Volume 38, No. 12/2000(December)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Original
5-fluorouracil alone versus 5-fluorouracil plus folinic acid in the treatment of colorectal carcinoma: meta-analysis
L. Lo Bello, G. Pistone, S. Restuccia, E. Vinci, G. Mazzoleni and M. Malaguarnera
Abstract
L. Lo Bello2, G. Pistone1, S. Restuccia1, E. Vinci1, G. Mazzoleni1 and M. Malaguarnera1
1Institute of Internal Medicine and Geriatrics, and 2Department of Electronic Engineering, University of Catania, Catania, Italy
Objective: Innovative techniques in the field of artificial intelligence could help to resolve several methodological problems. A model taking into account all the parameters involved in a therapy can foresee the results of each type of treatment or therapeutic protocol on patients at different stages of a disease. We used a Computer Decision Support System in order to verify the reliability and efficacy of this method on chemotherapy of colorectal carcinoma. Material and methods: We analyzed 8 randomized clinical trials employing 5-fluorouracil alone (5-FU) or 5-fluorouracil (5-FU) plus leucovorin (FA) in the management of advanced colorectal carcinoma. Computer Decision Support System (CDSS) was used to perform four basic tasks: data acquisition and organization; data recruitment; combination of the various principles and specific data; user-friendly display of the analysis results and responses to treatment. Results: In the majority of the studies examined, the death rates were lower in patients treated with 5-FU + FA than in those on 5-FU alone, even though the difference was not statistically significant. However, there were wide fluctuations in the efficacy/ tolerability ratio between the two protocols investigated, depending on the patients’ clinical status. Our data showed that a strong attack using 5-FU + FA is feasible whenever the patients’ clinical conditions are not particularly severe, whereas a moderate attack using 5-FU alone is recommended as the patients’ clinical condition worsens. Conclusion: The use of CDSS in the management of colorectal carcinoma indicates which therapy is the best in terms of efficacy, overall survival and incidence of side effects.Correspondence to:
Dr. M. Malaguarnera; Istituto di Medicina Interna e Geriatria, Ospedale Cannizzaro, via Messina 829, I-95126 Catania, Italy
Original
Independent determinants of the efficacy of nitrate therapy
R. Jansen, M.G. Niemeyer, T.J. Cleophas and A.H. Zwinderman
Abstract
R. Jansen1, M.G. Niemeyer2, T.J. Cleophas3 and A.H. Zwinderman4
1Academic Hospital, Groningen, 2Martini Hospital, Groningen, 3Albert Schweitzer Hospital, Dordrecht and 4Academic Hospital, Leiden, The Netherlands
Background: Asymmetric dosage regimens of isosorbide mononitrate provide better antianginal efficacy and quality of life in patients with stable angina pectoris than the daily administration of multiple small doses of the compound. It is not known whether certain patient characteristics contribute to this improved benefit. Objective: To determine independent factors contributing to this improved benefit. Multiple linear regression analysis was performed with a self assessment study in 1350 patients with stable angina pectoris. Quality of life was assessed by the Marquis questionnaire for patients with angina and included the assessment of immobility, pain and psychological distress. Individual scores were calculated as the pooled sums of the assessment scores and were expressed on an ordinal scale of 10. Results: Age did not influence the improvement in benefit. Gender, rhythmic disturbances, peripheral artery disease and the concomitant use of calcium channel blockers or b-blockers were without effect. New York Heart Association angina classification was an independent variable: patients with a class I or II showed less benefit than did patients with class III or IV (p = 0.02). Obese patients as well as hypertensive patients (p = 0.04 and 0.02), and smokers also tended to benefit less (p = 0.08). In contrast, the presence of cholesterolemia and diabetes mellitus were associated with increase in the beneficial effect of nitrates on quality of life (p = 0.03 and 0.05). Conclusions: Patients with severe angina pectoris benefit better from nitrate therapy than do patients with New York Heart Association class I – II. Also, patients with coronary artery disease and concomitant diabetes mellitus or cholesterolemia may benefit better from nitric oxide donor therapy than patients without such condition. In contrast, patients with concomitant obesity, hypertension, or who are smokers may show less benefit.Correspondence to:
Dr. T.J. Cleophas; Box 306, NL-3300 AB Dordrecht, The Netherlands
Originla
Patterns of utilization of antihypertensive drug combinations in Bahrain: do they conform with international guidelines?
