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Abstract

Y. Kobayashi, H. Yasuba, M. Kudou, K. Hamada and H. Kita

Department of Respiratory Medicine, Takatsuki Red Cross Hospital, Osaka, Japan
Background: Esophageal candidiasis is one of the local side effects of inhaled corticosteroid treatment, and it is difficult to prevent this condition. Our previous report indicated that the prevalence of esophageal candidiasis among patients treated with inhaled fluticasone propionate dry powder (FP-dp) reached up to 37% in Japanese patients. Although a reduction in the daily dose of inhaled FP-dp can eliminate this infection, it may lead to asthma not being well-controlled in these patients. Objective: The aim of this study was to estimate whether switching to an equal daily dose of inhaled hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP), the oropharyngeal deposition of which is very low, can eliminate the infection without deterioration of asthma. Methods: A total of 10 stable asthmatic patients with esophageal candidiasis, induced by inhaled FP-dp treatment (400 or 800 mg/ day), were enrolled in this study. A second upper GI endoscopy was performed, more than 1 month but less than 3 months after switching to an equal dose of inhaled HFA-BDP with a tube spacer device, Duopacer. The patients’ medications were not changed during the study. Results: Esophageal candidiasis was eliminated in 9 of the 10 patients. The degree of candidiasis reduced in another patient. The forced expiratory volume in 1 sec (FEV1.0) did not worsen during the study. Conclusion: Switching from FP-dp to HFA-BDP with Duopacer is useful in preventing esophageal candidiasis. Correspondence to:
Y. Kobayashi, MD
Department of Respiratory Medicine
Takatsuki Red Cross Hospital
1-1-1, Abuno, Takatsuki, Osaka 569-1096, Japan
Email: yums13yk@takatsuki.jrc.or.jp

Abstract

T. Bildik, M. Tamar, S. Korkmaz, S. Gokcen, B. Ozbaran and S. Erermis

Department of Child Psychiatry, School of Medicine, Ege University, Izmir, Turkey
Observations made with lamotrigine add-on therapy with venlafaxine in this case give clues for some aspects of its use in adolescent-onset bipolar II disorder. An 18-year-old adolescent boy with a 3-year history of bipolar II disorder had experienced 2 episodes of hypomania and 4 episodes of major depression. He had been depressed for the last 3 months and had taken olanzapine 5 mg daily for over 6 weeks as mood stabilizer but was still depressed at referral. Other aspects of the patient history included anhedonia, psychomotor retardation, poor concentration, a feeling of hopelessness, hypersomnia, overeating, weight gain, low energy and a refusal to attend school. Parents reported that his symptoms had recently become more severe. His medicine was replaced by venlafaxine, which has a more rapid onset of action and is often used in bipolar depression, especially in patients with atypical depression. Since the clinical response at 6 weeks was only partial, lamotrigine was added to this regimen. The patient responded to lamotrigine after 3 weeks of treatment while on a dose of 50 mg/ day. After 6 weeks of treatment, whilst on a dose of 75 mg/day, his symptoms remitted completely with no evidence of any adverse effects. At the time of publication of this article, the patient had remained euthymic for a total of 8 months. The present report shows that lamotrigine add-on therapy with venlafaxine facilitated clinical remission and that this combination is well tolerated.Correspondence to:
Tezan Bildik, MD
Ege Üniversitesi TIP Fakültesi
Çocuk Psikiyatrisi AD
35100 Bornova, Izmir, Turkey
Email: tezanbildik@yahoo.com

