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Anette Mullertz - One of the best experts on this subject based on the ideXlab platform.
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Effect of food intake and co-administration of placebo self-nanoemulsifying drug delivery systems on the absorption of Cinnarizine in healthy human volunteers
European Journal of Pharmaceutical Sciences, 2016Co-Authors: Martin Lau Christiansen, Jakob Kristensen, Jette Jacobsen, Bertil Abrahamsson, Jens Rikardt Andersen, Rene Holm, Anette MullertzAbstract:Positive food effects may be observed for low aqueous soluble compounds, these effects could potentially be circumvented using lipid based formulations. However, as all compounds are not chemically stable in lipid based systems, alternative dosage regimes could be investigated to evade the stability issue. The two aims for this present study were therefore; i) to investigate if a nutritional drink, Fresubin Energy®, could induce food effect in humans for the poorly soluble compound Cinnarizine; and ii) to investigate if co-administration of a self-nano-emulsifying drug delivery systems (SNEDDS) with a conventional Cinnarizine tablet could reduce the observed food-effect. A commercial conventional Cinnarizine tablet was dosed to 10 healthy volunteers in a cross-over design in both fasted and fed state, with and without co-administration of a SNEDDS, with a one week wash-out period between dosing. The fed state was induced using a nutritional drink (Fresubin Energy®) and gastric emptying was assessed by administration of paracetamol as a marker. The pharmacokinetic analysis showed that the nutritional drink delayed the uptake and increased the fraction of absorbed Cinnarizine, indicative of a food effect on the compound. This was in agreement with a previous dog study and indicates that the nutritional drink can be used for inducing the same level of food effect in humans. Though not statistically significant, the co-administration of SNEDDS exhibited a tendency towards a reduction of the observed food effect and an increased absorption of Cinnarizine in the fasted state; based upon the individual ratios, which was not reflected in the mean data. However, the co-administration of SNEEDS in the fasted state, also induce a slower gastric emptying rate, which was observed as a delayed tmaxfor both Cinnarizine and paracetamol.
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elucidating the molecular interactions occurring during drug precipitation of weak bases from lipid based formulations a case study with Cinnarizine and a long chain self nanoemulsifying drug delivery system
Molecular Pharmaceutics, 2015Co-Authors: Philip Jonas Sassene, Thomas Rades, Mette Dalskov Mosgaard, Korbinian Lobmann, Flemming H Larsen, Anette MullertzAbstract:The aim of this study was to investigate if molecular interactions between the weak base Cinnarizine and lipolysis products were affecting the morphology of precipitated drug formed during in vitro lipolysis. In vitro lipolysis studies of a self-nanoemulsifying drug delivery system with or without Cinnarizine were conducted. The digestion phases (aqueous phase and pellet phase) were separated by ultracentrifugation, and the pellet was isolated and lyophilized. The lyophilized pellets were examined by X-ray powder diffraction, (13)C solid-state nuclear magnetic resonance ((13)C NMR), (1)H liquid-state NMR ((1)H NMR) spectroscopy and differential scanning calorimetry (DSC). The (13)C NMR data indicated that the carbonyl groups and aliphatic part of the lipids undergo structural changes when the pellet contains Cinnarizine. The (1)H NMR data suggests interactions occurring around the nitrogens on Cinnarizine and the carboxylic group of fatty acids. DSC thermograms showed Cinnarizine to be homogeneously incorporated into the lipids of the pellet, and no free amorphous Cinnarizine was present. The three techniques (13)C NMR, (1)H NMR, and DSC complement each other and suggest interactions to occur between fatty acids and Cinnarizine, which in turn favors amorphous precipitation.
