S. Irie, Y. Matsumura, M. Zdravkovic, L.V. Jacobsen and S. Kageyama ¹Kyushu Clinical Pharmacology Research Clinic, Fukuoka, ²Novo Nordisk Pharma Ltd., Tokyo, Japan and ³Novo Nordisk A/S, Bagsvaerd, Denmark and ⁴Division of Clinical Pharmacology and Therapeutics, Jikei University School of Medicine, Tokyo, Japan Objectives: Liraglutide is a once-daily human GLP-1 analog being developed as a Type 2 diabetes therapy. A dose-finding study in Japanese patients with Type 2 diabetes showed liraglutide to produce dosedependent decreases in HbA1C. Studies have also shown that, with stepped dose titration, liraglutide is well tolerated. This double-blind trial in 24 healthy Japanese men assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of once-daily subcutaneous (s.c.) liraglutide using doses exceeding those previously studied, and using the stepped titration approach. Materials and methods: Subjects were randomized to three groups in each of which 6 received liraglutide, and 2 placebo for 35 consecutive days. The daily dose of liraglutide was stepped from 5 µg/kg (s.c. abdomen, morning) to 10 and then 15 µg/kg at 7-day intervals. One group remained at this dose, the others titrating further to 20 and 25 µg/kg, respectively. Subjects remained at the study site from Day 21 until the end of the trial, with standard meals served during inhouse periods. Results: No safety issues, hypoglycemia, gastrointestinal or any other adverse events were observed. Liraglutide showed dose-dependent increases in the pharmacokinetic parameters of AUC0-24h, Cmax and Ctrough, while tmax, t1/2 and Vd/F were constant. Mean plasma glucose concentrations were similar across all treatment groups at baseline, but dose-dependent decreases in mean and postprandial plasma glucose were seen with liraglutide, although all values remained within normal ranges. There was a tendency for weight to decrease with liraglutide in comparison to placebo. Conclusions: Liraglutide appears to be well tolerated at doses of up to 25 mg/kg in Japanese subjects. Despite clear pharmacodynamic effects in this euglycemic cohort, a low risk for hypoglycemia was suggested together with good gastrointestinal tolerability.Correspondence to:
S. Irie, MD, PhD; Head of Kyushu Clinical Pharmacology Research Clinic, 13-16, Jigyo 2-chome, Chuo-ku, Fukuoka, 810-0064, Japan
Email: shin-irie@lta-med.com

S. Jank, T. Bertsche, W. Herzog and W.E. Haefeli ¹Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, ²Cooperation Unit Clinical Pharmacy and ³Department of Internal Medicine II, Psychosomatic and General Internal Medicine, University of Heidelberg, Heidelberg, Germany Objective: In order to use their drugs reliably, safely and correctly patients need to be well informed about their treatment, which applies in particular to critical dose drugs. The aim of this study was to investigate the patients’ knowledge on anticoagulants, and to identify patient characteristics associated with low knowledge. Patients and methods: Based on the Patient Information Leaflet, an 8-item multiple-choice test was developed, pre-tested and adapted. The final version was assessed in terms of readability and distributed to 59 anticoagulated medical inpatients of a German university hospital. The scoring range was 0 – 8 points (each correct answer giving 1 point). Results: The total knowledge level ranged between 12.5% and 87.5% (1/8 – 7/8 points) with an average of 55% (mean 4.4 ± 1.4 points). The topics most often answered not correctly included drug-drug and drug-food interactions. The statistical analysis of the association between knowledge on each topic and patient characteristic revealed a significant correlation between knowledge on drug-drug interactions and the patient’s education (Mann-Whitney-U-test: p = 0.032) and age (r = –0.34; p = 0.015). There was no significant correlation between the total test score and any of the patient characteristics. Conclusion: Healthcare professionals need to be aware that patients on oral anticoagulants may have significant knowledge gaps, particularly concerning drug-drug and drug-food interactions. In practice, the questionnaire, which was short, easy to read, and well accepted, might be used to identify the patients’ knowledge and individual knowledge gaps in order to subsequently tailor information to their needs.

