F. Jamali and A. Aghazadeh-Habashi Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta and EquiTech Corporation, Edmonton, Alberta, Canada Objective: Pain or its associated trauma impairs oral absorption of drugs due, perhaps, to a diminished disintegration and dissolution rate secondary to suppression of the vagal nervous system. We first examined whether ibuprofen absorption is impaired on suppressing vagus nerve activity in a rat model. Secondly, we examined if ibuprofen absorption in rats during vagal suppression and in humans experiencing dental pain is improved by enhancing disintegration and dissolution rate of the administered formulation. Methods: Vagal suppression was achieved in rats by administering 20 mg/kg propantheline i.p. 2 h and 1 h before gastric gavage of 20 mg/kg ibuprofen as small crushed pieces of a regular release and a fast-dissolving ibuprofen caplets. In humans, after surgical removal of wisdom teeth and emergence of pain, 2 × 200 mg ibuprofen as regular released (n = 14) and fast-dissolving (n = 12) caplets were administered. Serial blood sample were collected for bioavailability studies. Results: Vagal suppression resulted in significantly decreased absorption rate of ibuprofen enantiomers following administration of the regular release but not after fast-dissolving formulation. Human dental pain was associated with significantly slower absorption of ibuprofen enantiomers from the regular released as compared with the fast-dissolving caplets. Within the first hour post-dose the area under the plasma drug concentration-time curve was raised to 2.7-fold (p < 0.05) after the fast-dissolving as compared with the regular release formulations. There was a 1-h difference in the peak concentration time (tmax) between the two caplets. Conclusion: Impaired drug absorption appears to be due to slow disintegration and dissolution encountered during pain episodes.

Correspondence to:
F. Jamali, Ph.D.; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2N8, Canada
Email: fjamali@pharmacy.ualberta.ca

A.E. Sterin Prync, P. Yankilevich, P.R. Barrero, R. Bello, L. Marangunich, A. Vidal, M. Criscuolo, L. Benasayag, A.L. Famulari, R.O. Domínguez, M.A. Kauffman and R.A. Diez ¹Bio Sidus SA, Buenos Aires, Argentina, ²Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Laboratorio de Virología, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, Argentina, ³Centro Neurológico Integral, Buenos Aires, Argentina and ⁴Fundación Argentina contra las Enfermedades Neurológicas del Envejecimiento, Buenos Aires, Argentina Objectives: Recombinant human interferon-beta (IFN-b) is a well-established treatment for multiple sclerosis (MS). The regulatory process for marketing authorization of biosimilars is currently under debate in certain countries. In the EU, EMEA has clearly defined the process including overarching and product-specific guidelines, which includes clinical testing. Biosimilarity needs to be based on comparability criteria, including at least molecular characterization, biological activity relevant for the therapeutic effect and relative bioavailability (“bioequivalence”). In the case of such complex diseases as MS, where the effect of treatment is not so directly measurable, in vitro tools can provide additional data to support comparability. Genomic microarrays assays might be useful to compare multisource biopharmaceuticals. The aim of the present study was to compare the pharmacodynamic genomic effects (in terms of transcriptional regulation) of two recombinant human IFN-β1a preparations on lymphocytes of multiple sclerosis patients using a whole genome microarray assay. Methods: We performed an ex vivo whole genome expression profiling of the effect of two preparations of IFN-β1a on non-adherent mononuclears from five relapsing-remitting MS patients analyzing microarrays (CodeLink™ Human Whole Genome). Patients blood was drawn, PBMCs isolated and cultured in three different conditions: culture medium (control), 1,000 U/ml of IFN-β1a (BLA- (STOFERON™, Bio Sidus) and 1,000 U/ml of IFN-β1a (REBIF™, Serono) RNA was purified from non-adherent cells (mostly lymphocytes), amplified and hybridized. Raw data were generated by CodeLink™ proprietary software. Data normalization, quality control and analysis of differential gene expression between treatments were done using linear model for microarray data. Functional annotation analysis of IFN-β1a MS treatment transcription was done using DAVID. Results: Out of the approximately 45,000 human sequences examined, no evidence of differential regulation was found when both treatments were compared (minimum adjusted p-value > 0.999). The IFN-β1a effect differentially regulated the expression of 868 genes. The expression of standard markers such as GTP cyclohidrolase, MxA, and OAS isoenzymes A and B changed as a consequence of the action of IFN-β1a. Conclusions: This exhaustive and highly sensitive assay did not show differences in the genomic expression profile of these two products under the assayed experimental conditions. These results suggest that this technology might be useful for the initial comparison of biosimilars, being part of a comprehensive comparability program that includes clinical testing.Correspondence to:
A.E. Sterin Prync, Bio Sidus SA, Constitución 4234 (C1254ABX), Buenos Aires, Argentina
Email: a.prync@biosidus.com.ar