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Cinnarizine food effects in beagle dogs can be avoided by administration in a self nano emulsifying drug delivery system snedds
European Journal of Pharmaceutical Sciences, 2014Co-Authors: Martin Lau Christiansen, Jakob Kristensen, Jette Jacobsen, Bertil Abrahamsson, Rene Holm, Mads Kreilgaard, Anette MullertzAbstract:Abstract Purpose To elucidate if a SNEDDS approach can eliminate the food-effect on Cinnarizine absorption and to, investigate if a nutritional drink, Fresubin energy, could mimic food effect in dogs for the poorly soluble compound Cinnarizine. Method A conventional tablet, a SNEDDS capsule or a SNEDDS tablet, containing Cinnarizine, were dosed to beagles dogs in fed or fasted state ( n = 5), with a one week wash-out period between dosing. Dogs were pre-treated with pentagastrin. Fed state was induced by a nutritional drink (Fresubin Energy®). The food-effect was evaluated by comparing T max , C max and Bioavailability ( F ) for the different formulations. Results Food effect was observed on all three parameters for the conventional tablet; T max was delayed 2.5 times and bioavailability increased in fed state (from 20.9 ± 5.7 to 53.8 ± 30.1). Apart from an extended T max (2.5 and 3.3 times longer in fed state compared to fasted state for the SNEDDS tablets and SNEDDS capsules respectively), food effect on absorption for the SNEDDS capsules and SNEDDS tablets was not observed. The SNEDDS capsules had a higher bioavailability in both fed and fasted state compared to SNEDDS tablets ( F fasted = 58.1 ± 16.7, vs. 32.7 ± 11.5), ( F fed = 79.3 ± 14.7 vs. 43.7 ± 6.7) There were no significant differences in bioavailability between the conventional tablet in fed state and the SNEDDS capsules. Conclusion Food effect was observed when dosing Cinnarizine with ingestion of the nutritional drink Fresubin Energy. Food effect on Cinnarizine could be significantly reduced by dosing either as a SNEEDS capsule or a SNEDDS tablet, however, the SNEDDS tablet resulted in an overall lower absorption than the SNEDDS capsules in both fed and fasted state. The delay in fed state absorption could not be changed by dosing with SNEDDS formulations.
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bioavailability of Cinnarizine in dogs effect of snedds loading level and correlation with Cinnarizine solubilization during in vitro lipolysis
Pharmaceutical Research, 2013Co-Authors: Anne Larsen, Bertil Abrahamsson, Pernilla Akesson, Anna Jureus, Lasse Saaby, Ragheb Aburmaileh, Jesper Ostergaard, Anette MullertzAbstract:Purpose To investigate the effect of increasing the loading level of the poorly soluble drug Cinnarizine in a self-nanoemulsifying drug delivery system (SNEDDS) both in vitro and in vivo.
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precipitation of a poorly soluble model drug during in vitro lipolysis characterization and dissolution of the precipitate
Journal of Pharmaceutical Sciences, 2010Co-Authors: Philip Jonas Sassene, Matthias Manne Knopp, Janne Z Hesselkilde, Vishal Koradia, Thomas Rades, Anne Larsen, Anette MullertzAbstract:ABSTRACT: Precipitation of Cinnarizine during in vitro lipolysis of a self-microemulsifying drug delivery system (SMEDDS) was characterized to gain a better understanding of the mechanisms behind the precipitation. During in vitro lipolysis of the SMEDDS with or without Cinnarizine, samples were taken at several timepoints and ultracentrifuged. Cinnarizine content in the pellet increased from 4% to 59% during lipolysis. The precipitation of Cinnarizine during in vitro lipolysis correlated well with the degree of lipid digestion, determined by sodium hydroxide addition. The pellet from the endpoint of lipolysis was isolated and subjected to dissolution in biorelevant media. Dissolution rate of Cinnarizine from pellets containing precipitated Cinnarizine was initially 10-fold higher than dissolution from blank pellet spiked with crystalline Cinnarizine, reaching more than 50% drug dissolved in the first minute. Pellets were further characterized by X-ray powder diffraction (XRPD) and polarized light microscopy (PLM). Both methods indicated the presence of liquid crystalline phases of calcium fatty acid soaps, but no presence of crystalline Cinnarizine in the pellet. Overall, dissolution studies along with XRPD and PLM analysis indicate that Cinnarizine precipitating during in vitro lipolysis of this SMEDDS is not crystalline, suggesting an either amorphous form or a molecular dispersion.
Rene Holm - One of the best experts on this subject based on the ideXlab platform.