Abstract

M. Margreiter, K. Ludl, W. Phleps and S.T. Kaehler

¹Private Practice, Kundl,
²Novartis Consumer Health – Gebro GmbH, Fieberbrunn, Austria
A multicenter, parallel-group, randomized, double-blind, active-controlled clinical trial, involving 169 outpatients at 9 centers, was conducted to assess the efficacy of a fixed bacterium combination of Lactobacillus gasseri and Bifidobacterium longum in the therapy of acute diarrhea. In particular, this clinical trial was designed to prove equivalent therapeutic efficacy of a fixed bacterium combination versus an exhaustive investigated mono-bacterium medicinal product. All patients, free to carry on usual daily activities, received 1 capsule 3 times a day of either a fixed bacterium combination of Lactobacillus gasseri and Bifidobacterium longum or Enterococcus faecium mono-bacterium. All treatments were continued for a maximum of 6 days in line with the normal course of acute diarrhea. Primary efficacy criterion was the severity and duration of diarrhea assessed by the ensemble of stool frequency as change from baseline and stool consistency at trial Day 2, 3 and 4, and time in days until normal bowel function (recovery). The median duration of diarrhea was 2.70 days versus 2.67 days (fixed bacterium combination of Lactobacillus gasseri and Bifidobacterium longum versus mono-bacterium Enterococcus feacium). The total mean difference of duration of diarrhea was –0.072 days. This result can be considered equivalent. However, the proportion of patients with complete recovery tended to be higher in the fixed bacterium combination group (92.6% versus 87.1%) resulting in a number needed to treat (NNT) of 18.1. The fixed bacterium combination reduced the number of unformed stools by 80% and the mono-bacterium by 75% during the first 2 days of treatment. Both treatments were well tolerated. Oral therapy with a fixed combination of Lactobacillus gasseri and Bifidobacterium longum shortens the duration and decreases the severity of acute self-limiting diarrhea in adults comparable to an effective mono-bacterium medicinal product. It therefore appears to be a useful and safe treatment for this disease.Correspondence to:
S.T. Kaehler, PhD
Medical Department
Novartis Consumer Health – Gebro GmbH
6391 Fieberbrunn, Austria
Email: stefan.kaehler@gebro.com

Abstract

G. Wensing, R. Bauer, S. Unger, G. Rohde and R. Heinig

¹Instiute of Clinical Pharmacology, ²Department of Biometry, Bayer HealthCare AG, Wuppertal, Germany
Objectives: To investigate the pharmacodynamic effects of the combined administration of vardenafil and ethanol on blood pressure and heart rate and to study the mutual pharmacokinetic interaction, safety and tolerability of the combination. Methods: 12 healthy male subjects aged 18 – 45 years received 3 different single-dose treatments in a randomized, double-blind, placebo-controlled crossover design: 20 mg vardenafil plus 0.5 g/kg ethanol, vardenafil plus placebo and ethanol plus placebo. Heart rate (HR) as well as systolic (SBP) and diastolic blood pressure (DBP) were measured in supine position after 15 min of rest at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 15 and 24 h post dosing using a validated oscillometric sphygmomanometer. Vardenafil, vardenafil metabolite M-1 and ethanol pharmacokinetics were assessed. Results: There were no statistically significant differences between treatments in DBP and SBP. Significantly higher increases in HR were seen when the combination vardenafil/ethanol and ethanol/placebo treatment, respectively, was compared with vardenafil/placebo treatment. The difference between the 2 treatments including ethanol, however, was not significant. All hemodynamic changes were not clinically relevant. The pharmacokinetics of vardenafil and ethanol were not changed in the treatment “vardenafil + ethanol” compared to the respective treatment with vardenafil and ethanol alone. The most frequently reported adverse events were vasodilation and nasal congestion, well-known side effects of PDE-5 inhibitors such as vardenafil. Conclusion: Concomitant administration of vardenafil and alcohol was well-tolerated. No clinically relevant pharmacodynamic or pharmacokinetic interactions were detected.Correspondence to:
PD Dr. med. G. Wensing
Head Pharmacodynamics
Bayer HealthCare AG
Global Clinical Pharmacology, Pharmacodynamics
42096 Wuppertal, Germany
Email: georg.wensing@bayerhealthcare.com

