amitriptyline hydrochloride. DESIGN AND SETTING: Open-label trial of paroxetine conducted at 2 outpatient sites in Ohio. PARTICIPANTS AND INTERVENTION: Thirty-one adults (mean age, 37 years; 20 women) with chronic tension-type headache (mean, 25 headache days per month) who had failed to respond (less than 30% improvement) to treatment with either amitriptyline (n = 13) or matched placebo (n = 18). All participants were treated with paroxetine (up to 40 mg per day) in a 9-month protocol. OUTCOME MEASURES: Monthly headache index calculated as the mean of pain ratings (0 to 10 scale) recorded by participants in a diary 4 times per day, number of days per month with at least moderate pain (pain rating of 5 or greater), and analgesic medication use. RESULTS: In patients who had not responded to amitriptyline, paroxetine failed to reduce chronic tension-type headaches or analgesic medication use. In patients who had not responded to placebo, paroxetine produced modest reductions in chronic tension-type headaches and analgesic use. CONCLUSIONS: We found no evidence that chronic tension-type headaches that failed to respond to tricyclic antidepressant therapy with amitriptyline improved when subsequently treated with paroxetine. More support was found for the efficacy of paroxetine in patients with chronic tension-type headaches who had failed to respond to placebo. (+info)