Volume 45, No. 5/2007(May)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Therapeutics
Comparative clinical study of the efficacy and safety of a S-metoprolol ER tablet versus a racemate metoprolol ER tablet in patients with chronic stable angina
P. Aneja, A. Srinivas and A. Das Biswas
Abstract
P. Aneja, A. Srinivas and A. Das Biswas
1Care and Cure, New Delhi, 2Vikram Hospital and Heart Center, Mysore,
and 3R.G. Kar Medical College, Kolkata, India
Objective: To compare the efficacy and safety of a S-metoprolol extended release (ER) tablet (50 mg) versus a racemate metoprolol ER tablet (100 mg) in the management of angina. Methods: An open-label, prospective, comparative study in a clinical setting was conducted in Indian patients. Patients (n = 50 in each group) with a history of angina pectoris, with or without hypertension, were administered study medications in a sequential 1:1 manner once daily for 8 weeks. The primary efficacy variable was a mean change from baseline in the number of angina attacks. The secondary efficacy variables were: mean change from baseline in the proportion of patients with no angina attacks, systolic blood pressure, diastolic blood pressure, heart rate, and proportion of blood pressure responders. Number of patients reporting adverse effects (AEs) and severity of AEs in both of the groups were compared. Results: All patients (n = 100) completed the study. In the S-metoprolol group the number of angina attacks (mean ± SEM) at baseline and after 2, 4 and 8 weeks of therapy were 6.3 ± 0.8, 3 ± 0.4, 1.8 ± 0.4 and 0.7 ± 0.2, respectively. In the metoprolol group these values were 5.8 ± 1, 3 ± 0.7, 1.4 ± 0.3 and 0.7 ± 0.2, respectively. The reduction in the number of angina attacks from baseline was significant (p < 0.0001) in both groups with no between-group difference. The response rate in angina (percentage of patients completely relieved of angina attacks clinically) was greater in the S-metoprolol group (72%) when compared to the metoprolol group (62%) (p > 0.05, NS). Both study groups showed significant (p < 0.0001) reduction in baseline systolic blood pressure (SBP), diastolic blood pressure (SBP) and heart rate (HR) in hypertensive patients and a clinically non-significant (p > 0.05, NS) change in normotensive patients. Among hypertensive patients, the response rate in angina was higher in the S-metoprolol group (74%) when compared to the metoprolol group (61%) (p > 0.05, NS). In the S-metoprolol group four patients reported AEs: fatigue (n = 4), dry mouth (n = 1), dizziness (n = 1), dyspnea (n = 2), and mild rash (n = 1). In the metoprolol group three patients reported AEs: fatigue (n = 2), dyspnea (n = 1) and dizziness (n = 1). No statistically significant difference was detected between the groups in AE frequency/severity. Conclusion: In routine clinical practice in the management of angina (with or without coexisting hypertension), S-metoprolol administered at half the dose of the racemate, shows similar efficacy, safety and a trend towards a higher response rate.
Correspondence to:
Dr. P. Aneja
Consultant Physician and Cardiologist
Care and Cure
81/Pocket A-1/Sector 8
Rohini, New Delhi-110085, India
Email: pankajaneja@hotmail.com
Therapeutics
Ketorolac as a pre-emptive analgesic in retinal detachment surgery: a prospective, randomized clinical trial
G. Vlajkovic, R. Sindjelic and I. Stefanovic
Abstract
G. Vlajkovic, R. Sindjelic and I. Stefanovic
1Institute for Anesthesia and Resuscitation, 2Institute for Eye Diseases,
Clinical Center of Serbia, Belgrade University Medical School, Belgrade, Serbia
Objective: Retinal detachment surgery is associated with a high incidence of post-operative pain, nausea and vomiting. Previous studies demonstrated a beneficial role of pre-emptive analgesia using regional anesthetic blocks for this type of surgery. The aim of the present study was to evaluate the pre-emptive analgesic effect of ketorolac in patients undergoing retinal detachment surgery under general anesthesia. Methods: With the approval of the Institutional Ethics Committee and written informed consent, 60 adult patients were randomized prospectively, in a double-masked manner, to receive intravenously either ketorolac 30 mg or saline placebo 30 min before operation. Pain scores at 2, 6, 12, 18 and 24 h after surgery, the number of patients requiring post-operative analgesia, total consumption of analgesics, the incidence of oculocardiac reflex as well as the incidence and severity of post-operative nausea and vomiting were recorded. Results: The ketorolac group required post-operative analgesia less frequently than the placebo group (p < 0.0001). The ketorolac group had significantly lower pain scores at all measurement time points (p < 0.001) and lower intra- and post-operative total consumption of analgesics (p < 0.01). The incidence and severity of nausea and vomiting were lower in patients given ketorolac when compared with placebo-treated patients (p < 0.05). The incidence of oculocardiac reflex was not significantly different between groups (p = 0.14). Conclusions: The use of ketorolac for pre-emptive analgesia is effective in patients undergoing retinal detachment surgery under general anesthesia.Correspondence to:
Dr. G. Vlajkovic
Institute for Anesthesia and Resuscitation
Clinical Center of Serbia
Belgrade University Medical School
Dr. Koste Todorovica 8
11000 Belgrade, Serbia
Email: gvlajkov@eunet.yu
Pharmacoeconomics
Atypical antipsychotic therapy for treatment of schizophrenia in Hong Kong Chinese patients - a cost analysis
W.L. Law, H.Y Hui, W.M. Young and J.H.S. You
Abstract
W.L. Law, H.Y Hui, W.M. Young and J.H.S. You
1Hospital Authority, Hong Kong SAR, 2Center for Pharmacoeconomics Research, School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong
Objective: To evaluate the direct medical cost of atypical antipsychotic therapy for schizophrenia among Hong Kong Chinese patients and to identify factors affecting the cost of treatment. Methods: In this retrospective database analysis, patient data were retrieved from three Hong Kong public hospitals. Patients aged >= 18 years who received an initial prescription for olanzapine, risperidone, quetiapine or amisulpride between April 1 and September 30, 2003; and had an ICD-10-coded diagnosis of schizophrenia were included. Patient data were collected for a maximum duration of 1 year before and after treatment initiation. Primary outcome measures were the schizophrenia-related direct medical costs. Demographic and clinical factors were analyzed by multiple regression analysis to identify influential factors for the cost of atypical antipsychotic therapy. Results: A total of 325 patient records were reviewed and 82 patients were included in the analysis. Cost per patient per month for clinic visits (US$ 67 ± 41 versus US$ 78 ± 41), medications (US$ 8 ± 12 versus US$ 97 ± 83), and the total cost per patient per month (US$ 314 ± 898 versus US$ 431 ± 914) increased significantly after treatment initiation (US$ 1 = HK$ 7.8). Previous duration of hospitalization (RR = 1.00, 95% CI = 1.00 – 1.01), history of substance abuse (RR = 1.26, 95% CI = 1.05 – 1.52) and use of depot antipsychotics (RR = 1.22, 95% CI = 1.05 – 1.42) were associated with higher cost of atypical antipsychotic therapy. Conclusion: The total direct medical cost increased significantly after initiation of atypical antipsychotic therapy in a cohort of Chinese patients with schizophrenia. History of drug abuse, use of depot antipsychotics and prior duration of hospitalization were positive predictors of cost of therapy.Correspondence to:
J.H.S. You, PharmD, BCPS
Center for Pharmacoeconomics Research
School of Pharmacy, Faculty of Medicine
The Chinese University of Hong Kong
Shatin, N.T., Hong Kong
Email: joyceyou@cuhk.edu.hk
Pharmacokinetics
Pharmacokinetics of sarizotan after oral administration of single and repeat doses in healthy subjects
S. Krösser, J. Tillner, M. Fluck, W. Ungethüm, P. Wolna and A. Kovar
Abstract
S. Krösser, J. Tillner, M. Fluck, W. Ungethüm, P. Wolna and A. Kovar
1Department of Clinical Pharmacology and Pharmacokinetics, 2Department of Non-Clinical Drug Metabolism and Pharmacokinetics, 3Department of Biostatistics and Data Science, Merck KGaA, Darmstadt, Germany
Objective: Sarizotan is a 5-HT1A receptor agonist with high affinity for D3 and D4 receptors. Here we report the pharmacokinetic and tolerability results from four Phase 1 studies. Materials: Two single-dose (5 – 25 mg, n = 25, 0.5 – 5 mg, n = 16) and two multiple-dose (10 and 20 mg b.i.d., n = 30, 5 mg b.i.d., n = 12) studies with orally administered sarizotan HCl were carried out in healthy subjects. Methods: Plasma sarizotan HCl concentrations were measured using a validated HPLC method and fluorescence or MS/MS detection. Pharmacokinetic parameters were obtained using standard non-compartmental methods. Results: Sarizotan was rapidly absorbed, group-median times to reach maximum concentration (tmax) ranged from 0.5 – 2.25 h after single doses and during steady state. Maximum plasma concentration (Cmax) and tmax were slightly dependent on formulation and food intake, whereas area under the curve (AUC) was unaffected by these factors. AUC and Cmax increased dose-proportionally over the tested dose range. Independently of dose and time, sarizotan HCl plasma concentrations declined polyexponentially with a terminal elimination half-life (t1/2) of 5 – 7 h. Accumulation factors corresponded to t1/2 values, and steady state was reached within 24 h. Plasma metabolite concentrations were considerably lower than those of the parent drug. The ratio metabolite AUC : parent drug AUC was time- and dose-independent for all three metabolites suggesting that the metabolism of sarizotan is non-saturable in the tested dose range. Conclusions: The pharmacokinetics of sarizotan were dose-proportional and time-independent for the dose range 0.5 – 25 mg). The drug was well-tolerated by healthy subjects up to a single dose of 20 mg. Correspondence to:
Dr. S. Krösser Department of Clinical Pharmacology and Pharmacokinetics Merck KGaA Frankfurter Straße 250 64293 Darmstadt, Germany
Email: Sonja.Kroesser@merck.de
Drug Utilization
Under-utilization of gastroprotective drugs in patients with NSAID-related ulcers
H.E. Vonkeman, R.W. Fernandes and M.A.F.J. van de Laar
Abstract
H.E. Vonkeman, R.W. Fernandes and M.A.F.J. van de Laar
1Department of Rheumatology and Clinical Immunology,
Medisch Spectrum Twente Hospital and University of Twente,
2Stroinkslanden Pharmacy, Enschede, The Netherlands
Objective: To determine the proportion of patients with a risk of NSAID gastropathy receiving adequate gastroprotection. Methods: This observational study was performed between November 2001 and December 2003. We selected patients who were hospitalized with perforated and bleeding gastroduodenal ulcers attributable to NSAID use and controls without ulcers. Data were collected on their sociodemographic characteristics, actual and recent medication, comorbidity and medical history. For each patient and control the number of different risk factors associated with NSAID gastropathy was calculated. A composite risk factor (CRF) was obtained from the sum of all separate risk factors. Results: During the observational period a total of 388 patients using NSAID were included in the study, 104 patient cases and 284 matched community-based controls. The mean CRF was significantly higher in patient cases than in controls (cases mean CRF 3.31 (SD 1.67) and controls mean CRF 2.76 (SD 1.45), p = 0.002). A total of 148 (38%) patients used an adequate preventive strategy. Significant variables for using a preventive strategy were concomitant use of steroids (corrected odds ratio 4.22, 95% CI 2.11 – 8.47, p < 0.001), a history of gastroduodenal ulcers (corrected odds ratio 2.90, 95% CI 1.51 – 5.56, p = 0.001) and concomitant use of low-dose aspirin (corrected odds ratio 1.96, 95% CI 1.18 – 3.25, p = 0.01). Among patients with 4 or more risk factors associated with NSAID gastropathy, 47% still did not use adequate gastroprotection. Conclusion: Gastroprotective drugs are greatly under-utilized in patients with a risk of NSAID gastropathy.
Correspondence to:
H.E. Vonkeman, MD
Department of Rheumatology and Clinical Immunology
Medisch Spectrum Twente Hospital
PO Box 50 000,
7500 KA Enschede, The Netherlands
Email: H.Vonkeman@ziekenhuis-mst.nl
Adverse Drug Reactions
Fatal hyponatremia and other metabolic disturbances associated with psychotropic drug polypharmacy
Z. Vucicevic, V. Degoricija, Z. Alfirevic and D. Vukicevic-Badouin
Abstract
Z. Vucicevic, V. Degoricija, Z. Alfirevic and D. Vukicevic-Badouin
1Department of Emergency Medicine, 2Department of Clinical Pharmacology, University Department of Medicine, “Sestre milosrdnice” University Hospital, Zagreb, Croatia
Objective: To report a case of fatal hyponatremia, marked hyperglycemia, and acute pancreatitis following simultaneous administration of paroxetine, fluphenazine, haloperidol and olanzapine. Case summary: A 44-year-old non-diabetic male was admitted unconsciously, with severe hyponatremia, hyperglycemia and bradypnea. The patient had a history of long-term treatment with paroxetine, fluphenazine, haloperidol and olanzapine. Upon arrival, the plasma sodium level was 104 mmol/l, and blood glucose was 940 mg/dl. The therapy consisted of ventilatory support and intensive correction of hyponatremia and hyperglycemia. 2 hours later, hypotension and refractory cardiac arrest occurred. The autopsy disclosed severe cerebral edema as cause of death, and a modest hemorrhagic pancreatitis. Discussion: Paroxetine is a selective serotonin reuptake inhibitor which stimulates antidiuretic hormone (ADH) release and may cause the syndrome of inappropriate ADH secretion with consecutive hyponatremia. Fluphenazine and haloperidol may contribute to this syndrome. Fluphenazine, and particularly olanzapine are associated with an increased incidence of diabetes. Olanzapine has been reported as a risk factor for acute pancreatitis. The Naranjo probability scale was not applicable because of almost immediate lethal outcome. Conclusion: Polypharmacy increases the risk of various adverse reactions. Adverse effects of paroxetine and many antipsychotic drugs, such as hyponatremia and hyperglycemia, should be monitored periodically to prevent complications. The role of olanzapine in the etiology of acute pancreatitis remains to be evaluated.