Correspondence to:
Prof. W.E. Haefeli, MD; Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Email: walter.emil.haefeli@med.uni-heidelberg.de

K. Umemura, Y. Ikeda, K. Kondo, K. Hirata, H. Amagishi, Y. Ishihama and Y. Tokura ¹Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, ²Maruho Co., Ltd., Kyoto R and D Center, Kyoto and ³Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan Maxacalcitol (22-oxacalcitriol), a vitamin D3 analogue, is widely used for the treatment of psoriasis in Japan. The effects of topically applied dermatologic preparations have routinely been assessed by their pharmacodynamic profiles and their concentrations in the skin correlate well with these profiles. Objectives: Recently, a maxacalcitol lotion formulation (M514102) was developed for the treatment of psoriatic lesions on the face and scalp. To predict the clinical efficacy of the lotion, we investigated the cutaneous bioavailability of topically applied lotion and compared this with that of its ointment formulation in healthy subjects. Methods: In the first study, 12 subjects were divided into two groups of 6 each and were treated with the ointment or lotion. Six drug application sites were randomly selected on the left volar forearm. After 0, 2, 4, 6, 8 and 10 h, the formulations were gently removed and tape stripping was performed. Maxacalcitol was extracted from the tape strips and quantified by liquid chromatographic tandem mass spectrometry. In the second study, four drug application sites were randomly selected on the left volar forearm in the 12 subjects. The ointment was applied and spread over two sites and the lotion was applied in the same manner over the remaining two sites. After 8 h, the preparations were gently removed and followed by tape stripping. Results: The average concentrations of maxacalcitol in the stratum corneum (SC) at 2, 4, 6, 8 and 10 h after application were 6.9 ± 3.3, 12.8 ± 6.2, 11.8 ± 4.6, 13.1 ± 5.2 and 12.3 ± 3.1 µg/g for the ointment and 3.1 ± 1.0, 9.1 ± 3.1, 13.9 ± 3.4, 13.1 ± 4.1 and 15.5 ± 3.1 µg/g for the lotion, respectively. A steady state was observed at approximately 4 and 6 h after application of the ointment and lotion, respectively. In the second study, there was no significant difference between the average of the SC concentrations of the ointment and lotion at 8 h. Conclusions: In conclusion, we observed that assessment of cutaneous bioavailability by using tape stripping was reproducible. Accordingly, the cutaneous bioavailability of the lotion was comparable to that of its ointment. Hence, treatment with the lotion is expected to be as effective as that with the ointment.Correspondence to:
K. Umemura, MD, PhD; Department of Pharmacology, Hamamatsu University School of Medicine, Handayama 1-20-1, Hamamatsu 432-8014, Japan
Email: umemura@hama-med.ac.jp

