Volume 41, No. 7/2003(July)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Review
Clinical trials in Russia and Eastern Europe: Recruitment and quality
P. Platonov
Abstract
P. Platonov
Evidence Clinical and Pharmaceutical Research, St. Petersburg, Russia, and Lund University, Lund, Sweden
Objective: To review the current situation of clinical trials in Russia and Eastern Europe. Findings: The volume of clinical trials in these territories is increasing. The quality of the data obtained, ethical care and compliance with Good Clinical Practice guidelines is at least as good as anywhere else. United States Food and Drug Administration inspection data indicate that sites in these countries are often superior to those elsewhere. Large-scale clinical trials conducted in these territories have been subsequently published in mainstream journals. Territory-specific attention must be paid to communications’ equipment and language. However, this is countered, for example, by the fact that most clinical research associates in Russia hold degrees in medicine, that patients with previously untreated disease are more easily found than in North America or Western Europe, and the participation of large, purpose-built, healthcare institutions. Conclusion: Eastern Europe and Russia are well-established locales for clinical trials. These territories offer a solution to the competition for patients among clinical trials in North America or Western Europe.
Pediatric medicine
The influence of locally implanted high doses of gentamicin on hearing and renal function of newborns treated for acute hematogenous osteomyelitis
M. Kos, E. Jazwinska-Tarnawska, M. Hurkacz, K. Orzechowska-Juzwenko, W. Pilecki and J. Klempous
Abstract
M. Kos, E. Jazwinska-Tarnawska, M. Hurkacz, K. Orzechowska-Juzwenko, W. Pilecki and J. Klempous
1Department of Pediatric Surgery, Marciniak Hospital Wroclaw,
2Department of Clinical Pharmacology, Wroclaw Medical University, and 3Department of Pathophysiology, Wroclaw Medical University, Wroclaw, Poland
Background: Osteomyelitis and arthritis still present a serious diagnostic and therapeutic problem. Difficulties arise in particular in the treatment of acute hematogenic osteomyelitis (AHO) in newborns where mega-doses of gentamicin are administered locally for about 3 weeks. Gentamicin possesses strong oto- and nephrotoxicity and the occurrence of these adverse effects depends on the duration of treatment and the serum drug concentration. Objective: Aim of the study was to evaluate the influence of local gentamicin application on auditory and kidney functions. Material and methods: Twenty newborns (14 boys and 6 girls) with AHO were treated at the Department of Pediatric Surgery, Marciniak Hospital, Wroclaw, Poland, by local implantation of miniseptopal or gentamicin sponge. Serum urea, creatinine, antibiotic concentrations and NAG activity/g creatinine ratio in urine were estimated before and 1, 4, 8, 16 days after the operation and compared to values in the control group. Brainstem-evoked auditory potentials (BAEP) were examined before, during the first 3 weeks, and 6 – 11 months after gentamicin implantation. Results: Mean gentamicin serum concentrations were: 0.67 ± 0.98 mg/l on the 1st day, 0.16 ± 0.37 mg/l on the 4th day, 0.03 ± 0.09 mg/l on the 8th day, 0.01 ± 0.03 mg/l on the 16th day after operation and did not exceed the upper limit of the therapeutic range. N-acetyl-b-D-glucosaminidase (NAG)/g creatinine in urine ratios were satisfactory: 77.91 ± 36.22 UI/g before the operation, 146.51 ± 82,27 UI/g on the 4th, 162 ± 111 UI/g on the 8th, 168 ± 59.83 UI/g on the 16th day after operation and were statistically significantly (p < 0.05) higher than values in the control group. Serum urea and creatinine levels were in the normal range in all groups. Initial BAEP were well in the normal range in 15 of 16 children before treatment and in 14 of 16 children after treatment. Conclusions: Locally applied gentamicin as miniseptopal or sponge in newborns produces gentamicin concentrations close to the minimal therapeutic serum concentration which are present over a prolonged period. The raised NAG values in urine and normal serum urea and creatinine levels during treatment with gentamicin without concomitant clinical symptoms of renal failure suggest subclinical destruction of the renal tubules. Lack of change in BAEPs shows that there is no impairment of auditory function.