P. Gallagher, C. Ryan, S. Byrne, J. Kennedy and D. O’Mahony ¹Department of Geriatric Medicine, Cork University Hospital, Wilton, Cork, ²School of Pharmacy and ³Department of Medicine, University College Cork, Cork, Ireland Objective: Older people experience more concurrent illnesses, are prescribed more medications and suffer more adverse drug events than younger people. Many drugs predispose older people to adverse events such as falls and cognitive impairment, thus increasing morbidity and health resource utilization. At the same time, older people are often denied potentially beneficial, clinically indicated medications without a valid reason. We aimed to validate a new screening tool of older persons’ prescriptions incorporating criteria for potentially inappropriate drugs called STOPP (Screening Tool of Older Persons’ Prescriptions) and criteria for potentially appropriate, indicated drugs called START (Screening Tool to Alert doctors to Right, i.e. appropriate, indicated Treatment). Methods: A Delphi consensus technique was used to establish the content validity of STOPP/START. An 18-member expert panel from academic centers in Ireland and the United Kingdom completed two rounds of the Delphi process by mail survey. Inter-rater reliability was assessed by determining the kappa-statistic for measure of agreement on 100 data-sets. Results: STOPP is comprised of 65 clinically significant criteria for potentially inappropriate prescribing in older people. Each criterion is accompanied by a concise explanation as to why the prescribing practice is potentially inappropriate. START consists of 22 evidence-based prescribing indicators for commonly encountered diseases in older people. Inter-rater reliability is favorable with a kappa-coefficient of 0.75 for STOPP and 0.68 for START. Conclusion: STOPP/START is a valid, reliable and comprehensive screening tool that enables the prescribing physician to appraise an older patient’s prescription drugs in the context of his/her concurrent diagnoses.Correspondence to:
Dr. D. O’Mahony, Department of Medicine, University College Cork, Ireland
Email: denis.omahony@mailp.hse.ie

A. Ghanizadeh Assistant Professor of Child and Adolescent Psychiatry, Shiraz University of Medical Sciences, Hafez Hospital, Shiraz, Iran Objective: To survey the knowledge and attitude of pharmacists towards Attention Deficit Hyperactivity Disorder (ADHD) and the drug ritalin. Method: A self-reported questionnaire on knowledge and attitude towards ADHD and ritalin was completed by pharmacists. Results: About 40% of respondents agreed that ADHD is due to biological and genetic vulnerabilities and causation. A total of 63% reported that the cause is a chaotic and dysfunctional family and 91% of the respondents believed that ADHD children misbehave primarily because they refuse to follow rules and complete assignments. About 85.5% reported that ritalin is used for enhancement of concentration and most of them (80%) recommended ritalin as the best medication. However, about 70% reported that they are not in favor of taking ritalin for ADHD and it should not be recommended for ADHD except in very severe cases. Conclusion: Although the subjects have a sound knowledge of ADHD, some gaps exist and there is not a favorable attitude toward treatment with ritalin. It seems that these pharmacists are not better informed than teachers in regard to some of ADHD characteristics. There is a gap between knowledge and attitude toward ritalin. Only a few respondents had the opportunity of learning about ADHD. The results could be used in the revision of university educational curricula for students of pharmacology and also for planning educational courses for continuous medical education programs. They should be provided with more up-to-date knowledge.Correspondence to:
A. Ghanizadeh, MD, Department of Psychiatry, Hafez Hospital, Shiraz, Iran
Email: ghanizad@sums.ac.ir

U. Hinkel, C. Schuijt and J.F. Erckenbrecht ¹Boehringer Ingelheim GmbH, Ingelheim and ²Florence Nightingale Hospital, Düsseldorf-Kaiserswerth, Germany Objectives: Constipation is one of the most frequent gastrointestinal symptoms. Traditionally, drug therapy for constipation is not prescribed and controlled by physicians. Instead, laxatives are sold by pharmacists as over-the-counter (OTC) medication. The aim of this study was to explore the safety and usage pattern of the OTC laxative sodium picosulfate use by collecting data from patients at their pharmacies. The study describes how self-treatment of constipation is practiced. In addition, the characteristics of patients buying the contact laxative, sodium picosulfate, for self-treatment of constipation were analyzed. Methods: The survey was a pharmacy-based observational study (PHOBS) in community pharmacies in Germany. Participating pharmacists asked customers requesting a specific contact laxative to participate in the study. Customers gave verbal informed consent to study participation before receiving a structured questionnaire to be completed at home and then returned to the pharmacy. Results: Data from 1,845 patients recruited by 243 pharmacies were collected. Compliance with the recommended dosage of 5 – 10 mg/day was 96%, compliance with the indication of constipation was 99%. More than 90% rated the efficacy as “very good” to “good”. There was no weakening of the efficacy rating with increasing duration of use. 8% of patients reported mild-to-moderate adverse events. Nearly 60% of respondents reported to be satisfied with less than 1 bowel movement per day. Therefore, users appear to have a rational way of using OTC laxatives. Conclusions: Self-medication of constipation with sodium picosulfate is efficacious and considered to be safe.Correspondence to:
U. Hinkel, RPh, Medicine CHC, Boehringer Ingelheim GmbH, Bingerstraße, 55216 Ingelheim, Germany
Email: ulrika.hinkel@ing.boehringer-ingelheim.com