M. Dirjomuljono, I. Kristyono, R.R. Tjandrawinata and D. Nofiarny ¹,²Department of Ear, Nose, Throat, Faculty of Medicine, University of Airlangga/Dr. Soetomo General Hospital, Surabaya, ³Dexa Laboratories of Biomolecular Sciences and ⁴Corporate Department of Medical Information and Clinical Research, Dexa Medica Group, Jakarta, Indonesia Acute tonsillopharyngitis is characterized by tonsil or pharyngeal inflammation and mostly is a virus in origin; thus, treatment that covers both the inflammation and inadequate immune response against the pathogenic organism is needed. NSPN extract containing Nigella sativa and Phyllanthus niruri extracts has both antiinflammatory and immunomodulatory effects. A comparative, parallel, randomized, double-blind, placebo-controlled study with a treatment period of 7 days was conducted to examine clinical effectiveness of Nigella sativa and Phyllanthus niruri extract (NSPN extract). Of 200 enrolled patients, 186 patients completed the study, 12 patients withdrew and 2 patients were principally screened failure but inadvertently included. NSPN capsules, each containing 360 mg Nigella sativa and 50 mg Phyllanthus niruri extracts, were orally administered 3 times 1 capsule daily for 7 days. At Hour 5 or 6 of the first dosing of study medication, the sore throat assessed as swallowing pain and difficulty, was markedly alleviated in the NSPN group. In line with the significant alleviation of pain, from Days 0 to 2 of treatment, subjects in the NSPN group also needed significantly less escape “analgesic” therapy (paracetamol tablets) than those in the placebo group. At the end of treatment (Day 7), a significantly greater proportion of patients in the NSPN group than in the placebo group had their sore throat completely relieved. NSPN extract was also found to be safe and well tolerated in acute tonsillopharyngitis patients. This study proved significant benefits of NSPN extract in the treatment of acute tonsillopharyngitis as compared to placebo.Correspondence to:
Prof. M. Dirjomuljono; Department of Ear, Nose, Throat, Faculty of Medicine, University of Airlangga, Dr. Soetomo General Hospital, Surabaya, Graha Elnusa Building 7th Floor, Jl. TB Simatupang Kav 1B, Jakarta 12560, Indonesia
Email: eleanora.anggiara@dexa-media.com

M. Okada, K. Suzuki, M. Matsumoto, K. Takada, M. Nakashima, T. Nakanishi, H. Horikoshi, T. Higuchi, Y. Hosono and F. Ohsuzu

G.D. Mendes, F.D. Mendes, C.C. Domingues, R.A. de Oliveira, M.A. da Silva, L.S. Chen, J.O. Ilha, C.E. Fernandes and G. De Nucci ¹Department of Pharmacology, Faculty of Medical Sciences, ²Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), ³Cartesius Development of Clinical Research, Campinas, SP, and ⁴Institute of Mathematics and Statistics, Department of Statistics, University of São Paulo (USP), and ⁵Department of Gynecology and Obstetrics, ABC Faculty of Medical Sciences, São Paulo, SP, Brazil Objective: To assess the bioequivalence of three ibuprofen formulations (Test formulation: ibuprofen (400 mg capsule) manufactured by Cardinal Health Brasil 402 Ltda. (Sorocaba, Brazil) and licensed to Boehringer Ingelheim do Brasil Quim. e Farm. Ltda. (São Paulo, Brazil); Reference formulation (1): ibuprofen (Advil®; 2 × 200 mg coated tablet) from Wyeth-Whitehall Ltda. (Itapevi, Brazil); Reference formulation (2): ibuprofen (Alivium®; 8 ml × 50 mg/ml solution) from Schering Plough S.A. (Rio de Janeiro, Brazil)) in 24 healthy volunteers of both sexes. Methods: The study was conducted using an open, randomized, three-period crossover design with at least 5-day washout interval. Plasma samples were obtained over a 24-h period. Plasma ibuprofen concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) with negative ion electrospray ionization using multiple reaction monitoring (MRM). The following pharmacokinetic parameters were obtained from the ibuprofen plasma concentration vs. time curves: AUClast, AUCtrunctmax, AUCinf and Cmax. Results: The limit of quantification for ibuprofen was 0.1 µg × ml–1. The geometric mean with corresponding 90% confidence interval (CI) for Test/Reference (1) percent ratios were 114.24% (90% CI = 105.67, 123.50%) for Cmax, 98.97% (90% CI = 94.69, 103.44%) for AUClast and 99.40% (90% CI = 95.21, 103.78%) for AUCinf. The geometric mean and respective 90% confidence interval (CI) for Test/Reference (2) percent ratios were 108.38% (90% CI = 100.19, 117.25%) for Cmax, 100.79% (90% CI = 96.39, 105.40%) for AUClast and 101.26% (90% CI = 96.94, 105.77%) for AUCinf; tmax for the 400 mg Test capsule was shorter than that for the 2 × 200 mg Reference (1) tablets (p < 0.002). Conclusion: Since the 90% CI for AUClast, AUCinf and Cmax ratios were within the 80 – 125% interval proposed by the US FDA, it was concluded that ibuprofen formulation manufactured by Cardinal Health Brasil 402 Ltda. and licensed to Boehringer Ingelheim do Brasil Quim. e Farm. Ltda. is bioequivalent to the Advil® and Alivium® formulations with regard to both the rate and the extent of absorption.Correspondence to:
G.D. Mendes, DDS, PhD; 415 Jesuino Marcondes Machado Avenue, Campinas, SP 13092-320, Brazil
Email: gugamendes@terra.com.br

