Background: The metabolism of drugs and other xenobiotics is mediated by enzymes whose activities can be modulated by different compounds. The activities of these modulators have the potential to be used to optimize d...
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Background: The metabolism of drugs and other xenobiotics is mediated by enzymes whose activities can be modulated by different compounds. The activities of these modulators have the potential to be used to optimize drug action, prevent toxicity, or identify the enzymes involved in a reaction. This approach requires that selective agents be used for specific enzymes. However, selectivity of action has been poorly characterized in vivo. Methods: This study investigated the effect of 3 and 28 days of treatment with quinidine (200 mg daily) and rifampin (INN, rifampicin) (600 mg daily) on the activities of four cytochrome P450 enzymes and N-acetyltransferase in 28 healthy young male volunteers divided into three groups with a cocktail of drug probes used, including caffeine, mephenytoin, debrisoquin (INN, debrisoquine), and dapsone. Results: Quinidine selectively and almost completely inhibited the activity of CYP2D6 from day 3 through day 28 without affecting any other enzymes. Rifampin showed evidence of time-dependent induction of the activities of all measured oxidative routes of metabolism but decreased the acetylation ratio in fast acetylators. The quinidine/rifampin combination resulted in selective CYP2D6 inhibition and induction of all other enzymes evaluated over this time period, suggesting that predictable complex interactions occur with the drug combination. Conclusions: These observations illustrate the value of simultaneous assessment of the effect of modulators on the activities of multiple specific enzymes with the drug cocktail approach.
Study objective: This study was conducted to compare the clinical and spirometric effects of continuous and intermittent nebulization of salbutamol in acute severe asthma. Methods: Forty-two consecutive patients prese...
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Study objective: This study was conducted to compare the clinical and spirometric effects of continuous and intermittent nebulization of salbutamol in acute severe asthma. Methods: Forty-two consecutive patients presenting to the emergency department for acute severe asthma (peak expiratory flow [PEF] mean+/-SD, 24%+/-12% predicted) were prospectively randomly assigned to receive 27.5 mg of salbutamol by either continuous or intermittent nebulization over a 6-hour period. The continuous nebulization group received 15 mg of salbutamol during the first hour and 12.5 mg over the next 5 hours. The intermittent nebulization group received 5 mg of salbutamol every 20 minutes during the first hour and 2.5 mg hourly over the next 5 hours. All participants received oxygen and intravenous hydrocortisone. Clinical and spirometric assessment was performed at baseline, 40 minutes, 60 minutes, and at 3 and 6 hours after the start of the nebulization. Secondary endpoints were the respective rates of hospitalization and treatment failure. Results: A significant clinical and spirometric improvement was observed in both groups over baseline as soon as the 40th minute and was sustained thereafter (absolute PEF increase at the sixth hour 30%+/-18% and 32%+/-22% in the continuous and intermittent nebulization groups, respectively;P<.01 over baseline). PEF and the clinical score evolved similarly in both groups. There was no difference between the groups regarding the failure rate of the initial bronchodilator treatment to terminate the asthma attack (3 [14%] in the continuous nebulization group and 2 [9.5%] in the intermittent nebulization group, absolute difference 4.5% [95% confidence interval -14% to 23%]). Eight (38%) patients and 9 (43%) patients from the continuous and intermittent nebulization groups, respectively, required hospitalization according to predefined criteria (absolute difference 4.8% [95% confidence interval -24% to 34%]).
The efficacy and toxicity of cladribine (2-CdA) + prednisone (P) versus chlorambucil (Chl) + P were compared in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia (CLL) in a ran...
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The efficacy and toxicity of cladribine (2-CdA) + prednisone (P) versus chlorambucil (Chl) + P were compared in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia (CLL) in a randomized, multicenter prospective trial. Eligible patients were assigned to either 2-CdA 0.12 mg/kg per day in 2-hour infusions and P 30 mg/m(2) per day for 5 consecutive days or Chi 12 mg/m(2) per day and P 30 mg/m(2) per day for 7 consecutive days. Three courses were administered at 28-day intervals or longer if myelosuppression developed. The therapy was finished if complete response (CR) was achieved. Of 229 available patients 126 received 2-CdA+P and 103 received ChI+P as a first-line treatment. OR and overall response rates were significantly higher in the patients treated with 2-CdA+P (47% and 87%, respectively) than in the patients treated with ChI+P (12% and 57%, respectively) (P = .001), Progression-free survival was significantly longer in the 2-CdA-treated group (P = .01), but event-free survival was not statistically different. Thirteen percent of patients were refractory to 2-CdA+P and 43% to ChI+P (P = .001). Drug-induced neutropenia was more frequently observed during 2-CdA+P (23%) than ChI+P therapy (11%) (P = .02), but thrombocytopenia occurred with similar frequency in both groups (36% and 27%, respectively). Infections were seen more frequently in the 2-CdA+P-treated group (56%) than in the ChI+P-treated group (40%;P = .02), Death rates have so far been similar in patients treated with 2-CdA (20%) and with ChI (17%), The probability of overall survival calculated from Kaplan-Meier curves at 24 months was also similar for both groups (78% and 82%, respectively). (C) 2000 by The American Society of Hematology.
