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Abstract

C. Knabe, T. Sudhop, K. von Bergmann and D. Lütjohann

Department of Clinical Pharmacology, University of Bonn, Germany
Objective: The conversion of cholesterol into bile acids occurs via a long cascade of enzymatically regulated oxidative processes. Our aim was to examine if an upregulation of hepatic cholesterol 7a-hydroxylase (CYP7A1) in humans by cholestyramine, a bile acid-binding resin, has an effect on the degradation of brain-specific 24S-hydroxycholesterol. Patients and methods: Six normocholesterolemic male volunteers received 4 g cholestyramine b.i.d. for 2 weeks in an open, prospective exploratory trial. Serum concentrations of lipoproteins and triglycerides were measured by routine enzymatic assays. Sterols and oxysterols were measured by gas chromatography/mass spectrometry. Results: Total and LDL-cholesterol decreased on the average by 9.3% (p = 0.002) and 19.8% (p = 0.001) after 2 weeks of treatment, respectively. Absolute serum concentrations of 7a-hydroxycholesterol, a marker for bile acid production, increased 4-fold after 2 weeks, while 24S- and 27-hydroxycholesterol remained unchanged. Treatment with cholestyramine elevated serum levels of lathosterol, an indicator for the endogenous synthesis of cholesterol, by 146% (p = 0.009). Conclusion: In addition to lowering serum concentrations of total cholesterol and LDL-cholesterol, cholestyramine at a dose rate of 4 g b.i.d. causes a significant increase in the CYP 7A1 catalyzed 7a-hydroxylation of cholesterol and an up-regulation of endogenous cholesterol synthesis, as proven indirectly by an increase in serum lathosterol levels. Total serum levels of 24S- and 27-hydroxycholesterol remained unchanged indicating that an up-regulation in CYP7A1 activity is not responsible for the subsequent oxidative degradation of these hydroxylated sterols.Correspondence to:
D. Lütjohann, PhD, Department of Clinical Pharmacology, University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany
Email: dieter.luetjohann@ukb.uni-bonn.de

Abstract

W. Klövekorn, A. Tepe and U. Danesch

¹Dermatology Practice, Gilching, ²Weber and Weber GmbH and Co. KG, Research and Development, Inning, Germany
Objective: Only a few clinical trials have been published on the topical treatment of atopic dermatitis with herbal ointments. An ointment containing extracts from Mahonia aquifolium, Viola tricolor and Centella asiatica has previously been studied in open uncontrolled trials with children. However, no data exist on adult patients in a randomized controlled trial. Methods: A total of 88 patients with mild-to-moderate atopic dermatitis were enrolled in a double-blind, vehicle-controlled, randomized, half-side comparison. Patients between 18 and 65 years of age were treated for 4 weeks with an ointment containing Mahonia aquifolium, Viola tricolor and Centella asiatica. The primary endpoint was a summary score for erythema, edema/papulation, oozing/crust, excoriation and lichenification according to a 4-point scale. Secondary efficacy variables were assessment of pruritus severity (10 cm VAS) and a global assessment of effectiveness as well as tolerability. Results: The study ointment reduced the primary and secondary endpoints slightly more than the base cream which was used as vehicle; the differences were not statistically significant. Since the climatic conditions during the study duration varied from very mild and sunny to very cold and dry, a post-hoc subanalysis was performed with a subset of 64 patients whose treatment was at a mean outside temperature of 10 °C or less. Under these conditions the primary endpoint showed high statistical significance. Conclusion: In this trial, an ointment containing Mahonia aquifolium, Viola tricolor and Centella asiatica could not be proven to be superior to a base cream for patients with mild-to-moderate atopic dermatitis. However, a subanalysis indicated that the cream might be effective under conditions of cold and dry weather.
Correspondence to:
Dr. W. Klövekorn, Hautarztpraxis, Römerstraße 4, 82205 Gilching, Germany
Email: dr.kloevekorn@t-online.de

Abstract

A. Tanaka, K. Suemaru, T. Otsuka, K. Ido, T. Nishimiya, I. Sakai, H. Hasegawa, M. Yasukawa, T. Inoue, M. Murase and H. Araki