M. Di Marco, J.F. Marier, M.P. Ducharme, I. Morin, C. Engel, S. Gulbranson, N.R. Thudi, D. Murpani, A. Rampal, T. Monif, T.S. Koundinya, K. Deo and T. Monif ¹MDS Pharma Services, St.-Laurent (Montréal), ²Pharsight Co. Québec, QC, Canada, ³Cetero Research, Cary, NC, ⁴MDS Pharma Services, Phoenix, AZ, USA, ⁵Ranbaxy Pharmaceuticals Canada Inc., Mississauga, ON, Canada and ⁶Ranbaxy Laboratories Ltd., Gurgaon, Haryana, India Objective: Orlistat is a reversible lipase inhibitor for obesity management. Orlistat exerts its pharmacological activity in the lumen of the stomach and small intestine by binding with the active site of gastric and pancreatic lipases, with the consequent inhibition of the systemic absorption of dietary fat. The undigested triglycerides are not absorbed, resulting in caloric deficit and positive effect in weight control. The objective of this study was to assess, using fat excreted in feces, the pharmacodynamic equivalence of orlistat when administered as generic and innovator capsule formulations. Materials and methods: A total of 18 healthy volunteers (12 males and 6 females) followed a 5-day run-in diet period in order to become accustomed to a high fat diet. Subjects were then randomized to receive under fed conditions oral doses of orlistat (120 mg) 3 times daily for 10 consecutive days as the generic (Ranbaxy Laboratories) or innovator (Xenical, Roche Laboratories, Nutley, NJ, USA) capsule formulations. Subjects followed a standardized diet (2,500 kcal/day, 30% as fat) for the entire study. Feces were collected over the last 2 days of the run-in period (baseline) and over the last 5 days of the 2 treatment periods. The amount of fat in meals and feces was assayed with a limit of detection of 0.1 and 0.2%, respectively. Fecal fat excretion over 24 hours (FFE24, calculated as the percentage of amount of fat excreted in feces relative to the amount of fat ingested) was used as a pharmacodynamic endpoint to assess the therapeutic equivalence between the 2 orlistat formulations. An analysis of variance (ANOVA) was performed on FFE24 parameters. Results: Mean FFE24 values at baseline and after repeated oral administrations of the generic and innovator formulations of orlistat were 6.48, 20.0 and 19.6%, respectively. The ratio of least-squares means (LSM) of FFE24 of the generic to the innovator formulation was 99.1%, with 90% confidence intervals of 83.8 – 114.5%. Adverse events for the generic and innovator products were similar in nature and frequency. Conclusion: Mean FFE24 values were used as pharmacodynamic endpoints to assess equivalence between 2 formulations of orlistat. Results from this study suggest that pharmacodynamics of the generic capsule formulation of orlistat were similar to the marketed capsule formulation based on FFE24 values.Correspondence to:
T. Monif, PhD; Vice-President, Clinical Pharmacology and Pharmacokinetics, Ranbaxy Laboratories Ltd., Plot No. 20, Sector-18, Udyog Vihar Industrial Area, Gurgaon 122 015, Haryana, India
Email: tausif.monif@ranbaxy.com