Abstract

A. Lupp, U.D. Kuhn, E. Karge, G. Adam and C. Fleck

¹Institute of Pharmacology and Toxicology, ²Institute of Clinical Pharmacology, and ³Department of General and Visceral Surgery, Friedrich Schiller University, Jena, Germany
Objective: The use of cyclosporin A (CSA) and tacrolimus (TAC) in organ transplantation and in the therapy of immune disorders is often hampered by adverse effects, mainly nephro-, hepato- and neurotoxicity. For the development of these side effects, among others, an increased formation of reactive oxygen species, probably generated by the cytochrome P450 (CYP) system, has been accused. Since in this respect literature data are inconsistent, in the present study possible pro- and/or antioxidant effects of CSA and TAC and the involvement of the CYP system were re-evaluated in vitro. Methods: Effects of CSA and TAC were examined on CYP mediated oxidase functions by stimulated lipid peroxidation (LPO), H₂O₂ production, and lucigenin (LC) or luminol (LM) amplified chemiluminescence (CL) in liver microsomes of either untreated rats or of rats treated with b-naphthoflavone (BNF), phenobarbital (PB) or dexamethasone (DEX) and in human liver microsomes. Results: In rat liver microsomes, CSA displayed pro-oxidant properties (though only very slightly), whereas in human liver microsomes small antioxidant effects were seen. With TAC in both species the antioxidant capacity prevailed. Treatment of rats with BNF or DEX caused an increase in the pro-oxidant effects of CSA with respect to LPO or LM-CL, whereas in liver microsomes of DEX-treated rats H₂O₂ production and LC-CL were diminished. Conclusions: CSA seems to have both pro-oxidant and antioxidant properties, whereas with TAC mainly an antioxidant capacity was seen. The CYP system seems to be involved in the pro-oxidant influence of CSA. Whether pro-oxidant or antioxidant effects predominate may depend on the antioxidant capacity of a tissue and on the CYP isoforms mainly present. Correspondence to:
PD Dr. habil. A. Lupp Institute of Pharmacology and Toxicology Friedrich Schiller University 07740 Jena, Germany
Email: Amelie.Lupp@mti.uni-jena.de

Abstract

S.G. Yang, D.D. Kim, S.J. Chung and C.K. ShimS.G. Yang, D.D. Kim, S.J. Chung and C.K. Shim

Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Korea
Aim: We recently succeeded in preparing soft gelatin capsules containing a new self-nanoemulsifying formulation consisting of cyclosporin A (CsA), triacetin, polyoxyl 40 hydrogenated castor oil, polysorbate 20, medium chain triglycerides and medium chain mono- and diglycerides. The soft capsules containing the new formulation exhibited a significantly improved physical stability in terms of the appearance of the gelatin capsule shells and the composition of the fill mass during long-term storage, compared to commercially available soft capsules containing CsA, in which ethanol was employed as a cosolvent of CsA. In the present study, the influence of a fat-rich meal on the bioavailability of CsA from the soft capsule containing the new formulation (test drug) was evaluated and the results compared to those obtained with a representative soft capsule of CsA. Volunteers and methods: A randomized, open-label, 3-way crossover study was performed in the test capsules and reference soft capsules, in a fasted state or after a fat-rich breakfast. 18 healthy male volunteers received a single dose of the reference formulation (Neoral, Novartis AG, Basel, Switzerland) or test formulation (2 capsules each, 200 mg as CsA) with 240 ml of water with a 1-week washout period between the treatments, after a fat-rich (670 kcal, 45 g fat) breakfast (for the test drug, Treatment A; for the reference drug, Treatment B) or a 12-h fasting (for the test drug, Treatment C). Serial blood samples, collected over a 24-h period after the administration, were assayed for blood CsA concentrations using a specific monoclonal radioimmunoassay. Results: The differences in bioavailability parameters (i.e., AUC0-24h, AUC0-¥ and Cmax) between the treatments were within the range of 80 – 125% of the reference treatment. An analysis of variance (ANOVA) revealed no significant differences (p > 0.05) between subjects, formulations or periods. The 90% confidence intervals (CI) indicated that the differences between the treatments (Treatments A and B, Treatments A and C) were also within the criteria. Conclusion: These results indicate that the bioavailability of CsA from the test drug is equivalent to reference in the fed state, and is likely to be less influenced by a fat-rich meal. Therefore, the new formulation of CsA using triacetin appears to have an advantage over the commercial soft capsules of CsA using a volatile cosolvent such as ethanol.Correspondence to:
C.-K. Shim, PhD
Department of Pharmaceutics
College of Pharmacy
Seoul National University
San 56-1, Shinlim-dong, Kwanak-gu, Seoul, 151-742, Korea
Email: shimck@snu.ac.kr