A.L.F. Chan, H.J. Hsieh, Y.-A. Hsieh and S.-J. Lin ¹Department of Pharmacy, Chi Mei Medical Center, Tainan, Taiwan and ²Graduate Institute of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan Objective: To report a fatal case of amiodarone-induced acute hepatotoxicity after intravenous amiodarone administration and similar fatal cases review. Case summary: A 72-year-old woman with a history of hypertension, prior cardiovascular disease, atrial fibrillation and diabetes mellitus was admitted to the hospital with acute pyelonephritis and transferred to the intensive care unit due to cerebral infarction. An antidiabetic drug, a low dose of aspirin and intravenous amiodarone therapy was started. After receiving a second dose of amiodarone (1,200 mg; injection rate 1 mg/min), the woman developed ascites, jaundice, high levels of serum transaminases, decreased prothrombin time, and finally became unconscious. Immediately after treatment was discontinued, her extremely high hepatic parameters returned to normal. According to the Naranjo probability scale, this adverse reaction was highly probable. Discussion: The occurrence of acute liver damage after intravenous amiodarone is rare but harmful. It can be induced by polysorbate 80, a solubilizer, by immunomediated centrilobular necrosis, or by the presence of a functional PPAR-α gene. Conclusion: Amiodarone is an effective antiarrhythmic agent for preventing and treating atrial and ventricular arrhythmias. The molecular mechanism causing acute hepatic damage after amiodarone treatment is not clear. Therefore, amiodarone must be administered with care, and liver function should be monitored closely in patients treated with this drug.Correspondence to:
Dr. S.-J. Lin, Graduate Institute of Pharmacy, Kaohsiung Medical University, 100 Shi-Chuan 1st Rd, Kaohsiung, Taiwan
Email: cmh5500@mail.chimei.org.tw

R. Séchaud, C. Dutreix, S. Balez, F. Pommier, T. Dumortier, S. Morisson and E. Brun ¹Novartis Pharma AG, Basel, Switzerland, and ²Novartis Pharma SAS, Rueil-Malmaison, France Deferasirox (Exjade®, ICL670) is a new, once-daily oral iron chelator, recently approved as first-line therapy in the treatment of iron overload resulting from blood transfusions. In registration studies, deferasirox tablets were dispersed in non-carbonated water prior to administration. In routine clinical practice, however, patients may prefer to take the tablet dispersed in a flavored drink rather than with water. Objective: Stability and compatibility tests were performed to identify beverages suitable for the dispersion of tablets for further testing in man. This was followed by a pharmacokinetic study to assess the relative bioavailability of deferasirox tablets dispersed in two types of soft drinks, dispersed in water, and without dispersion. Methods: An open-label, randomized, 4-period, crossover study was carried out with 28 healthy volunteers who received single 20 mg/kg oral doses of deferasirox without dispersion, dispersed in orange juice, dispersed in apple juice and dispersed in non-carbonated water (reference). Deferasirox and Fe-[deferasirox]2 were measured in plasma using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were compared using standard bioequivalence tests. Results: Mean deferasirox AUC0-t were 1,040 ± 530, 1,010 ± 278, 882 ± 252 and 996 ± 352 h × µmol/l when deferasirox tablets were administered without dispersion, dispersed in orange juice, dispersed in apple juice and dispersed in water, respectively, indicating that these forms of deferasirox administrations met bioequivalence criteria. Therefore, the oral bioavailability of deferasirox tablets was not affected neither by the degree of dispersion nor by the type of drink (orange or apple juice versus water) used for dispersion. Conclusions: This study shows that deferasirox bioavailability is unaltered when dispersed with orange or apple juice compared with dispersion in water. Thus, in addition to water, patients have the option of taking deferasirox tablets in orange or apple juice. The degree of dispersion did not affect deferasirox bioavailability. Therefore, deferasirox therapy will not be compromised if dispersion of the tablet is not fully complete; although the latter should be avoided.Correspondence to:
Dr. R. Séchaud, Novartis Pharma AG, Exploratory Development – Drug Metabolism and Pharmacokinetics, WSJ-210.4.20, 4002 Basel, Switzerland
Email: romain.sechaud@novartis.com