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Abstract

K.K. Chandra, S. Malhotra, M. Gupta, A. Grover, N. Sharma and P. Pandhi

¹Department of Pharmacology, ²Department of Cardiology, and
³Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Objective: The current study was designed to investigate drug utilization in the management of unstable angina in India and to examine the changing trends in the management of unstable angina over the past 4 years. Methods: We conducted a prescription survey to examine the use of antianginal drugs in patients with unstable angina in a tertiary care Indian hospital. The use of concurrent medications such as antidiabetic, antihypertensive and lipid-lowering agents was also examined. This study results were compared with a similar study done in this institute 4 years earlier. Results: A total of 159 consecutive prescriptions were evaluated. Aspirin (86%), nitroglycerin infusion (77%) and low-molecular weight heparins (93%) were the most frequently prescribed drugs. Enoxaparin accounted for 76% of the total LMWH use. One of the heparins was used by 92% of all patients, angiotensin-converting enzyme inhibitors (ACEIs) and b-blockers by 70% and 67%, respectively. Lipid-lowering agents (57%), antidiabetic agents (16%) and antianxiety agents (33%), in addition to antianginals, were also frequently co-administered. Time trend analysis showed that the use of unfractionated heparin fell from 35% to 10% and the use of ACEIs and enoxaparin increased from 17% to 70% and from 51% to 71%, respectively. Conclusions: The study showed that unfractionated heparin is less frequently used in the treatment of unstable angina than in the past and that ACEIs are preferred to calcium channel blockers. Enoxaparin remains the most commonly used low-molecular weight heparin for this indication. A variety of low-molecular weight heparins are available for therapy but comparative clinical trials of efficacy and pharmacoeconomic studies comparing the various LMWHs still need to be carried out.Correspondence to:
Dr. P. Pandhi
Department of Pharmacology
Postgraduate Institute of Medical Education and Research
Chandigarh – 160012, India
Email: ppandhi17@hotmail.com, medinst@pgi.chd.nic.in

Abstract

T. Engl, W.-D. Beecken, M. Wolfram, D. Jonas and

Department of Urology and Pediatric Urology, Johann Wolfgang Goethe University, Frankfurt/Main, Germany
Because of the increasing percentage of the world male population suffering from erectile dysfunction (ED) and benign prostate syndrome (BPS), there is a need for new and innovative therapeutic approaches. Pharmacotherapy is an avenue presently being followed in the treatment of both these syndromes. A profound change in the therapy of ED has been obtained through use of the selective phosphodiesterase inhibitor sildenafil. The incidence of surgical intervention in BPS has been reduced by the introduction of uroselective a₁-receptor antagonists and the new 5a-reductase inhibitors (such as finasteride, dutasteride). The investigation of mechanisms in CXC chemokine expression also offers new therapeutic possibilities in these diseases.Correspondence to:
Dr. T. Engl Department of Urology and Pediatric Urology Johann Wolfgang Goethe University Theodor-Stern-Kai 7 D-60590 Frankfurt am Main, Germany
Email: Engl@em.uni-frankfurt.de

Abstract

A.-R. van Troostenburg, E.V. Clark, W.D.H. Carey, S.J. Warrington, W.D. Kerns, I. Cohn, M.H. Silverman, S. Bar-Yehuda, K.-L.L. Fong and P. Fishman