Abstract

J.F. Marier¹, H. Manthos¹, S. Kebir¹, S. Ferron¹, M. DiMarco¹, G. Morelli¹, S.K. Tippabhotla², T. Vijan², A.K. Singla², M. Garg² and T. Monif²

¹MDS Pharma Services, Montreal, Quebec, Canada, and
²Ranbaxy Laboratories Limited, Haryana, India
Aim: Zidovudine is a synthetic nucleoside analogue of thymidine with activity against the human immunodeficiency virus type 1 (HIV-1). In patients with HIV infections or the acquired immunodeficiency syndrome (AIDS), zidovudine is a first-line therapy that was shown to reduce morbidity, mortality, and hospitalization. A generic formulation of zidovudine offers the possibility of considerable savings to HIV/AIDS patients in developed and Third World countries. The objective of the current study was to characterize the pharmacokinetic and safety profiles of zidovudine administered as a generic tablet formulation relative to the innovator product. Volunteers and methods: A total of 68 healthy adult volunteers received a 300 mg oral dose of zidovudine as the generic formulation (AVIRO-Z 300 mg tablet, Ranbaxy Laboratories Limited) and as the innovator product (Retrovir® tablet, GlaxoSmithKline) in a randomized, 2-way crossover study. Multiple blood samples were collected over 12 hours and plasma concentrations of zidovudine were assayed using an LC/MS/MS method with an analytical range of 5.00 to 2,000 ng/ml. Pharmacokinetic parameters were calculated using non-compartmental methods. Results: Mean plasma concentrations of zidovudine declined in a mono-exponential manner, with mean concentration values falling below the limit of quantitation 12 hours after administration of both formulations. Mean area under the curve from time 0 to the last measurable concentration (AUC0-t), mean area under the curve from time 0 to infinity (AUC0-¥) and peak plasma concentrations (Cmax) of zidovudine for the generic tablet formulation (2,220.6 ng ´ h/ml, 2,236.0 ng ´ h/ml and 1,087.9 ng/ml, respectively) were very similar to those observed for the innovator product (2,139.7 ng ´ h/ml, 2,158.6 ng ´ h/ml and 1,066.5 ng/ml, respectively). Ratios of least-squares means and 90% confidence intervals of AUC0-t, AUC0-¥ and Cmax between the 2 formulations were within 80 – 125%, suggesting that the two tablet formulations displayed similar rate and extent of bioavailability. The oral clearance (CL/F) of zidovudine for the generic and innovator formulations were 2.11 l/h/kg and 2.16 l/h/kg, respectively. For the two formulations, adverse events were similar in nature and frequency. Conclusion: Since the two formulations displayed similar in vivo delivery rate of zidovudine in the bloodstream, the generic tablet formulation of zidovudine developed by Ranbaxy should be equally effective as the innovator product and is expected to produce considerable cost-savings in AIDS patients worldwide.Correspondence to:
Tausif Monif, PhD
Department of Clinical Pharmacology and Pharmacokinetics
Ranbaxy Laboratories Limited, Plot No. 20, Sector-18
Udyog Vihar Industrial Area
Gurgaon – 122 001, Haryana, India
Email: sudhakar.tippabhotla@ranbaxy.com

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Volume 44, No. 5/2006(May)