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exploring precipitation inhibitors to improve in vivo absorption of Cinnarizine from supersaturated lipid based drug delivery systems
European Journal of Pharmaceutical Sciences, 2021Co-Authors: Alexandra Roxana Ilie, Brendan T Griffin, Maria Vertzoni, Martin Kuentz, Ruzica Kolakovic, Anke Prudicpaus, Ahmed Malash, Hugo Bohets, Jilly Herman, Rene HolmAbstract:Abstract Supersaturated lipid-based drug delivery systems are increasingly being explored as a bio-enabling formulation approach, particularly in preclinical evaluation of poorlywater-soluble drugs. While increasing the drug load through thermally-induced supersaturation resulted in enhanced in vivo exposure for some drugs, for others, such as Cinnarizine, supersaturated lipid-based systems have not been found beneficial to increase the in vivo bioavailability. We hypothesized that incorporation of precipitation inhibitors to reduce drug precipitation may address this limitation. Therefore, pharmacokinetic profiles of Cinnarizine supersaturated lipid-based drug delivery systems with or without precipitation inhibitors were compared. Five precipitation inhibitors were selected for investigation based on a high throughput screening of twenty-one excipients. In vivo results showed that addition of 5% precipitation inhibitors to long chain monoglyceride (LCM) or medium chain monoglyceride (MCM) formulations showed a general trend of increases in Cinnarizine bioavailability, albeit only statistically significantly increased for Poloxamer 407 + LCM system (i.e. 2.7-fold increase in AUC0-24h compared to LCM without precipitation inhibitors). It appeared that precipitation inhibitors mitigated the risk of in vivo precipitation of Cinnarizine from sLBDDS and overall, bioavailability was comparable to that previously reported for Cinnarizine after dosing of non-supersaturated lipid systems. In summary, for drugs which are prone to precipitation from supersaturated lipid-based drug delivery systems, such as Cinnarizine, inclusion of precipitation inhibitors mitigates this risk and provides the opportunity to maximize exposure which is ideally suited in early efficacy and toxicology evaluation.
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Effect of food intake and co-administration of placebo self-nanoemulsifying drug delivery systems on the absorption of Cinnarizine in healthy human volunteers
European Journal of Pharmaceutical Sciences, 2016Co-Authors: Martin Lau Christiansen, Jakob Kristensen, Jette Jacobsen, Bertil Abrahamsson, Jens Rikardt Andersen, Rene Holm, Anette MullertzAbstract:Positive food effects may be observed for low aqueous soluble compounds, these effects could potentially be circumvented using lipid based formulations. However, as all compounds are not chemically stable in lipid based systems, alternative dosage regimes could be investigated to evade the stability issue. The two aims for this present study were therefore; i) to investigate if a nutritional drink, Fresubin Energy®, could induce food effect in humans for the poorly soluble compound Cinnarizine; and ii) to investigate if co-administration of a self-nano-emulsifying drug delivery systems (SNEDDS) with a conventional Cinnarizine tablet could reduce the observed food-effect. A commercial conventional Cinnarizine tablet was dosed to 10 healthy volunteers in a cross-over design in both fasted and fed state, with and without co-administration of a SNEDDS, with a one week wash-out period between dosing. The fed state was induced using a nutritional drink (Fresubin Energy®) and gastric emptying was assessed by administration of paracetamol as a marker. The pharmacokinetic analysis showed that the nutritional drink delayed the uptake and increased the fraction of absorbed Cinnarizine, indicative of a food effect on the compound. This was in agreement with a previous dog study and indicates that the nutritional drink can be used for inducing the same level of food effect in humans. Though not statistically significant, the co-administration of SNEDDS exhibited a tendency towards a reduction of the observed food effect and an increased absorption of Cinnarizine in the fasted state; based upon the individual ratios, which was not reflected in the mean data. However, the co-administration of SNEEDS in the fasted state, also induce a slower gastric emptying rate, which was observed as a delayed tmaxfor both Cinnarizine and paracetamol.
