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Dopaminergic challenge with Bromocriptine in patients with severe Traumatic Brain Injury
Clinical Therapeutics/Volume 37, Number 8S, 2015 Biosimilars: regulatory overview E. Sarkinovic; Z. Besovic; M. Drljevic; M. Sahman-Zaimovic; and S. Mugosa Agency For Medicines and Medical Devices, Podgorica, Montenegro Introduction: The first generation of biopharmaceutical products manufactured using recombinant technologies was launched in the 1982, and the most of them are now on the way to patent expiration or have already expired. As a result, pharmaceutical companies are developing “generic” version for biopharmaceutical product, referred to as biosimilars. Active substance of biopharmaceutical product represent a collection of recombinant proteins and not a single molecular entity, thus active substances in two biopharmaceutical product are unlikely to be identical. Biosimiliars are only similar and not identical to the innovator products and these small differences can have significant impact on the safety and efficacy of the medicine. The EU Directive 2001/83/EC, as amended, stated that where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided. The challenge is to determine the exact nature of the non-clinical and clinical program required to gain regulatory approval. The European Medicines Agency has taken the lead in issuing guidelines, most of which are still under review. The guidelines advocate pre-clinical and clinical testing of biosimilars prior to market authorization, complemented by tailored pharmacovigilance plans. Generally, the approval process varies according to the products, because significant differences exist between them, and allow products to be assessed on a case by case basis. These guidelines provide a valuable base from which to develop in this evolving regulatory environment. Conclusion: There are still many unsolved scientific issues regarding criteria, design, and analysis for the assessment of biosimilarity and/ or interchangeability of biosimilars. Detailed regulatory guidance for global harmonization is needed whenever possible.
The efficiency of calcium channels antagonists in angina pectoris associated with metabolic syndrome V. Revenco; M. Abras; V. Ochisor; and G. Mihalache State University of Medicine and Pharmacy “Nicolae Testemitanu” Background: Evaluation of antiischemic efficiency of calcium channels antagonists (lercanidipine and amlodipine), as also the metabolic effect of these drugs in patients with stable angina pectoris and metabolic syndrome. Material and Methods: The 6-week randomized open-label trial included 66 patients (mean age 58.18 ± 1.0 years) with functional classes II-III stable angina associated with metabolic syndrome. After 1 week wash-out period, a 2-week placebo run-in period, patients entered a 6-week treatment period with 10 mg of lercanidipine or 5 mg of amlodipine once daily. During the placebo run-in period and at the end of the study, the patients underwent clinical examination, electrocardiography, exercise testing; episodes of angina per week and sub-lingual nitroglycerin tablet consumption, lipid spectrum indicators and insulin resistance. Results: Total exercise duration was increased with 72.62 ± 23.24 sec. (P < 0.01) in amlodipine group and with 69.42 ± 13.89 sec. (P < 0.001) in lercanidipine group. Time to onset of anginous pain was increased with 39.5 ± 8.12 sec. (P < 0.001) in amlodipine group and with 78.57 ± 15,.04 sec. (P < 0.001) in lercanidipine group.
August 2015
Time to onset of ST-segment depression ≥ 1 mm was increased with 69.42 ± 13.89 sec. (P < 0.001) in amlodipine group and with 62.14 ± 12.77 sec. (P < 0.001) in lercanidipine group. Additionally, diary data showed reduction in episodes of angina (in amlodipine group from 6.07 ± 0.82 to 3.53 ± 0.65 (P < 0.001) and in lercanidipine group from 7.9 ± 0.83 to 4.54 ± 0.87 (P < 0.001)) and nitroglycerin tablet consumption (in amlodipine group from 3.76 ± 0.66 to 2.07 ± 0.44 (P < 0.01) and in lercanidipine group from 5.9 ± 0.74 to 3.09 ± 0.63 (P < 0.01)). No significant differences could be found between the pre and post treatment levels of lipid metabolism indicators and on insulin resistance. Conclusions: Lercanidipine and amlodipine are effective in reducing signs and symptoms of ischemia in patients with stable angina and metabolic syndrome; at the same time these drugs don’t have a significant influence on lipid metabolism indicators and on insulin resistance.