¹Division of Pharmacy, Ehime University Hospital, ²Department of Hospital Pharmacy, Matsuyama Shimin Hospital, ³Division of Laboratory Medicine, ⁴First Department of Internal Medicine, Ehime University School of Medicine, Ehime, Japan
Objective: Some formulas using the serum cystatin C level to estimate the GFR have recently been reported. However, there has been no report of a serum cystatin C-based formula for adjusting the dosage of the drugs cleared by the kidney. In this study, we compared the predictive performance of the serum vancomycin trough concentration predicted using serum cystatin C-based formulas. Method: The data were collected from 158 hospitalized patients. Five formulas have been published to predict the GFR using serum cystatin C. The cystatin C-based formulas were divided into two groups, formulas with or without anthropometric data. We predicted the serum vancomycin trough concentrations using VCM-TDM S_edition ver. 1.00 software. Results: In formulas with anthropometric data, the mean absolute error (MAE) using Hoek’s formula was 2.38, the MAE using Grubb’s 1 formula was 4.13, the MAE using Sjöström’s formula was 2.90, and the MAE using Cockcroft and Gault formula based on creatinine was 4.42. On the other hand, in formulas without an anthropometric data group, the MAE using Larsson’s formula was 3.07, and the MAE using Grubb’s 2 formula was 3.63. Conclusion: These results suggested that Hoek’s formula is the most useful formula for determining the initial dosage settings for vancomycin.Correspondence to:
K. Suemaru, PhD, Division of Pharmacy, Ehime University Hospital, 454 Shitsukawa, Toon, Ehime 791-0295, Japan
Email: suemaru@m.ehime-u.ac.jp

Abstract

R. Farah and J. Awad

¹Department of Internal Medicine F, ²Internal Medicine A Department, Western Galilee Hospital, Nahariya, Israel
We report a new case of a patient suffering from chronic hepatitis C (CHC) and treated with interferon-α_2a (IFN-α) who presented with the diagnosis of active pulmonary tuberculosis. Interferon was stopped and appropriate treatment with antituberculous drugs initiated. Several weeks later the patient was free of clinical symptoms. Our case demonstrates a rare association between interferon and tuberculosis since only one case in the literature has described a similar association.Correspondence to:
R. Farah, MD, Herzel Str. 122/7 Nahariya 22448, Department of Internal Medicine F, Western Galilee Hospital, P.O.B. 21, Nahariya 22100, Israel
Email: Raymond.Farah@naharia.health.gov.il

Abstract

W.M. Sweileh

Clinical Pharmacology, College of Pharmacy, Clinical Pharmacy Graduate Program, An-Najah National University, Nablus, Palestine
Objective: Low-dose aspirin and diuretics are commonly co-utilized in patients with cardiovascular diseases. The objective of this study was to investigate the effects of a low-dose aspirin-diuretic drug combination on renal function. Methods: In this cross-sectional retrospective study, all patients, excluding those on renal dialysis, admitted to the Internal Medicine Department of the Al-Watani Hospital, Nablus, Palestine, were included in the study. Medical data were obtained from patients’ medical files. Estimation of creatinine clearance was carried out using the Cockcroft-Gault equation. Patients on the target drug combination were compared with patients who were not receiving the target drug combination. An independent paired t-test and 1-way ANOVA were used to test for significance between groups. Statistics were carried out using the Statistical Package for Social Sciences (SPSS), version 13. Results: A total of 340 subjects (54.4% men) were included in the study. There were 90 patients on the target drug combination and designated as the study group. Of the remaining 250 patients comprising the control group, 114 received none of the target drugs and 136 received only one target medication. There was a significant (p < 0.001) difference in the levels of creatinine clearance between the two groups. Patients on the target drug combination had significantly lower creatinine clearance levels than those in the control group. Men in the study group had lower creatinine clearances than men in the control group and similar results were found for women. Patients in the study group with >= 2 chronic diseases, had lower creatinine clearances than patients in the control group with >= 2 chronic diseases. Similar results were found in patients with < 2 chronic diseases. Conclusion: Administration of a low-dose aspirin-diuretic drug combination was associated with significantly lower creatinine clearance levels. This finding was independent of gender and the number of chronic diseases present. Monitoring kidney function in patients receiving this drug combination is recommended.Correspondence to:
W.M. Sweileh, PhD, Associate Professor, Clinical Pharmacology, Dean, College of Pharmacy, Chairman, Clinical Pharmacy Graduate Program, An-Najah National University, Nablus, Palestine
Email: waleedsweileh@najah.edu