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Cinnarizine food effects in beagle dogs can be avoided by administration in a self nano emulsifying drug delivery system snedds
European Journal of Pharmaceutical Sciences, 2014Co-Authors: Martin Lau Christiansen, Jakob Kristensen, Jette Jacobsen, Bertil Abrahamsson, Rene Holm, Mads Kreilgaard, Anette MullertzAbstract:Abstract Purpose To elucidate if a SNEDDS approach can eliminate the food-effect on Cinnarizine absorption and to, investigate if a nutritional drink, Fresubin energy, could mimic food effect in dogs for the poorly soluble compound Cinnarizine. Method A conventional tablet, a SNEDDS capsule or a SNEDDS tablet, containing Cinnarizine, were dosed to beagles dogs in fed or fasted state ( n = 5), with a one week wash-out period between dosing. Dogs were pre-treated with pentagastrin. Fed state was induced by a nutritional drink (Fresubin Energy®). The food-effect was evaluated by comparing T max , C max and Bioavailability ( F ) for the different formulations. Results Food effect was observed on all three parameters for the conventional tablet; T max was delayed 2.5 times and bioavailability increased in fed state (from 20.9 ± 5.7 to 53.8 ± 30.1). Apart from an extended T max (2.5 and 3.3 times longer in fed state compared to fasted state for the SNEDDS tablets and SNEDDS capsules respectively), food effect on absorption for the SNEDDS capsules and SNEDDS tablets was not observed. The SNEDDS capsules had a higher bioavailability in both fed and fasted state compared to SNEDDS tablets ( F fasted = 58.1 ± 16.7, vs. 32.7 ± 11.5), ( F fed = 79.3 ± 14.7 vs. 43.7 ± 6.7) There were no significant differences in bioavailability between the conventional tablet in fed state and the SNEDDS capsules. Conclusion Food effect was observed when dosing Cinnarizine with ingestion of the nutritional drink Fresubin Energy. Food effect on Cinnarizine could be significantly reduced by dosing either as a SNEEDS capsule or a SNEDDS tablet, however, the SNEDDS tablet resulted in an overall lower absorption than the SNEDDS capsules in both fed and fasted state. The delay in fed state absorption could not be changed by dosing with SNEDDS formulations.
Mansoureh Togha - One of the best experts on this subject based on the ideXlab platform.
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Cinnarizine and sodium valproate as the preventive agents of pediatric migraine a randomized double blind placebo controlled trial
Cephalalgia, 2020Co-Authors: Man Amanat, Mansoureh Togha, Reza Azizi Malamiri, Morteza Heidari, Ali Reza Tavasoli, Elmira Agah, Mahtab Ramezani, Fariba Fashandaky, Mona SalehiAbstract:BackgroundFew migraine preventive agents have been assessed in a pediatric population. We evaluated the safety and efficacy of Cinnarizine and sodium valproate for migraine prophylaxis in children ...
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efficacy and safety of Cinnarizine in the prophylaxis of migraine in children a double blind placebo controlled randomized trial
Pediatric Neurology, 2014Co-Authors: Mahmoud Reza Ashrafi, Soodeh Salehi, Reza Azizi Malamiri, Morteza Heidari, Seyed Ahmad Hosseini, Mahboubeh Samiei, Ali Reza Tavasoli, Mansoureh ToghaAbstract:Abstract Background In spite of the high occurrence of migraine headaches in school-age children, there are currently no approved and widely accepted pharmacologic agents for migraine prophylaxis in children. Our previous open-label study in children revealed the efficacy of Cinnarizine, a calcium channel blocker, in migraine prophylaxis. A placebo-controlled trial was conducted to demonstrate the efficacy and safety of Cinnarizine in the prophylaxis of migraine in children. Trial design A double-blind, placebo-controlled, parallel-group study conducted in a tertiary medical center in Tehran, Iran. Methods Children (5-17 years) who experienced migraines with and without aura, as defined on the basis of 2004 International Headache Society criteria, were recruited into the study. Children were excluded if they had complicated migraine, epilepsy, or a history of use of migraine prophylactic agents. Each participant was randomly assigned to receive Cinnarizine (a single 1.5 mg/kg/day dose in children weighing less than 30 kg and a single 50 mg dose in children weighing more than 30 kg, administered at bedtime) or placebo. The frequency, severity, and duration of headaches over the trial period were assessed and adverse effects were monitored. Results A total of 68 children (34 in each group) with migraine were enrolled and 62 participants completed the study. After 3 months of taking Cinnarizine or placebo, children in both groups experienced significantly reduced frequency, severity, and duration of headaches compared with baseline measurements ( P P = 0.023), suggesting that Cinnarizine was significantly more effective than placebo in reducing the frequency of headaches. No serious adverse effects of the medications were observed in the treated children, including no abnormal weight gain or extrapyramidal signs. Conclusion Our results indicate that the use of Cinnarizine at doses administered in this study is effective and safe for prophylaxis of migraine headaches in children.