Chemopreventive effect of copaifera reticulata oilresin on 1,2dimethylhydrazine-induced preneoplastic lesions in Rat colon J.M. Senedese1,2; R.A. Furtado1; D.C. Tavares1; and J.K. Bastos1,2 Universidade de Franca, Franca, São Paulo, Brazil; and 2 Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil Background: Colorectal cancer is a major cause of death; its incidence is increasing worldwide. Experimental studies have suggested that plant food components can suppress cancer development through a variety of different mechanisms. Chemoprevention is defined by the use of natural, synthetic, biological or chemical agents that can reverse, suppress or prevent carcinogenesis. Plants produce a conspicuous structural diversity of metabolites and represent the largest source of active compounds; they are perhaps the earliest source of drugs for human use. Copaifera reticulata, known as “copaiba”, “pau-de-óleo”, belongs to the Leguminosae family and occurs in fields and grasslands in the northern and northeastern parts of Brazil. This studies describes the effects of C. reticulata oilresin on the 1,2 dimethylhydrazine (DMH) - aberrant crypt foci (ACF) in the colon of male Wistar rats. Preneoplastic lesions of the colonic mucosa, the ACF, are one of the early morphological changes on the DMHstimulated colonic mucosal surface in rode. Material and Methods: The oilresin of C. retiulata was administered to rats by gavage at daily doses of 20, 40 and 80 mg/kg body weight. To evaluate the ACF assay, animals were acclimatized for one week (week 1) and then treated with the C. reticulata oilresin five times a week for four weeks (weeks 2 to 5). The rats received sc (subcutaneous) injections of DMH (40 mg/kg) on days 2 and 5 of weeks 2 and 3, to induce ACF. Animals were euthanized at week 5; i.e., four weeks after the first DMH treatment. Results: The groups treated with 40 and 80 mg/kg C. reticulata oilresin during and after DMH treatment presented significantly lower numbers of ACF and aberrant crypts compared with the DMH group. Conclusion: The C. reticulate oilresin significantly reduced ACF induced by DMH, suggesting that the oilresin has a protective effect against colon carcinogenesis. 1
Dopaminergic challenge with Bromocriptine in patients with severe Traumatic Brain Injury J.B. Celik; A. Duman; O. Arun; and I.Ö. Önal Selcuk University Faculty of Medicine, Konya, Turkey
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Clinical Therapeutics Introduction: Bromocriptine Mesylate (BC) is an ergot derivative with potent dopamine receptor agonist activity. It is licensed to reduce plasma levels of prolactin. BC has central nervous effects, and is used in patients with Parkinson’s disease. There are few randomized controlled trials with BC conducted in moderate traumatic brain injury (TBI) with conflicting results (1). We aim to present our single center experience on dopaminergic challenge using off-label BC in patients with severe TBI. Material and Methods: TBI patients with Glasgow Coma Score (GCS) of < 5 (GCS: worst score= 3, best score= 15) at admission to the ICU received 2.5mg of BC q.i.d after hemodynamic stability was ensured and no further neurologic improvement was observed during course of management. BC was started and discontinued on the discretion of the ICU team. Long term cognitive tests are currently under assessment. Results: A total of 8 patients were treated with BC. The average age was 42.7yrs (78-18) (5M/3F). Table 1: GCS of patients on admission, beginning of treatment, end of treatment and discharge. GCS admission GCS start GCS end 1 2 3 4 5 6 7 8
3 5 3 3 3 3 3 4
4 5 3 3 6 3 4 4
8 5 6 5 10 4 4 4
BC started on day 28 15 11 7 28 9 24 9
Days on Days in GCS BC ICU discharge 8 7 30 23 8 7 14 34
37 39 41 44 39 75 38 79
8 5 12 6 10 3 died 8
Conclusions: Our results show some neurologic improvement as assessed by GCS. More research is warranted before BC can be recommended in TBI.
Reference 1. Frenette AJ, et al. Efficacy and safety of dopamine agonists in traumatic brain injury: a systematic review of randomized controlled trials. J Neurotrauma. 2012;29:1–18.