K.A. Jassim Al Khaja, R.P. Sequeira and V.S. Mathur
Abstract
K.A. Jassim Al Khaja, R.P. Sequeira and V.S. Mathur
College of Medicine and Medical Sciences, Arabian Gulf University, Bahrain
Objectives: To explore the prescribing pattern and rationale of antihypertensive combination drug therapy at the level of primary health care centers; and to analyze the extent of physicians’ adherence to dosage range of antihypertensives in combination regimens as recommended by Guidelines Subcommittee of WHO/ISH 1999. Subjects, material and methods: A prescribing survey of antihypertensive combination regimens among patients with uncomplicated essential hypertension was conducted in 7 out of a total of 18 health centers in Bahrain. The relevant data for our study was collected using cards designed for chronically ill patients. Results: A total of 2414 hypertensive patients (62.9%), of a 3838 study population, were on monotherapy, whereas 1414 (37.1%) were on antihypertensive combination therapy. Among those who were treated with drug combinations, 85.1% (n = 1212) received two-drug, 14.2% (n = 202) received three-drug and four- and five-drug regimens were used by 0.6% and 0.07%, respectively. Prescription analysis revealed that 17 different two- and three-antihypertensive drug combinations were prescribed for each category. The four major two-drug regimens were ranked in the following order: a b-blocker with a diuretic (40.4%) used more frequently in females than in males (p < 0.0001), a b-blocker with a calcium channel blocker (19.7%), a b-blocker with an ACE inhibitor (12.8%) and a diuretic with an ACE inhibitor (7.3%) – used more frequently in males than in females (p = 0.001, 0.01, and 0.028, respectively). The most frequently prescribed three-drug regimens were diuretic and a b-blocker plus either an ACE inhibitor (30.7%) or a calcium channel blocker (22.3%), b-blocker plus an ACE inhibitor and a calcium channel blocker (16.3%), and a diuretic plus an ACE inhibitor and a calcium channel blocker (11.4%). There was no gender-related difference among triple-drug regimens. There was a trend towards using high doses of the b-blocker atenolol, ACE inhibitors and methyldopa. Conclusion: The prescribing patterns of some practising physicians were analyzed in terms of conformity with guidelines of combination of drugs and dosages. The use of antihypertensive combination therapy and the doses of individual drugs in combination regimens seem to be partly non-compliant with guidelines issued by WHO recommendations; this is illustrated by excessive prescription of some irrational combinations, as well as limited prescription of some rational combinations. In addition, a tendency to use high doses of certain classes of antihypertensive combinations was observed.Correspondence to:
Dr. K.A. Jassim Al Khaja; Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, P.O. Box No. 22979, Arabian Gulf University, Bahrain
Original
Midazolam 12 mg is moderately counteracted by 250 mg caffeine in man
M.J. Mattila, P. Vainio, M.-L. Nurminen, J. Vanakoski and T. Seppälä
Abstract
M.J. Mattila, P. Vainio, M.-L. Nurminen, J. Vanakoski and T. Seppälä
Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Helsinki, Finland
Objective: Caffeine (Caf) counteracts various effects of benzodiazepines (BZDs). Since the effects of zolpidem, a short-acting atypical GABAA-BZD agonist, were not antagonized by Caf, we studied an interaction between Caf and midazolam (Mid) in healthy volunteers. Subjects, materials and methods: In Study 1, 108 healthy students divided to 6 parallel groups were given Mid 12 mg (capsule) and Caf 125 and 250 mg (in decaffeinated coffee), alone and in combinations in the double-blind placebo-controlled manner. Objective and subjective tests were done before and at 45 and 90 min after intake. Ranked D-values (changes from baseline) were analyzed by one-way contrast ANOVA and Scheffe’s tests. In Study 