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Cinnarizine versus topiramate in prophylaxis of migraines among children and adolescents a randomized double blind clinical trial
Iranian journal of child neurology, 2014Co-Authors: Mahmoud Reza Ashrafi, Zeinab Najafi, Masih Shafiei, Kazem Heidari, Mansoureh ToghaAbstract:How to Cite This Article: Ashrafi MR, Najafi Z, Shafiei M, Heidari K, Togha M. Cinnarizinev ersus Topiramate in Prophylaxis of Migraines among Children and Adolescents: A Randomized, Double-Blind Clinical Trial. Iran J Child Neurol. 2014 Autumn;8(4): 18-27. Abstract Objective Migraines, a common health problem in children and adolescents, still do not have an FDA approved preventive treatment for patients under the age of 18 years. This study compares and contrasts the efficacy and safety of Cinnarizine and topiramate in preventing pediatric migraines. Materials & Methods In this randomized, double-blind clinical trial 44 migrainous (from 4–15 years of age) were equally allocated to receive Cinnarizine or topiramate. The primary efficacy measure was monthly migraine frequency. Secondary efficacy measures were monthly migraine intensity and ≥ 50% responder rate. Efficacy measures were recorded at the baseline and at 4, 8, and 12 weeks of treatment. Results During the double-blind phase of the study, monthly migraine frequency and intensity were significantly decreased in both the Cinnarizine and topiramate groups when compared to the baseline. However, at the end of the study, the Cinnarizine group exhibits a significant decrease from the baseline in the mean monthly migraine intensity when compared to the topiramate group (4.7 vs. 3, respectively; 95% CI = -0.8 to -3.2). Conclusion No significant difference between Cinnarizine and topiramate was found for the prevention of pediatric migraines. Both treatments were well tolerated. References Hershey AD, Winner PK. Pediatric Migraine: Recognition and Treatment. J Am Osteopath Assoc. 2005;105:2S-8. Lewis DW, Yonker M, Winner P, Sowell M. The treatment of pediatric migraine. Pediatric Annals. 2005;34:448-460. Abu-Arefeh I, Russell G. Prevalence of headache and migraine in schoolchildren. BMJ. 1994;309:765-769. Linet MS, Stewart WF, Celentano DD, Ziegler D, Sprecher M. An Epidemiologic Study of Headache among Adolescents and Young Adults. JAMA: The Journal of the American Medical Association. 1989;261:2211-2216. Stewart WF, Linet MS, Celentano DD, Van Natta M, Ziegler D. Age- and sex-specific incidence rates of migraine with and without visual aura. Am J Epidemiol. 1991;134:1111-1120. Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of Migraine Headache in the United States. JAMA: The Journal of the American Medical Association. 1992;267:64-69. Split W, Neuman W. Epidemiology of Migraine among Students from Randomly Selected Secondary Schools in Lodz. Headache: The Journal of Head and Face Pain. 1999;39:494-501. Hershey AD, Kabbouche MA, Powers SW. Treatment of pediatric and adolescent migraine. Pediatr Ann. 2010;39:416-423. Hershey AD, Powers SW, Vockell AL, LeCates S, Kabbouche MA, Maynard MK. PedMIDAS: development of a questionnaire to assess disability of migraines in children. Neurology. 2001;57:2034-2039. Lewis D, Ashwal S, Hershey A, Hirtz D, Yonker M, Silberstein S. Practice Parameter: Pharmacological treatment of migraine headache in children and adolescents. Neurology. 2004;63:2215-2224. Brandes JL, Saper JR, Diamond M, et al. Topiramate for Migraine Prevention. JAMA: The Journal of the American Medical Association. 2004;291:965-973. Lakshmi CVS, Singhi P, Malhi P, Ray M. Topiramate in the Prophylaxis of Pediatric Migraine: A Double-Blind Placebo-Controlled Trial. Journal of Child Neurology. 2007;22:829-835. Lewis D, Winner P, Saper J, et al. Randomized, Double- Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Topiramate for Migraine Prevention in Pediatric Subjects 12 to 17 Years of Age. Pediatrics. 