Evaluation of Cardiovascular safety of Darinaparsin (organic arsenic compound) in Japanese and Korean patients with peripheral T-cell Lymphoma Y. Kumagai1; H. Cai2; J. Barrett2; T. Shiraishi3; Y. Hayashi3; Y. Sonehara4; and F. Nagahama4 1 Kitasato University School of Medicine, Kanagawa, Japan; 2 ZIOPHARM Oncology, Inc., Boston, MA, United States; 3A2 Healthcare Corporation, Tokyo, Japan; and 4Solasia Pharma K.K., Tokyo, Japan Background or Introduction: Darinaparsin is an organic arsenical composed of dimethylated arsenic linked to glutathione, and has similar structure to one of the intermediates of the arsenic detoxification pathway. Its place in the natural metabolic pathway of inorganic arsenic is expected to result in lower cardiotoxicity than inorganic arsenic. Two phase I studies of darinaparsin have been conducted in patients with peripheral T-cell lymphoma (PTCL) in Japan and Korea, respectively. Since use of an inorganic arsenic compound is limited by cardio toxicity, the potential of darinaparsin to prolong QTcF and any possible relationship between darinaparsin plasma concentration and change in QTcF was assessed in these studies. Material and Methods: Patients received a 1-hour IV infusion at 200 or 300 mg/m2 on 5-consecutive days of 21-day or 28-day cycle. Patients received triplicated ECG assessment and PK plasma sample were taken on Day 1 and 5 at 0, 1, 2, 4 hours after initiation of dosing of darinaparsin
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in Cycle 1, on Day 2 before dosing, and on Day 6 at matched time with dosing time on Day 1-5. Time-matched baseline ECG was determined at −20, −22, −23, −24 hours before the planned initiation time of dosing. All ECGs were read by a central ECG laboratory and overread by a cardiologist for verification of interval measurements. Result: ECG data were available for 26 patients; 17 Japanese patients and 6 Korean patients. No subjects showed QTcF > 500 msec and delta QTcF > 60 msec throughout the study period. Concentrationdependent nor treatment-duration-independent effect on the QTcF were not identified. There was no significant relationship between the plasma concentration of darinaparsin and a change in QTcF. Conclusion: The study results suggested that darinaparsin, an organic arsenic compound, has no significant effect on cardiovascular safety in Japanese and Korean PTCL patients.
The difference of Vkor activity and its inhibition by warfarin between Vitamin K1 Epoxide and Vitamin K2 Epoxide M. Kawano; T. Araki; and K. Yamamoto Gunma University Graduate School of Medicine, Japan; and Gunma University Hospital, Japan Introduction: Vitamin K (VK) plays an important role in activation of blood clotting factors. VK is oxidized by δ -glutamyl carboxylase to synthesize clotting factors, and is then reduced by VK oxide reductase (VKOR) to be recycled for reuse. The redox center of VKOR against VK1 epoxide (VK1E) was reported as 132Cys-X-X-135Cys by some in vitro studies. However, the redox center of VKOR against VK2E and its reaction type have not been identified. In this study, to clarify the difference of reuse intravital between VK1 and VK2, we assessed the difference of metabolism pattern of VKsE by VKOR. Material and Methods: Metabolic activity of VKOR against VKsE and inhibitory activity of warfarin (WF) to VKOR were measured using pooled human hepatic microsome. The concentrations of produced VK1 and VK2 were determined as an index of VKOR activity by UPLC/UV method. Metabolic activity was estimated using Michaelis-Menten equation, and inhibition type and constant (Ki value) were determined by Lineweaver-Burk plot and Dixon-plot. Results: The clearance of VK2E was around 7-fold higher than that of VK1E (0.054 and 0.0072 pmol/min/mg protein, VK2E vs VK1E). S- and R- WF inhibited the reduction activity of VKOR against VK2E around 6-fold stronger than that against VK1E. Additively, VK1E competitively inhibited reduction reaction of low concentration of VK2E, while VK1E did not inhibit the metabolism of high concentration of VK2E. Conclusions: Our data indicated the difference of inhibition type of VK1E against metabolism of low and high concentration of VK2E by VKOR. VK1E and VK2E may be bound to the same site of VKOR high affinity site, while VK2E, but not VK1E may be also bound to another low affinity site. In next study, we should clarify the detail of binding site of VKOR to VK2E and the difference on the interaction of VKsE with warfarin.