¹HMR, Central Middlesex Hospital, London, UK, ²CanFite BioPharma Ltd., Petach-Tikva, Israel, and ³Calvert Laboratories, Inc., Olyphant, PA, USA
Objectives: To assess safety, tolerability, pharmacokinetics and hemodynamic effects of oral CF101, an A3 adenosine receptor (A3AR) agonist, in healthy men. Methods: One single and 1 repeated dose, parallel-group, ascending dose, double-blind and placebo-controlled study in normal volunteers. In the single dose study, n = 15 subjects received 1, 5 or 10 mg oral CF101; in each group 1 subject received placebo, the remainder active CF101. In the repeat-dose study, n = 28 subjects received repeated 12-hourly oral doses of CF101 (2, 3, 4 or 5 mg) for 7 days, in each group 2 subjects received placebo, the remainder active CF101. Test materials: Single-dose study: CF101 in 30% Cremophor RH40. Multiple-dose study: CF101 in 0.5% methylcellulose suspension. Both studies: the corresponding vehicles were used as placebos. Galenicals were prepared remotely from the clinical study site to ensure double-blind nature of the study. Results tolerability: Single doses up to 5 mg CF101 were safe and well-tolerated. However, the single dose of 10 mg CF101 was associated with flushing, tachycardia, nausea and vomiting, which were viewed as dose-limiting in normal volunteers. Single doses of CF101 (as well as the first of the multiple doses) were associated with increases in heart rate (8 – 24 beats/min after 5 mg and 18 – 55 beats/min after 10 mg). Multiple doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. However, the 5 mg multiple-dose group reported headache, drowsiness, hot flushes and dizziness on standing; this declined with dosing duration and was not dose-limiting in this study. Adverse events were commonest near tmax. Results pharmacokinetics: For oral CF101, the tmax was always 1 – 2 h post-dose and t1/2 about 9 h, in both the single- and multiple-dose studies. For a single 5 mg dose (mean ± SD) Cmax = 81.6 ± 23.6 ng/ml in the single dose study, and 63.6 ± 22.0 ng/ml after the first of the multiple doses; AUCinf was 904.0 ± 221.9 ng.h/ml and 596.1 ± 196.6 ng.h/ml for the 2 studies, respectively. After 7 days of multiple dosing there was little change, and AUC0-24h = 601.0 ± 163.6 ng.h/ml. These pharmacokinetic parameters were linearly proportional to dose in the other treatment groups. Results pharmacodynamics: Increases in heart rate were related to plasma concentration and evident only in the upper range of concentrations observed. There were no changes on ECG monitoring beyond sinus tachycardia, and, in particular, no evidence of PR prolongation in any subject (n = 43). In comparison with single doses, this response was almost absent after 7 days of dosing. Leucocytosis (increases up to about 1.5 × 109/l after 5 and 10 mg) was similarly transient and reversible after multiple dosing. Conclusions: Single oral doses up to 5 mg CF101 and repeated doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. Multiple-dose CF101 pharmacokinetics were unchanged and predictable from single-dose estimates, and were linearly proportional to dose. Increases in heart rate and neutrophil count were reversible during multiple dosing and were not dose-limiting in the repeat dose study. CF101 warrants further study for its efficacy in treating human disease.Correspondence to:
Dr. S. Warrington
Hammersmith Medicines Research (HMR)
Central Middlesex Hospital
London, NW10 7NS, UK
Email: swarrington@hmrlondon.com

Abstract

S. Schröder¹, A. Jetter¹, M. Zaigler¹, R. Weyhenmeyer², G. Krumbiegel², W. Wächter² and U. Fuhr¹

¹Department of Pharmacology, Clinical Pharmacology, University of Cologne, Cologne, and ²Madaus AG, Cologne, Germany
Background and objectives: The antimuscarinic drug trospium chloride is hydrophilic and therefore does not enter the CNS when used for the treatment of overactive bladder disturbances. However, the same property is the main reason for low and variable oral bioavailability. The present study was performed to assess the influence of intestinal site on absorption of the drug as the basis for the development of modified release preparations. Methods: In a change-over pilot study, 8 healthy male volunteers received single 20 mg doses of trospium chloride orally as a tablet (reference), as Eudragit-coated tablets dissolving at pH 6.0 (local administration into the small intestine), and rectally via a mini enema (corresponding to local administration into the large intestine). Plasma concentrations of trospium chloride were determined up to 36 hours after administration using GC/MS. Results: Extent and rate of trospium chloride absorption declined rapidly upon administration into more distal regions of the gastrointestinal tract. Cmax (median: 6.42 ng/ml) and AUC(0-tlast) (42.28 ng/ml × h) were highest and tmax (3.5 h) was shortest after administration of the reference tablet. AUC(0-tlast) reached 78% (90% CI 43 – 139%) after small intestine administration and 2% (90% CI 1 – 9%) following rectal administration, respectively, relative to the values for the oral tablet. Conclusion: Trospium chloride is absorbed primarily in the upper gastrointestinal tract. Development of modified release preparations must balance prolonged apparent absorption rates of the drug against a decrease in bioavailability.
Correspondence to:
Prof. Dr. U. Fuhr
Department of Pharmacology
University of Cologne, Clinical Pharmacology
Gleueler Straße 24
D-50931 Köln, Germany
Email: uwe.fuhr@medizin.uni-koeln.de