2009;123:924-934. Winner P, Pearlman EM, Linder SL, et al. Topiramate for Migraine Prevention in Children: A Randomized, Double-Blind, Placebo-Controlled Trial. Headache: The Journal of Head and Face Pain. 2005;45:1304-1312. Winner P, Gendolla A, Stayer C, et al. Topiramate for Migraine Prevention in Adolescents: A Pooled Analysis of Efficacy and Safety. Headache: The Journal of Head and Face Pain. 2006;46:1503-1510. Campistol J, Campos J, Casas C, Herranz JL. Topiramate in the prophylactic treatment of migraine in children. Journal of Child Neurology. 2005;20:251-253. Hershey AD, Powers SW, Vockell A-LB, LeCates S, Kabbouche M. Effectiveness of Topiramate in the Prevention of Childhood Headaches. Headache: The Journal of Head and Face Pain. 2002;42:810-818. Unalp A, Uran N, Ozturk A. Comparison of the effectiveness of topiramate and sodium valproate in pediatric migraine. J Child Neurol. 2008;23:1377-1381. Younkin DP. Topiramate in the treatment of pediatric migraine. Headache: The Journal of Head and Face Pain. 2002;42:456. Rossi P, Fiermonte G, Pierelli F. Cinnarizine in migraine prophylaxis: efficacy, tolerability and predictive factors for therapeutic responsiveness. An open-label pilot trial. Funct Neurol. 2003;18:155-159. Togha M, Ashrafian H, Tajik P. Open-label trial of Cinnarizine in migraine prophylaxis. Headache. 2006;46:498-502. Togha M, Rahmat Jirde M, Nilavari K, Ashrafian H, Razeghi S, Kohan L. Cinnarizine in refractory migraine prophylaxis: efficacy and tolerability. A comparison with sodium valproate. J Headache Pain. 2008;9:77-82. Headache Classification Committee of The International Headache Society. The International Classification of Headache Disorders, 2nd edn. Cephalalgia. 2004;24(Suppl. 1):1–160. Tonekaboni SH, Ghazavi A, Fayyazi A, Khajeh A, Taghdiri MM, AbdollahGorji F, Azargashb E. Prophylaxis of Childhood Migraine: Topiramate Versus Propranolol. Iran J Child Neurol. 2013 Winter; 7 (1):9-14. Fallah R, AkhavanKarbasi S, Shajari A, Fromandi M. The Efficacy and Safety of Topiramate for Prophylaxis of Migraine in Children. Iran J Child Neurol. 2013 Autumn; 7(4):7-11. Ferraro D, Di Trapani G. Topiramate in the prevention of pediatric migraine: literature review. J Headache Pain. 2008;9:147-150.
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Cinnarizine for the prophylaxis of migraine associated vertigo a retrospective study
SpringerPlus, 2014Co-Authors: Foad Taghdiri, Mansoureh Togha, Soodeh Razeghi Jahromi, Farshid RefaeianAbstract:To assess the efficacy and safety of Cinnarizine for the prophylaxis of migraine associated vertigo in the vestibular migraine and migraine with brainstem aura. Vestibular migraine and migraine with brainstem aura are two principal clinical syndromes that frequently are associated with vertigo. Since Cinnarizine is a well-tolerated calcium channel blocker which has acceptable effect on both vertigo and migraine headache, we carried out this study to evaluate the efficacy and safety of this medication in vestibular migraine and also migraine with brainstem aura associated with vertigo. This was a retrospective, single-center, open-label, investigation of the effects of Cinnarizine on vestibular migraine and migraine with associated with vertigo. We assessed the change in monthly frequency of vertigo and also frequency, duration and intensity of migraine attacks after one, two and three months of Cinnarizine administration. The mean frequency of vertigo and also the mean frequency, duration and intensity of migraine headaches per month were reduced significantly after three months of Cinnarizine therapy (all p < 0.001). This study suggests that Cinnarizine is safe and effective in reducing both headache and vertigo aspects of “migraine plus vertigo” among the patients who suffer from either vestibular migraine or migraine with brainstem aura associated with vertigo.