The qualities of sore throat index (QUASTI): first use in a clinical trial testing the effects of Flurbiprofen 8.75 Mg lozenge on patient-reported qualities of throat pain B. Schachtel1,2; S. Aspley3; A. Shephard3; G. Smith3; K. Sanner2; L. Savino2; E. Schachtel2; M. Lorton2; and T. Shea4 1 Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, USA; 2Schachtel Research
Volume 37 Number 8S
The efficiency of calcium channels antagonists in angina pectoris associated with metabolic syndrome V. Revenco; M. Abras; V. Ochisor; and G. Mihalache State University of Medicine and Pharmacy “Nicolae Testemitanu” Background: Evaluation of antiischemic efficiency of calcium channels antagonists (lercanidipine and amlodipine), as also the metabolic effect of these drugs in patients with stable angina pectoris and metabolic syndrome. Material and Methods: The 6-week randomized open-label trial included 66 patients (mean age 58.18 ± 1.0 years) with functional classes II-III stable angina associated with metabolic syndrome. After 1 week wash-out period, a 2-week placebo run-in period, patients entered a 6-week treatment period with 10 mg of lercanidipine or 5 mg of amlodipine once daily. During the placebo run-in period and at the end of the study, the patients underwent clinical examination, electrocardiography, exercise testing; episodes of angina per week and sub-lingual nitroglycerin tablet consumption, lipid spectrum indicators and insulin resistance. Results: Total exercise duration was increased with 72.62 ± 23.24 sec. (P < 0.01) in amlodipine group and with 69.42 ± 13.89 sec. (P < 0.001) in lercanidipine group. Time to onset of anginous pain was increased with 39.5 ± 8.12 sec. (P < 0.001) in amlodipine group and with 78.57 ± 15,.04 sec. (P < 0.001) in lercanidipine group.
August 2015
Time to onset of ST-segment depression ≥ 1 mm was increased with 69.42 ± 13.89 sec. (P < 0.001) in amlodipine group and with 62.14 ± 12.77 sec. (P < 0.001) in lercanidipine group. Additionally, diary data showed reduction in episodes of angina (in amlodipine group from 6.07 ± 0.82 to 3.53 ± 0.65 (P < 0.001) and in lercanidipine group from 7.9 ± 0.83 to 4.54 ± 0.87 (P < 0.001)) and nitroglycerin tablet consumption (in amlodipine group from 3.76 ± 0.66 to 2.07 ± 0.44 (P < 0.01) and in lercanidipine group from 5.9 ± 0.74 to 3.09 ± 0.63 (P < 0.01)). No significant differences could be found between the pre and post treatment levels of lipid metabolism indicators and on insulin resistance. Conclusions: Lercanidipine and amlodipine are effective in reducing signs and symptoms of ischemia in patients with stable angina and metabolic syndrome; at the same time these drugs don’t have a significant influence on lipid metabolism indicators and on insulin resistance.