OBJECTIVES To compare the hemodynamic effects of twice daily metoprolol tartrate (MT) and once daily metoprolol succinate (MS) in congestive heart failure patients. BACKGROUND Adverse hemodynamic effects with MT demon...
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OBJECTIVES To compare the hemodynamic effects of twice daily metoprolol tartrate (MT) and once daily metoprolol succinate (MS) in congestive heart failure patients. BACKGROUND Adverse hemodynamic effects with MT demonstrated during initiation persist with drug readministration during chronic therapy. METHODS Patients were randomly assigned to 6.25 mg MT or 25 mg MS orally and the dose was gradually increased to a target of 50 mg twice a day or 100 mg once a day, respectively. Hemodynamic measurements were obtained at baseline and after three months of therapy-both before and after drug readministration. RESULTS Long term metoprolol therapy produced significant functional, exercise and hemodynamic benefits with no difference in response between either metoprolol preparation in the 27 patients (MT [14], MS [13]). When full dose metoprolol was readministered during chronic therapy, there were parallel adverse hemodynamic effects in both drug groups. Cardiac index decreased by 0.6 liters/min/m(2) (p < 0.0001) with MT and by 0.5 liters/min/m(2) (p < 0.0001) with MS. Systematic vascular resistance increased by 253 dyne-sec-cm(-5) (p < 0.001) with MT and by 267 dyne-sec-cm(-5) (p < 0.0005) with MS. Stroke volume index decreased by 7.0 ml/m(2) (p < 0.0005) with MT and by 6.5 ml/m(2) (p < 0.0001) with MS, while SVC;I decreased by 6.2 g-m/m(2) (p < 0.0005) with MT and by 6.0 g-m/m(2) (p < 0.001) with MS. CONCLUSION Metoprolol tartrate and MS produce similar hemodynamic and clinical effects acutely and chronically despite the fourfold greater starting dose of MS used in this study. A more rapid initiation with readily available starting doses of MS may offer distinct advantages compared with MT in treating chronic heart failure patients with beta-adrenergic blocking agents. (C) 1999 by the American College of Cardiology.
Ninety-eight new molecular entities applications approved between 1987 to 1991 (period I) and 193 applications for new molecular entities between 1992 to 1997 (period II) were surveyed for drug-drug interaction studie...
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Ninety-eight new molecular entities applications approved between 1987 to 1991 (period I) and 193 applications for new molecular entities between 1992 to 1997 (period II) were surveyed for drug-drug interaction studies. In period I (used as a comparator), 32 applications contained drug-drug interaction studies for a total of 117 studies. In period II, 106 applications reported drug-drug interaction studies, and the number of studies per new molecular entity ranged from 0 to 15. Most studies (77%) were performed in healthy subjects, with 44% using crossover designs, 7% using parallel designs, and the remaining using fixed sequence designs, The most common dosing scheme for new molecular entities/interacting drug was multiple dose (47%), whereas single dose/multiple dose was used in 31% of studies, and single dose/single dose was used in 18% of studies. Of the 540 drug-drug interaction studies submitted in period II, 80 (15%) resulted in clinically significant labeling statements, Submissions for new molecular entities to the Center for Drug Evaluation and Research divisions most likely to include drug-drug interaction studies were neuropharmacology, cardiorenal, antiviral, and antiinfective drugs, Some drug classes such as oncology drug products and radioimaging products were least likely to include drug-drug interaction studies in their submissions. We conclude that the use of drug-drug interaction studies in the drug development process has increased between the two periods.
Background survivors of acute myocardial infarction (MI) complicated by heart failure and/or resulting in left ventricular dysfunction are at heightened risk for subsequent death and major nonfatal cardiovascular even...
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Background survivors of acute myocardial infarction (MI) complicated by heart failure and/or resulting in left ventricular dysfunction are at heightened risk for subsequent death and major nonfatal cardiovascular events. Inhibition of the renin-angiotensin system with an angiotensin-converting enzyme inhibitor has consistently been demonstrated to result in reductions in these risks by approximately 20%. The development of angiotensin II receptor blockers offers a new, more specific, and theoretically more complete pharmacologic mode to inhibit the adverse influence of angiotensin II. Methods Valsartan in Acute Myocardial Infarction (VALIANT) is a multicenter, double-blind, randomized, active controlled parallel group study comparing the efficacy and safety of long-term treatment with valsartan, captopril, and their combination in high-risk patients after MI. The trial is designed with 3 arms, giving equal statistical consideration to survival comparisons of captopril versus the angiotensin II receptor blocker valsartan, as well as the combination of captopril plus valsartan, compared with a proven effective dose of captopril. This 14,500-patient trial is designed with an 86% power to detect a 15% reduction in mortality rate with either use of valsartan compared with captopril. The trial encourages optimal individualization of other proven therapies in acute and chronic infarction, and the international patient body ensures good representation of multiple practice patterns. Conclusion VALIANT ii a large international investigative effort that will evaluate the role of valsartan in the menage ment of patients with MI associated with heart failure and/or left ventricular dysfunction. The use of a proven dose of captopril and the comparator arms with valsartan alone or in combination with captopril provides a unique test of whether the angiotensin II receptor blocker can make an additional improvement in clinical outcomes beyond angiotensin-converting enzyme inhibitors
PURPOSE: Gastrointestinal microbleeding, as assessed by the measurement of (51)chromium-labeled red blood cells, is a marker of the mucosal injury associated with the use of nonsteroidal anti-inflammatory drugs. This ...