Abstract

D. Rosique-Robles, J.M. Vicent Verge, J. Borrás-Blasco, V. Giner-Marco, E. Casterá, A. Galan-Brotons and J. Abad

¹Hospital Pharmacy, Pharmacy Service, ²Clinical Oncology, Oncology Service, Hospital de Sagunto, Spain
Objective: To report the successful desensitization of a patient with a hypersensitivity reaction to oxaliplatin. Case summary: A 57-year-old woman with metastatic colon cancer was receiving oxaliplatin, fluorouracil and leucovorin every 2 weeks and showed a partial response to therapy. During the fourth cycle, an anaphylactic reaction with palpitations and rash occurred. The patient was hypotensive with mild pulmonary wheezing. Since oxaliplatin was the probable cause of the hypersensitivity reaction, therapy with this drug was discontinued. Therapy in the patient was continued using cetuximab and irinotecan but this resulted in progression of the cancer. In view of the initial satisfactory response to the oxaliplatin-based regimen, it was decided to attempt desensitization to oxaliplatin using a protocol adapted from carboplatin regimens. The desensitization procedure was successful and the patient subsequently tolerated an additional three cycles using this regimen without further symptoms of hypersensitivity. Discussion: In cases with moderate-to-severe reactions to oxaliplatin, reexposure is not usually considered. However, a need to use first-line therapy when there is recurrence of the cancer has encouraged the development of rapid desensitization procedures which allow patients to be treated with medications to which they have previously shown hypersensitivity reactions. A combination of premedication using intravenous dexamethasone and a desensitization regimen was designed which was used successfully to increase concentrations and flow rates of oxaliplatin. Conclusions: Hypersensitivity reactions to oxaliplatin are not rare and physicians need to be aware of these. When substitution of another antineoplastic drug is not feasible, oxaliplatin desensitization should be considered even when hypersensitivity reactions to oxaliplatin are severe.
Correspondence to:
J. Borrás-Blasco, PharmD, PhD, Pharmacy Department, Hospital de Sagunto, Avda Ramon y Cajal s/n. Sagunto 46520 (Valencia) Spain
Email: jborrasb@sefh.es

Abstract

E.R.W. van den Tweel, M. Relleke and P. Muniz Piniella

Clinical R&D Department, Synthon BV, Nijmegen, The Netherlands
Objective: This study was undertaken to compare the pharmacokinetic profiles of paroxetine oral solution and paroxetine tablets in healthy volunteers under fasting conditions. Methods: In this randomized, openlabel, single-dose, 2-way cross over, laboratory-blind bioequivalence study healthy volunteers alternately received one 20 mg dose paroxetine as an oral solution (20 mg/20 drops) and one 20 mg dose paroxetine as a tablet. Doses were separated by a 23-day interval. Results: A total of 48 subjects enrolled in the study; there were 26 males and 22 females with a median age of 25.5 years and a median weight of 73.6 kg. Both formulations were well tolerated, with no serious adverse events reported. Two subjects discontinued the study. Paroxetine was rapidly absorbed, the rate and extent of absorption of the two formulations were similar, and no statistically significant differences in half-life were observed between formulations. Conclusion: The oral solution and tablet formulations of paroxetine were bioequivalent and therefore may be safely interchanged. The oral solution may be a useful tool to ease administration and for tapering off paroxetine treatment.Correspondence to:
E.R.W. van den Tweel, PhD, Clinical R&D Department, Synthon BV, P.O. Box 7071, 6503 GN Nijmegen, The Netherlands
Email: Evelyn.vandentweel@synthon.nl

Abstract

A.M. Al-Mohizea, A.A. Kadi, A.M. Al-Bekairi, S.A. Al-Balla, M.J. Al-Yamani, K.I. Al-Khamis, E.M. Niazy and Y.M. El-Sayed

¹Department of Pharmaceutics, College of Pharmacy, King Saud University, ²Department of Medicine, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia
This study was done to compare the bioavailability of a new tablet formulation of gemifloxacin (gemifloxacin 320 mg/tablet) with that of the reference product (factive 320 mg/tablet). The bioequivalence of a single dose (320 mg) was assessed for gemifloxacin included in the test and reference products by comparing the pharmacokinetic parameters derived from the plasma concentration-time profiles following administration to 24 healthy male volunteers in a balanced, 2-period, 2-sequence, 2-way crossover design. Plasma concentrations of gemifloxacin were analyzed by a validated and sensitive HPLC assay developed in-house. The mean plasma concentration-time profiles are almost superimposable. 18 ANOVAs were performed to compare gemifloxacin plasma levels of the two formulations at each sampling time and there were no statistical differences between the two formulations. The parameters used to measure bioavailability were AUC0-t, AUC0-¥ and Cmax and they were calculated by a model-independent method. The parametric 90% confidence intervals of the mean values for the test/reference ratio were in each case well within the bioequivalence acceptable boundaries of 80 – 125% for AUC0-t, AUC0-¥ and Cmax. Data obtained in this study prove, by appropriate statistical methods, the essential similarity of plasma levels of gemifloxacin from the test product with those from the reference product suggesting equal clinical efficacy of these two products.
Correspondence to:
A.M. Al-Mohizea, PhD, Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
Email: amohizea@ksu.edu.sa

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Volume 45, No. 11/2007(November)