Abstract

M. Tandon, P. Pandhi, S.K. Garg and S.K. Prabhakar

¹Department of Pharmacology, and ²Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Introduction: The antiepileptic drug phenytoin has a high degree of plasma protein binding. Therefore, total phenytoin levels in plasma are misleading indicators of clinical efficacy. This study was designed to investigate whether serum albumin-adjusted phenytoin levels in Indian patients with epilepsy predict clinical outcome better than total phenytoin levels. Patients and methods: Fifty patients with epilepsy were included in the study and were followed-up for a period of 6 months. Serum albumin levels were estimated spectrophotometrically using the bromocresol green dye method, and serum phenytoin levels were estimated using high pressure liquid chromatography. Values were expressed as mean ± SEM. Corrected phenytoin levels were calculated using the Sheiner-Tozer equation.

Corrected phenytoin levels =
Measured total phenytoin (mmol/l) / {(albumin g/l ×0.9)+0.1/40}

Results: At Visit 1, mean serum albumin levels were 44.1 ± 1.1 mmol/l and mean serum phenytoin levels were 33.9 ± 2.8 g/l. After correction of the total phenytoin levels using the Sheiner-Tozer equation, 30% of the patients shifted to a different category. The follow-up visits showed similar results. Throughout the study, the corrected phenytoin levels were better indicators of clinical outcome than the total levels. In 23% of patients there was a significant difference between total and corrected phenytoin levels. Conclusion: In patients with serum albumin levels in the hyper- and hypoalbuminemic range, corrected phenytoin levels were better indicators of clinical outcome. In developing countries like India, where estimation of free drug levels is expensive and suitable equipment is not available in most centers, serum albumin-adjusted levels can be used by pharmacologists to predict response and thus assist in clinical decision-making.Correspondence to:
Dr. P. Pandhi
Department of Pharmacology
Postgraduate Institute of Medical Education and Research
Chandigarh 160012, India
Email: ppandhi17@hotmail.com, medinst@pgi.chd.nic.in

Abstract

B. Meyer¹, F. Traunmüller¹, A. Hamwi³, U.M. Hollenstein¹, G.J. Locker², W.R. Sperr², T. Staudinger², R. Thalhammer-Scherrer³, H. Burgmann¹ and F. Thalhammer¹

¹Department of Internal Medicine I, Division of Infectious Diseases,
²Department of Internal Medicine I, Intensive Care Unit, and
³Department of Laboratory Medicine, University of Vienna, Austria
Objective: Continuous venovenous hemofiltration (CVVH) is widely used in the management of critically ill patients, but only few administration guidelines for antimicrobial drugs are available. It is unclear whether the use of a filter for more than 24 hours might lead to less efficient extraction. This study describes the pharmacokinetics of teicoplanin during CVVH using a highly permeable membrane. Methods: Pharmacokinetics of teicoplanin during continuous hemofiltration with a new (group 1) and a 24-h used (group 2), highly permeable polyamide membrane were assessed in 3 patients. Results: The teicoplanin serum concentrations (44.0 ± 18.5 mg/l vs 109.5 ± 34.5 mg/l) and half-life of teicoplanin (4.6 ± 1.1 h vs 5.2 ± 0.7 h) differed significantly between the 2 groups indicating a smaller elimination of the drug on the second day. Substantial binding of teicoplanin to filter membranes could explain this observation. Conclusion: The results suggest that daily adjustment of the dosage is necessary to achieve sufficient teicoplanin concentrations and a fixed dosage recommendation is not suitable for this drug.
Correspondence to:
Prof. Dr. F. Thalhammer
Department of Internal Medicine I
Division of Infectious Diseases
Währinger Gürtel 18-20
A-1090 Vienna, Austria
Email: florian.thalhammer@meduniwien.ac.at

Abstract

A.M. Rossi, V. Maggini, E. Fredianelli, D. Di Bello, A. Pietrabissa, F. Mosca, R. Barale and G.M. Pacifici