2, six healthy subjects took Mid 15 mg (tablet) with and without Caf 300 mg. The dynamic effects were analyzed as in Study 1 and the plasma concentrations were assayed. Results: In Study 1, learn effects after placebo (ad +15%) were seen for letter cancellation and digit symbol substitution tests. Midazolam alone significantly (p < 0.05 vs. D-placebo) reduced letter cancellation and digit symbol substitution, lowered flicker fusion, impaired digit learning and caused subjective calmness on VAS. Caffeine alone did not differ from placebo objectively, yet improved quick-wittedness and contentedness on VAS. In the combinations, Mid+Caf 125 mg differed from placebo objectively as Mid alone, whereas Mid + Caf 250 mg did not. Mid + Caf 250 mg differed from Mid on digit substitution, but did not differ from Mid+Caf 150 mg in impairing memory and causing subjective sedation. In Study 2, Mid 15 mg caused sedation and Caf 300 mg increased plasma Mid at 45 min. Mid + Caf did not differ from Mid alone objectively, but did so subjectively on VAS (p > 0.05). Conclusion: In conclusion, in a parallel group study, sedative effects of Mid 12 mg were only moderately antagonized by Caf 250 mg but not by Caf 125 mg. In a crossover study, a weak interaction was found subjectively but not in objective measures.Correspondence to:
Dr. M.J. Mattila; Institute of Biomedicine, Pharmacology and Toxicology, University of Helsinki, P.O.B. 8, Siltavuorenpenger 10, FIN-00014 Helsinki
Original
Effect of food and gender on the pharmacokinetics of RP 73401, a phosphodiesterase IV inhibitor
D. Argenti, S.K. Vaccaro, B. Shah, M.S. Gillen, S. Rohatagi and B.K. Jensen
Abstract
D. Argenti, S.K. Vaccaro, B. Shah, M.S. Gillen, S. Rohatagi and B.K. Jensen
Department of Drug Metabolism and Pharmacokinetics and Department of Clinical Pharmacology, Aventis Pharmaceuticals, Bridgewater, NJ, USA
Objective: Early exploratory clinical pharmacokinetic studies can provide valuable information for the design and control of subsequent phase 2 studies. This philosophy was instituted for the compound RP 73401, a specific phosphodiesterase IV inhibitor, that was being developed simultaneously for delivery by both oral and pulmonary routes of administration. The objective of these studies was to separately evaluate the effect of food and gender on the pharmacokinetics of RP 73401 using small-scale focused pilot studies. Methods: In the first study, 400 mcg of inhaled RP 73401 were administered to male and female healthy volunteers (n = 8 f, 8 m. In the second study, 400 mcg oral RP 73401 were administered to healthy male volunteers (n = 8) in the fed and fasted state in a crossover fashion. Serial plasma samples were collected for 24 hours and analyzed for RP 73401 using an HPLC method with post-column photochemical reaction and fluorescence detection that had a minimum quantifiable limit of 10 pg/ml. Pharmacokinetic parameters were calculated using non-compartmental techniques. Results: Comparison of male and female pharmacokinetics following inhalation administration showed no statistically significant differences in the absorption and disposition of RP 73401 with respect to AUC, Cmax, tmax, and t1/2 values. Conversely, RP 73401 administered subsequently to a high fat meal showed a 51% reduction in Cmax and a 5-fold prolongation in tmax as compared to the fasted state. However, there was no statistically significant difference in the systemic availability of RP 73401 as assessed through AUC0-¥ comparisons. Conclusions: These results successfully allowed the uncomplicated inclusion of females in oral and inhalation studies with RP 73401 and indicated the need to address oral drug dosing conditions in order to minimize sources of pharmacokinetic variability in subsequent phase 2 studies.Correspondence to:
Dr. S. Rohatagi; Aventis Pharmaceuticals, Drug Metabolism and Pharmacokinetics (M-250), Rt. 202-206, Bridgewater, NJ 08807-0800, USA