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efficacy and safety of Cinnarizine in the prophylaxis of migraine headaches in children an open randomized comparative trial with propranolol
Acta Neurologica Belgica, 2012Co-Authors: Mansoureh Togha, Reza Azizi Malamiri, Neda Rashidiranjbar, Solmaz Asa, F Mahvelati, Mahmoud Reza AshrafiAbstract:Migraine headaches are common in children. Early diagnosis and appropriate interventions are mandatory to prevent decades of suffering and diminished quality of life. There is need for data regarding the efficacy and safety of prophylactic agents in children with migraine; therefore, we designed a randomized clinical trial to compare the efficacy and safety of Cinnarizine with that of a well-known prophylactic agent (propranolol) in the prophylaxis of pediatric migraine headache. A total of 120 patients aged between 6 and 17 years were recruited and 113 patients succeeded in completing all phases of the trial. Of them, 57 patients were given Cinnarizine, and propranolol was administered in 56 patients. Reduction in headache frequency was the main response to treatment. Cinnarizine reduced the baseline headache frequency by more than 50% in 74.6% of patients and the mean headache frequency per month was reduced from 11.851 ± 0.739 (mean ± SEM) to 3.358 ± 0.739 (mean ± SEM) attacks per month (P < 0.001). In the propranolol group, more than 50% reduction of the baseline headache frequency was seen in 72.5% of patients and the mean headache frequency per month was reduced from 10.264 ± 0.830 (mean ± SEM) to 2.774 ± 0.830 (mean ± SEM) attacks per month (P < 0.001). No significant difference was seen in 50% reduction of the baseline headache frequency between treatment groups (P = 0.358). No significant adverse effects were reported. In this open study, Cinnarizine appeared thus as effective as propranolol and safe for the prophylaxis of migraine in children, but this remains to be confirmed in a double-blind placebo-controlled trial.
Christopher J H Porter - One of the best experts on this subject based on the ideXlab platform.
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transformation of poorly water soluble drugs into lipophilic ionic liquids enhances oral drug exposure from lipid based formulations
Molecular Pharmaceutics, 2015Co-Authors: Yasemin Sahbaz, Trihung Nguyen, Hywel David Williams, Jessica Saunders, Leigh Ford, Susan A Charman, Peter J Scammells, Christopher J H PorterAbstract:Absorption after oral administration is a requirement for almost all drug products but is a challenge for drugs with intrinsically low water solubility. Here, the weakly basic, poorly water-soluble drugs (PWSDs) itraconazole, Cinnarizine, and halofantrine were converted into lipophilic ionic liquids to facilitate incorporation into lipid-based formulations and integration into lipid absorption pathways. Ionic liquids were formed via metathesis reactions of the hydrochloride salt of the PWSDs with a range of lipophilic counterions. The resultant active pharmaceutical ingredient–ionic liquids (API–ILs) were liquids or low melting point solids and either completely miscible or highly soluble in lipid based, self-emulsifying drug delivery systems (SEDDS) comprising mixtures of long or medium chain glycerides, surfactants such as Kolliphor-EL and cosolvents such as ethanol. They also readily incorporated into the colloids formed in intestinal fluids during lipid digestion. Itraconazole docusate or Cinnarizine ...