Drug utilization
Factors influencing antimicrobial utilization at a university hospital during
a period of 11 years
V. Vlahovic-Palcevski, G. Palcevski, Z. Mavric and I. Francetic
Abstract
V. Vlahovic-Palcevski, G. Palcevski, Z. Mavric and I. Francetic
1Unit for Clinical Pharmacology, 2Pediatric Clinic, 3Department of Medicine, University Hospital Center, Rijeka and 4Department of Medicine, Clinical Pharmacology Unit, University Hospital Center, Zagreb, Croatia
Objective: A number of factors may influence antibiotic prescribing. The objective of this study was to identify trends in antimicrobial prescribing during a period of 11 years at the University Hospital Center Rijeka (UHC), Croatia, and to identify possible factors that might have influenced changes in prescribing patterns. This may help in establishing criteria for future intervention. Methods: Antimicrobial utilization was evaluated retrospectively for the 11-year period from 1990 – 2000. It was measured in defined daily doses (DDDs) per 100 bed days using the ATC Index with DDDs 2000. Results: During the investigation period, marked differences were noted in total and individual antimicrobial consumption. In the first 4 years of this study, the utilization of all groups of antimicrobials decreased, while in its second part (i.e. from 1995 – 1997) an increase in utilization of all antimicrobial groups occurred. Changes in utilization of groups of antimicrobials did not coincide completely with the changes in total antimicrobial utilization. The most prominent changes were a decrease in penicillin and cephalosporin utilization, and an increase of macrolides and aminoglycosides utilization from 1997 – 2000. Ampicillin and cefalexin were mostly prescribed as single antibiotics during a 5-year period (1990 – 1995) with the exception of 1 year (1994) when a marked decline in antimicrobial utilization was noted. In the following years, amoxicillin and amoxicillin with enzyme inhibitor became the most-used antimicrobials. Conclusion: Various factors influenced antimicrobial utilization during the investigation period. There were factors that directly influenced prescribing, e.g. the physicians’ prescribing habit, guidelines, policy and formulary. Other factors directly influenced utilization, e.g. availability of a drug through purchasing, dispensing, procurement, pricing etc.
Complementary and alternative medicine
Prevalence and pattern of use of complementary and alternative medicine (CAM) in hypertensive patients of a tertiary care center in India
N. Shafiq, M. Gupta, S. Kumari and P. Pandhi
Abstract
N. Shafiq, M. Gupta, S. Kumari and P. Pandhi
1Department of Pharmacology, and 2Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Objective: To study the prevalence and pattern of use of complementary and alternative medicine (CAM) in patients with essential hypertension. Method: 521 consecutive patients visiting the Hypertension Clinic at the Postgraduate Institute of Medical Education and Research, Chandigarh, India, over a 6-month period were interviewed. Information was gathered on the patients’ demographics, type(s) of CAM used, sequence of seeking CAM and conventional medicine, sources of recommendation, reasons for opting for CAM and areas of satisfaction and dissatisfaction associated with the use of CAM. Patients were also asked if they had informed their doctor about CAM use. Results: It was observed that 63.9% of patients overall used CAM. Ayurveda was the most commonly used CAM (56.7%), followed by herbal medicines (14.4%). The most commonly cited reason by patients for using CAM was fear of adverse drug reactions of conventional medicines (59.0%). However, more than half of the patients eventually became dissatisfied using CAM. Only 5.4% of CAM users had informed their medical doctors about the use of CAM. Conclusion: A significant proportion of patients receiving conventional treatment for hypertension also use CAM therapies. A better understanding of the pattern of CAM use amongst these patients will help dispel prevalent misconceptions concerning CAM and, at the same time, assist conventional practitioners to critically evaluate possible gaps or omissions in their own prescribing habits.