Chemopreventive effect of copaifera reticulata oilresin on 1,2dimethylhydrazine-induced preneoplastic lesions in Rat colon J.M. Senedese1,2; R.A. Furtado1; D.C. Tavares1; and J.K. Bastos1,2 Universidade de Franca, Franca, São Paulo, Brazil; and 2 Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil Background: Colorectal cancer is a major cause of death; its incidence is increasing worldwide. Experimental studies have suggested that plant food components can suppress cancer development through a variety of different mechanisms. Chemoprevention is defined by the use of natural, synthetic, biological or chemical agents that can reverse, suppress or prevent carcinogenesis. Plants produce a conspicuous structural diversity of metabolites and represent the largest source of active compounds; they are perhaps the earliest source of drugs for human use. Copaifera reticulata, known as “copaiba”, “pau-de-óleo”, belongs to the Leguminosae family and occurs in fields and grasslands in the northern and northeastern parts of Brazil. This studies describes the effects of C. reticulata oilresin on the 1,2 dimethylhydrazine (DMH) - aberrant crypt foci (ACF) in the colon of male Wistar rats. Preneoplastic lesions of the colonic mucosa, the ACF, are one of the early morphological changes on the DMHstimulated colonic mucosal surface in rode. Material and Methods: The oilresin of C. retiulata was administered to rats by gavage at daily doses of 20, 40 and 80 mg/kg body weight. To evaluate the ACF assay, animals were acclimatized for one week (week 1) and then treated with the C. reticulata oilresin five times a week for four weeks (weeks 2 to 5). The rats received sc (subcutaneous) injections of DMH (40 mg/kg) on days 2 and 5 of weeks 2 and 3, to induce ACF. Animals were euthanized at week 5; i.e., four weeks after the first DMH treatment. Results: The groups treated with 40 and 80 mg/kg C. reticulata oilresin during and after DMH treatment presented significantly lower numbers of ACF and aberrant crypts compared with the DMH group. Conclusion: The C. reticulate oilresin significantly reduced ACF induced by DMH, suggesting that the oilresin has a protective effect against colon carcinogenesis. 1
Dopaminergic challenge with Bromocriptine in patients with severe Traumatic Brain Injury J.B. Celik; A. Duman; O. Arun; and I.Ö. Önal Selcuk University Faculty of Medicine, Konya, Turkey
e93
Clinical Therapeutics Introduction: Bromocriptine Mesylate (BC) is an ergot derivative with potent dopamine receptor agonist activity. It is licensed to reduce plasma levels of prolactin. BC has central nervous effects, and is used in patients with Parkinson’s disease. There are few randomized controlled trials with BC conducted in moderate traumatic brain injury (TBI) with conflicting results (1). We aim to present our single center experience on dopaminergic challenge using off-label BC in patients with severe TBI. Material and Methods: TBI patients with Glasgow Coma Score (GCS) of < 5 (GCS: worst score= 3, best score= 15) at admission to the ICU received 2.5mg of BC q.i.d after hemodynamic stability was ensured and no further neurologic improvement was observed during course of management. BC was started and discontinued on the discretion of the ICU team. Long term cognitive tests are currently under assessment. Results: A total of 8 patients were treated with BC. The average age was 42.7yrs (78-18) (5M/3F). Table 1: GCS of patients on admission, beginning of treatment, end of treatment and discharge. GCS admission GCS start GCS end 1 2 3 4 5 6 7 8
3 5 3 3 3 3 3 4
4 5 3 3 6 3 4 4
8 5 6 5 10 4 4 4
BC started on day 28 15 11 7 28 9 24 9
Days on Days in GCS BC ICU discharge 8 7 30 23 8 7 14 34
37 39 41 44 39 75 38 79
8 5 12 6 10 3 died 8
Conclusions: Our results show some neurologic improvement as assessed by GCS. More research is warranted before BC can be recommended in TBI.
Reference 1. Frenette AJ, et al. Efficacy and safety of dopamine agonists in traumatic brain injury: a systematic review of randomized controlled trials. J Neurotrauma. 2012;29:1–18.