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PURPOSE: Gastrointestinal microbleeding, as assessed by the measurement of (51)chromium-labeled red blood cells, is a marker of the mucosal injury associated with the use of nonsteroidal anti-inflammatory drugs. This study tested the hypotheses that cyclooxygenase-2 specific inhibition with rofecoxib would cause less fecal blood loss than a therapeutic dose of ibuprofen and would be equivalent to placebo. SUBJECTS AND METHODS: In this randomized, double-blind group study, gastrointestinal blood loss was assessed by measurement of fecal (51)chromium radioactivity during a 1-week placebo baseline period and during 4 weeks of treatment with rofecoxib) (25 mg or 50 mg once daily), ibuprofen (800 mg three times daily), or placebo in 67 healthy subjects. Gastrointestinal blood loss during treatment weeks 2 to 4 (versus the baseline period) was expressed as the geometric mean ratio of fecal radioactivity in weeks 2 to 4 compared with baseline. RESULTS: Ibuprofen caused significantly (P <0.001) greater gastrointestinal blood loss (geometric mean ratio of 5.2, 95% confidence interval [CI]: 4.2 to 6.3) than the 25-mg dose of rofecoxib (2.6, 95% CI: 2.2 to 3.1), the 50-mg dose of rofecoxib (2.6, 95% CI: 2.2 to 3.0), or placebo (2.1, 95% CI: 1.8 to 2.5). In contrast, gastrointestinal blood loss with both doses of rofecoxib were equivalent to placebo by a predetermined clinical similarity bound. CONCLUSIONS: In healthy subjects, treatment with rofecoxib, at 2 to 4 times the doses that are currently recommended for the treatment of patients with osteoarthritis, produced significantly less fecal blood loss than a therapeutic dose of ibuprofen and was equivalent to placebo. (C) 2000 by Excerpta Medica, Inc.
The body's ability to meet the stresses of cancer therapy declines in later life. Because the decline may vary and is only weakly linked to chronologic age, a thorough functional assessment should be undertaken in...
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The body's ability to meet the stresses of cancer therapy declines in later life. Because the decline may vary and is only weakly linked to chronologic age, a thorough functional assessment should be undertaken in all elderly cancer patients. The results can guide decisions about how to treat the cancer.
Administration of triadimefon (TDF) [1-(4-chlorophenoxy)-3,3-dimethyl-1-(1-H-1,2,4-triazol-1-yl)-2-butanone] in rodents incites heightened locomotor and stereotypy response, primarily through potentiation of dopaminer...
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Administration of triadimefon (TDF) [1-(4-chlorophenoxy)-3,3-dimethyl-1-(1-H-1,2,4-triazol-1-yl)-2-butanone] in rodents incites heightened locomotor and stereotypy response, primarily through potentiation of dopaminergic activity. In the present study, 8 male Sprague-Dawley rats received repeated injections, on alternate days (100 mg/kg, 14 days) of TDF or corn oil. Enhanced locomotor and stereotypy behavioral patterns occurred in response to TDF injections, lasting until the 12th day of injection. Tolerance to this effect was evident by a lack of response to TDF injection by the 14(th) day. Similarly, a withdrawal period and challenge dose of TDF (5 days, 25 mg/kg) was ineffective in espousing locomotor or stereotypy behavioral changes. Cross sensitization to cocaine was also evident, since withdrawal and a challenge dose (8 days, 5 mg/kg) was also ineffective. Adaptative biochemical changes in dopaminergic function were examined after both acute (100 nl kg) and repeated administration of TDF (100 mg/kg, 14 days) by examining [H-3] dopamine (DA) uptake and DA release in both striatal (ST) and nucleus accumbens (NA) tissue. In corroboration with behavioral pattern indicating development of tolerance, there were significant changes in dopaminergic function. Repeated TDF exposure in vivo resulted in significant attenuation of ST and NA DA uptake in response to TDF (10(-4) to 10(-7) M) or cocaine (10(-5) to 10(-8) M) in vitro. Acute exposure to TDF in vivo also attenuated ST DA inhibitory effects of cocaine and TDF. Repetitive administration of TDF in vivo had no effect on in vitro TDF- or amphetamine-stimulated release of ST or NA DA. However, there was a significant reduction in amphetamine-stimulated DA release in animals after acute exposure to TDF in vivo. It was concluded from this study that the effects of chronic TDF exposure may primarily involve effects on DA uptake in the ST and NA.
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