Bioavailability section
Assessment of the bioequivalence of two oxcarbazepine oral suspensions versus a film-coated tablet in healthy subjects
G. Flesch, D. Tudor, J. Denouel, J. Bonner and R. Camisasca
Abstract
G. Flesch, D. Tudor, J. Denouel, J. Bonner and R. Camisasca
1Clinical Pharmacology, Novartis Pharma AG, Basel, Switzerland, 2Boomerang Pharmaceutical Communications, Mulhouse, 3DMPK, Rueil-Malmaison, France, and 4Clinical Pharmacology, Novartis Pharmaceuticals, Horsham, UK
Oxcarbazepine (trileptal) oral suspension has been reformulated and a study was performed to compare the bioavailability after single doses and at steady state of the current and former oral suspension versus the marketed film-coated tablets and to compare the bioavailability of the current and former oral suspension. The results support the switch from the former oral suspension to the current oral suspension and also from both oral suspensions to the film-coated tablet and vice versa. The study was an open-label, single-center, 3-way crossover trial. Each treatment period consisted of a single dose of 600 mg oxcarbazepine on Day 1, 600 mg oxcarbazepine b.i.d. repeated administration from Day 4 up to including Day 7, and a final dose of 600 mg oxcarbazepine administered on the morning of Day 8. Blood samples were taken on Day 1, Day 7 and Day 8 (pre-dose). Plasma concentrations of the main metabolite of oxcarbazepine (MHD) were determined using a validated HPLC assay. The 2 oral suspensions were compared with the film-coated tablet as reference formulation under fasted conditions. Also the current oral suspension was compared with the former oral suspension. These comparisons were made using data following single dose administration and under steady state conditions. Plasma AUC for single dose and AUC(0-12h) at steady state and plasma Cmax, log-transformed (natural base) were used for the assessment of bioequivalence. The 90% confidence interval (CI) approach was used for testing bioequivalence. Bioequivalence was accepted if CI was contained within the region (0.8, 1.25). At steady state, both the former and the current oral suspensions showed bioequivalence with the film-coated tablet with respect to AUC and Cmax. The current oral suspension was also bioequivalent when compared to the former oral suspension with respect to AUC and Cmax. After single dose, the former oral suspension was bioequivalent when compared to the film-coated tablet with respect to both AUC and Cmax. However, the current oral suspension was bioequivalent to both the film-coated tablet and the former oral suspension with respect to AUC but not to Cmax.
Bioavailability section
Comparative bioavailability of two immediate-release tablets of lisinopril/hydrochlorothiazide in healthy volunteers
A.R. Gascón, A. Cuadrado, M.A. Solinís, R.M. Hernández, E. Ramírez, R. Dalmau and J.L. Pedraz
Abstract
A.R. Gascón1,3, A. Cuadrado2,3, M.A. Solinís1,3, R.M. Hernández1,3, E. Ramírez1,3, R. Dalmau4 and J.L. Pedraz1,3
1Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, 2Clinical Trial Unit, Txagorritxu Hospital,Vitoria, 3Pharmaceutical Development Unit, LEIA Foundation, Vitoria, and 4Inkeysa, Barcelona, Spain
Aim: Two formulations of lisinopril/hydrochlorothiazide (20 mg/12.5 mg) were evaluated for bioequivalence after single dosing in healthy volunteers. Methods: The study was conducted according to an open, randomized, 2-period crossover design with a 2-week washout interval between doses. Twenty-four volunteers participated and all completed the study successfully. Lisinopril and hydrochlorothiazide were determined in plasma by HPLC. The pharmacokinetic parameters AUC0-t, AUC0-¥, Cmax and Cmax/AUC0-¥ were tested for bioequivalence after logarithmic transformation of data and ratios of tmax were evaluated non-parametrically. Results: For lisinopril, the parametric analysis revealed the following test/reference ratios and their confidence intervals (90% CI): 1.01 (0.84 – 1.22) for AUC0-t, 0.98 (0.81 – 1.19) for AUC0-¥, 1.02 (0.83 – 1.25) for Cmax and 1.03 (0.99 – 1.08) for Cmax/AUC0-¥. The 90% CI for tmax was 0.94 – 1.07. All parameters showed bioequivalence between both formulations. As for hydrochlorothiazide, test/reference ratios and their confidence intervals (90% CI) were: 1.05 (0.95 – 1.17), 1.02 (0.93 – 1.12) for AUC0-¥, 0.99 (0.89 – 1.07) for Cmax and 0.97 (0.90 – 1.04) for Cmax/AUC0-¥. The 90% CI for tmax was 1.00 – 1.41. All parameters showed bioequivalence between both formulations except for tmax. A discrete fall in both systolic (SBP) and diastolic (DBP) blood pressure was observed after drug administration. The time course of both parameters was similar for the 2 formulations. Heart rates also followed a similar time profile. Conclusions: The bioequivalence of the 2 formulations of lisinopril/hydrochlorothiazide was demonstrated.