Evaluation of Cardiovascular safety of Darinaparsin (organic arsenic compound) in Japanese and Korean patients with peripheral T-cell Lymphoma Y. Kumagai1; H. Cai2; J. Barrett2; T. Shiraishi3; Y. Hayashi3; Y. Sonehara4; and F. Nagahama4 1 Kitasato University School of Medicine, Kanagawa, Japan; 2 ZIOPHARM Oncology, Inc., Boston, MA, United States; 3A2 Healthcare Corporation, Tokyo, Japan; and 4Solasia Pharma K.K., Tokyo, Japan Background or Introduction: Darinaparsin is an organic arsenical composed of dimethylated arsenic linked to glutathione, and has similar structure to one of the intermediates of the arsenic detoxification pathway. Its place in the natural metabolic pathway of inorganic arsenic is expected to result in lower cardiotoxicity than inorganic arsenic. Two phase I studies of darinaparsin have been conducted in patients with peripheral T-cell lymphoma (PTCL) in Japan and Korea, respectively. Since use of an inorganic arsenic compound is limited by cardio toxicity, the potential of darinaparsin to prolong QTcF and any possible relationship between darinaparsin plasma concentration and change in QTcF was assessed in these studies. Material and Methods: Patients received a 1-hour IV infusion at 200 or 300 mg/m2 on 5-consecutive days of 21-day or 28-day cycle. Patients received triplicated ECG assessment and PK plasma sample were taken on Day 1 and 5 at 0, 1, 2, 4 hours after initiation of dosing of darinaparsin
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in Cycle 1, on Day 2 before dosing, and on Day 6 at matched time with dosing time on Day 1-5. Time-matched baseline ECG was determined at −20, −22, −23, −24 hours before the planned initiation time of dosing. All ECGs were read by a central ECG laboratory and overread by a cardiologist for verification of interval measurements. Result: ECG data were available for 26 patients; 17 Japanese patients and 6 Korean patients. No subjects showed QTcF > 500 msec and delta QTcF > 60 msec throughout the study period. Concentrationdependent nor treatment-duration-independent effect on the QTcF were not identified. There was no significant relationship between the plasma concentration of darinaparsin and a change in QTcF. Conclusion: The study results suggested that darinaparsin, an organic arsenic compound, has no significant effect on cardiovascular safety in Japanese and Korean PTCL patients.
The difference of Vkor activity and its inhibition by warfarin between Vitamin K1 Epoxide and Vitamin K2 Epoxide M. Kawano; T. Araki; and K. Yamamoto Gunma University Graduate School of Medicine, Japan; and Gunma University Hospital, Japan Introduction: Vitamin K (VK) plays an important role in activation of blood clotting factors. VK is oxidized by δ -glutamyl carboxylase to synthesize clotting factors, and is then reduced by VK oxide reductase (VKOR) to be recycled for reuse. The redox center of VKOR against VK1 epoxide (VK1E) was reported as 132Cys-X-X-135Cys by some in vitro studies. However, the redox center of VKOR against VK2E and its reaction type have not been identified. In this study, to clarify the difference of reuse intravital between VK1 and VK2, we assessed the difference of metabolism pattern of VKsE by VKOR. Material and Methods: Metabolic activity of VKOR against VKsE and inhibitory activity of warfarin (WF) to VKOR were measured using pooled human hepatic microsome. The concentrations of produced VK1 and VK2 were determined as an index of VKOR activity by UPLC/UV method. Metabolic activity was estimated using Michaelis-Menten equation, and inhibition type and constant (Ki value) were determined by Lineweaver-Burk plot and Dixon-plot. Results: The clearance of VK2E was around 7-fold higher than that of VK1E (0.054 and 0.0072 pmol/min/mg protein, VK2E vs VK1E). S- and R- WF inhibited the reduction activity of VKOR against VK2E around 6-fold stronger than that against VK1E. Additively, VK1E competitively inhibited reduction reaction of low concentration of VK2E, while VK1E did not inhibit the metabolism of high concentration of VK2E. Conclusions: Our data indicated the difference of inhibition type of VK1E against metabolism of low and high concentration of VK2E by VKOR. VK1E and VK2E may be bound to the same site of VKOR high affinity site, while VK2E, but not VK1E may be also bound to another low affinity site. In next study, we should clarify the detail of binding site of VKOR to VK2E and the difference on the interaction of VKsE with warfarin.
The qualities of sore throat index (QUASTI): first use in a clinical trial testing the effects of Flurbiprofen 8.75 Mg lozenge on patient-reported qualities of throat pain B. Schachtel1,2; S. Aspley3; A. Shephard3; G. Smith3; K. Sanner2; L. Savino2; E. Schachtel2; M. Lorton2; and T. Shea4 1 Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, USA; 2Schachtel Research
Volume 37 Number 8S