¹Department of Human and Environmental Sciences, Laboratory of Genetics and Environmental Mutagenesis, ²Department of Neurosciences, Section of Pharmacology, Medical School, Pisa, and ³Department of Oncology, Section of Surgery, Cisanello Hospital at the
Human sulfotransferases catalyze sulfate conjugation and 2 polymorphic genes, SULT1A1 and SULT1A2 in this family of transferases have been identified, encoding for 2 isoenzymes with very similar properties and substrate specificities. In order to test the hypothesis that variability in sulfation is due to genetic polymorphism in SULT1A1, the sulfation rate of 4-nitrophenol, a diagnostic substrate, was measured in 50 human liver samples and the genotype at the SULT1A1 locus was analyzed. The rate of 4-nitrophenol sulfation varied from 473 – 1,405 pmol/min/mg between the 5th and 95th percentiles, with a median and a mean ± SD of 757 and 807 ± 292 pmol/min/mg, respectively. The activities detected among the SULT1A1*2/*2 homozygotes (5 cases) were significantly lower than those of the other 2 genotypes, SULT1A1*1/*1 and SULT1A1*1/*2 (5 and 40 cases, respectively), whereas there was no significant difference found between the SULT1A1*1/*1 and SULT1A1*1/*2 genotypes. To evaluate the possible influence of SULT1A2 polymorphism, genotype assays were also performed for this locus. No SULT1A2*2/*2 carrier, 26 SULT1A2*1/*1 and 24 SULT1A2*1/*2 were detected in the population sample under study. However, no correlation between the rate of 4-nitrophenol sulfation and the SULT1A2 genotype was detected. These results confirm that the variation in the rate of 4-nitrophenol sulfation in human liver is mainly due to SULT1A1. Since SULT1A1*1/*2 polymorphism accounts for no more than 10% of the phenotypic variation seen in this cohort, other factors must also contribute to the variability in the rate of 4-nitrophenol sulfation in human liver. However, on the basis of the data obtained, variations in age, gender and liver function as possible causative factors can be excluded. The IC50 of quercetin, a potent inhibitor of 4-nitrophenol sulfation, was measured in the liver samples and ranged from 4.6 to 17.3 nM between the 5th and 95th percentiles. The median and the mean ± SD were 7.7 nM and 8.3 ± 2.5 nM, respectively. There was a weak but significant correlation between the IC50 value and age of the liver donors (r = 0.283, p = 0.046). The observed variation did not correlate with the genotypes at the SULT1A1 and SULT1A2 loci.Correspondence to:
Dr. G.M. Pacifici
Associate Professor in Pharmacology
Department of Neurosciences
Section of Pharmacology, Medical School
Via Roma 55
I-56126 Pisa, Italy
Email: pacifici@biomed.unipi.it

Abstract

T. Engl, I. Natsheh, I. Müller, W.-D. Beecken, D. Jonas and R.A. Blaheta

Zentrum der Chirurgie, Klinik für Urologie und Kinderurologie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main, Germany
The branched-chain fatty acid valproate (valproic acid; VPA) displays antitumoral properties by blocking tumor growth, progression and invasion. Recent data have shown that VPA reduces the angiogenic activity of endothelial cells. The object of this study was to investigate whether endothelial modulation might also influence the level of chemotactic mediators. Endothelial cells were isolated from human umbilical cord veins (HUVEC) and treated with VPA-concentrations ranging from 0.125 mM to 1 mM. The mRNA level of CXC-chemokines was investigated by reverse transcriptase-polymerase chain reaction. The proliferative activity of HUVEC was measured as well. VPA evoked a striking increase in the neutrophil chemoattractants CXCL1, CXCL3, CXCL4, CXCL5 and a moderate increase in CXCL6 with maximal effects after a 3-day incubation period. Other CXC-chemokines and CXC-receptors remained unaffected. HUVEC growth was diminished time- and dose-dependently by VPA. We conclude that VPA treatment leads to alterations in the chemokine expression profile of endothelial cells. This might allow more neutrophils to reach the tumor area and trigger cytolysis.Correspondence to:
Dr. R. Blaheta
Zentrum der Chirurgie
Klinik für Urologie und Kinderurologie
Wissenschaftliches Labor
J.W.-Goethe-Universitätsklinik, Haus 23 A, EG 7
Theodor-Stern-Kai 7
D–60590 Frankfurt am Main, Germany
Email: Blaheta@em.uni-frankfurt.de

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Volume 42, No. 10/2004(October)