Bioavailability section
Comparative bioequivalence study of two isotretinoin soft gel capsule formulations in healthy male volunteers
M. Georgarakis, F. Zougrou, S. Tzavara, G. Kontopoulos and I. Tsiptsios
Abstract
M. Georgarakis, F. Zougrou, S. Tzavara, G. Kontopoulos and I. Tsiptsios
1Laboratory of Pharmaceutics and Drug Control, Department of Pharmacy, Aristotle University of Thessaloniki, 2Integrated Laboratory Services, Athens, 3Cardiologist Thessaloniki, and 4Laboratory of Clinical Neurophysiology, Hospital St. Paulus, Thessaloniki, Greece
Objective: To assess the bioequivalence of 2 oral isotretinoin (20 mg) soft gel capsule formulations. The reference preparation was Roaccutan/Roche while the test preparation was A-Cnotren/Pharmaten, Athens, Greece. Subjects, material and methods: The study was an open, randomized, 2-period, 2-sequence, 2-treatment crossover, involving 38 healthy male volunteer subjects. All volunteers completed the study. Isotretinoin plasma concentrations were measured by a fully validated HPLC method. Special care was taken through the collection and analysis of the samples due to instability of isotretinoin to light and temperature. Pharmacokinetic parameters used to assess bioequivalence were AUC0-last, AUC0-¥ for the extent of absorption and Cmax and Tmax for the rate of absorption. Statistical evaluation of Cmax, AUC0-last, AUC0-¥ was done after semilogarithmic transformation by 2-way analysis of variance (ANOVA). Tmax values were tested using the distribution-free Hodges-Lehman interval. Results: The parametric 90% confidence intervals for ratio T/R ranged from 95.20 – 103.20% (point estimate 99.10%) for AUC0-last, 94.57 – 102.30% (point estimate 98.36%) for AUC0-¥ and 94.81 – 102.90% (point estimate 98.77%) for Cmax, respectively. Based on the results of Tmax, kel and t1/2, too, there were no statistically significant differences. Conclusion: As a result, the 2 isotretinoin preparations in accordance with the European Union bioequivalence requirements, are equivalent with respect to rate and extent of absorption.
Bioavailability section
Bioequivalence study of
generic gliclazide and Diamicron formulations in healthy Thai male volunteers
N. Rojanasthien, C. Sugunta, S. Rungapinan, B. Kumsorn and C. Sangdee
Abstract
N. Rojanasthien, C. Sugunta, S. Rungapinan, B. Kumsorn and C. Sangdee
Division of Clinical Pharmacology, Department of Pharmacology,
Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
The objective of this study was to compare the bioequivalence of 80 mg gliclazide in healthy Thai males. A single dose of each preparation was administered after an overnight fast in a 2-period crossover design with a 2-week washout period. Serial blood samples were collected over a period of 60 hours. Plasma gliclazide concentrations were determined using HPLC and the pharmacokinetic parameters were analyzed by non-compartmental analysis. Results: The median time to reach the maximal concentration (Tmax) for the test formulation was identical to that of the reference Diamicron (11.5 h). Similarly, the mean elimination half-lives (t1/2) for the test (20.4 ± 7.8 h) and Diamicron (21.5 ± 9.4 h) were comparable. Analysis of variance was carried out using logarithmic transformations of AUC0-¥ and Cmax as well as non-transformed Tmax. The mean (90% CI) of the difference in Tmax (h) was 0.08 ((–1.44) – 1.61). The mean (90% CI) of the AUC0-¥ and Cmax ratios for (test/reference) were 1.08 (0.98 – 1.18) and 1.09 (0.89 – 1.34), respectively. Since these values fall within the bioequivalence criteria, our study demonstrates bioequivalence of the 2 products.