Correspondence to:
Z. Vucicevic, MD, PhD Department of Emergency Medicine University Department of Medicine “Sestre milosrdnice” University Hospital Vinogradska cesta 29 10000 Zagreb, Croatia
Email: zeljko.vucicevic@zg.t-com.hr
Bioavailability Section
Lack of bioequivalence between generic risperidone oral solution and originator risperidone tablets
S. van Os, M. Relleke and P. Muniz Piniella
Abstract
S. van Os, M. Relleke and P. Muniz Piniella
Synthon BV, Nijmegen, The Netherlands
Risperidone is an atypical antipsychotic, available in various formulations. Objective: The objective of the study was to compare the bioavailability of a generic oral solution of risperidone (Test formulation) and Risperdal tablets (Reference formulation). Both formulations contained 1 mg risperidone per dosing unit. Methods: The study was carried out in 32 healthy volunteers under fasting conditions. Risperidone and 9-hydroxyrisperidone concentrations in plasma were determined using HPLC/MS/MS. Results: The results show that the 90% confidence intervals for the geometric mean ratios of the solution and the tablet formulations were not within the acceptance range of 80 – 125% for risperidone, whereas the confidence intervals for 9-hydroxyrisperidone were within the acceptance range of 80 – 125%. Conclusion: Bioequivalence between the generic 1 mg/ml risperidone solution and the originator tablet formulation was not proven in this study.Correspondence to:
S. van Os, PhD
Synthon BV
P.O. Box 7071
6503 GN Nijmegen, The Netherlands
Email: sandra.vanos@synthon.nl
Bioavailability Section
Pharmacokinetic comparison of two 40 mg tablet formulations of citalopram using a new amperometric detection technique
M. Al-Ghazawi, M. Tutunji, M. Mohsen and S. Najjar
Abstract
M. Al-Ghazawi, M. Tutunji, M. Mohsen and S. Najjar
1Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, 2Chemistry Department, Faculty of Science, University of Jordan, 3Pharmaceutical Research Unit, Royal Scientific Society, Amman, 4The Jordan Sweden Medical and Sterilization Company (JOSWE), Na’oor, Jordan
Objectives: To assess the bioequivalence of two citalopram 40 mg tablet formulations (Lecital® of the Jordan Sweden Medical and Sterilization Co. (JOSWE) as a test product, and Cipramil® of Lundbeck (Denmark) as a reference product), and to develop a new high-performance liquid chromatography (HPLC) method using liquid-liquid extraction followed by addition of acid for the quantification of citalopram in human plasma. Methods: A single-blind, randomized, single-dose, 2-treatment, 2-period, 2-sequence, crossover bioequivalence study with a 20-day washout period in 24 healthy volunteers. The drug was administered with 240 ml of water after 10-h overnight fasting. After dosing, serial blood samples were collected for a period of 192 h. Plasma harvested from blood was analyzed for citalopram by a novel method using HPLC coupled with an electrochemical detector. The limit of quantitation of citalopram was 1.493 ng/ml. Matrix-based calibration curves were linear over the range 1.493 – 80.640 ng/ml for citalopram. Results: The average bioavailability and pharmacokinetic parameters of the two citalopram tablets were as follows: peak plasma concentration Cmax was 35.0 ± 10.04 ng/ml and 33.4 ± 7.80 ng/ml for Lecital® and Cipramil®, respectively. The time to peak plasma concentrations tmax were 3.81 ± 1.18 and 4.08 ± 1.54 h, while the plasma half-life (t1/2) values were 54.0 ± 7.50 and 54.7 ± 10.6 h. The area under the plasma concentration-time profiles AUC0-t were 1,820 ± 582 ng × h/ml and 1,660 ± 510 ng × h/ml, whereas the AUC0-¥ were 2,010 ± 663 ng × h/ml and 1,850 ± 577 ng × h/ml for Lecital® and Cipramil®, respectively. The 90% confidence intervals for test/reference ratio were found within the acceptable limits of 80 – 125%, consequently no significant difference was found between the test and reference. Conclusion: Based on the pharmacokinetic and statistical results, it was concluded that Lecital® 40 mg tablets of JOSWE is bioequivalent to Cipramil® 40 mg tablets of Lundbeck (Denmark).Correspondence to:
M. Al-Ghazawi Department of Biopharmaceutics and Clinical Pharmacy Faculty of Pharmacy University of Jordan P.O. Box 925819 Amman 11942, Jordan
Email: alghazam@ju.edu.jo