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phytantriol and glyceryl monooleate cubic liquid crystalline phases as sustained release oral drug delivery systems for poorly water soluble drugs ii in vivo evaluation
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Trihung Nguyen, Christopher J H Porter, Ian Larson, Tracey Hanley, Benjamin James BoydAbstract:Objectives Lipid-based liquid crystals formed from phytantriol (PHY) and glyceryl monooleate (GMO) retain their cubic-phase structure on dilution in physiologically relevant simulated gastrointestinal media, suggesting their potential application as sustained-release drug-delivery systems for poorly water-soluble drugs. In this study the potential of PHY and GMO to serve as sustained-release lipid vehicles for a model poorly-water-soluble drug, Cinnarizine, was assessed and compared to that of an aqueous suspension formulation. Methods Small-angle X-ray scattering was used to confirm the nanostructure of the liquid-crystalline matrix in the presence of the selected model drug, Cinnarizine. Oral bioavailability studies were conducted in rats, and disposition of lipid and drug in segments of the gastrointestinal tract was determined over time. Differences in the digestibility and stability of formulations under digestion conditions were investigated using an in-vitro lipolysis model. Key findings The oral bioavailability of Cinnarizine using the PHY formulation was 41%, compared to 19% for the GMO formulation and 6% for an aqueous suspension. The PHY formulation provided a Tmax for Cinnarizine of 33 h, with absorption apparent up to 55 h after administration. In contrast, the Tmax for the GMO formulation was only 5 h. The PHY formulation was retained in the stomach for extended periods of time, with 56% of lipid remaining in the stomach after 24 h, in contrast to less than 1% of the GMO formulation after 8 h, suggesting that gastric retention was a key aspect of the prolonged period of absorption, which correlated with the formulations' relative susceptibility to in-vitro lipolysis and degradation. Conclusions PHY provides a dramatic sustained-release effect for Cinnarizine on oral administration, which is linked to gastric retention of the formulation and its ability to resist digestive processing. Poorly digested liquid crystal lipid formulations therefore offer a novel class of sustained-release matrices for oral administration.
Avi Shupak - One of the best experts on this subject based on the ideXlab platform.
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a comparison of Cinnarizine and transdermal scopolamine for the prevention of seasickness in naval crew a double blind randomized crossover study
Clinical Neuropharmacology, 2012Co-Authors: Amnon Gil, Zohar Nachum, Dror Tal, Avi ShupakAbstract:OBJECTIVES The objective of the study was to compare the efficacy of transdermal scopolamine and Cinnarizine in the prevention of seasickness and their adverse reactions. METHODS Seventy-six naval crew members participated in a double-blind, randomized, crossover study. On 2 voyages, they were administered either a transdermal scopolamine patch containing 1.5 mg scopolamine and placebo tablets or 25-mg Cinnarizine tablets and a placebo patch. Subjects completed questionnaires for each voyage, reporting on the efficacy of the drugs, the severity of their adverse reactions, and the preferred treatment. RESULTS Subjects reported the scopolamine patch to be significantly more effective than the Cinnarizine tablet (P = 0.029). A moderate to high degree of drowsiness was attributed more frequently to Cinnarizine than to the scopolamine patch (34% and 17%, respectively; P < 0.02). Any adverse reaction, to at least a moderate degree, was more frequent with Cinnarizine (38%) than with the scopolamine patch (22%), although the significance of this association was borderline. A significantly greater percentage of subjects preferred transdermal scopolamine to Cinnarizine (41 vs 12%, P < 0.001). CONCLUSIONS Higher efficacy, a lower rate of adverse reactions, and convenience all led the participants of this study to prefer the scopolamine patch to Cinnarizine. Considering the 2 therapeutic options assessed in this study, and in light of the findings of previous studies, it is recommended that the scopolamine patch be used as the drug of choice for the treatment of seasickness among naval crew in particular and probably also among all other sea travelers.
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The effects of dimenhydrinate, Cinnarizine and transdermal scopolamine on performance.
Journal of Psychopharmacology, 2001Co-Authors: Carlos R. Gordon, Adi Gonen, Zohar Nachum, Ilana Doweck, Orna Spitzer, Avi ShupakAbstract:We assessed the influence of dimenhydrinate, Cinnarizine and transdermal scopolamine on the ability to perform simulated naval crew tasks. The effect of single doses of dimenhydrinate, 100 mg, Cinnarizine, 50 mg, and one transdermal scopolamine patch on psychomotor performance was evaluated using a double-blind, placebo-controlled, randomized, crossover design in three separate studies. A total of 60 young naval crew (20 for dimenhydrinate, 15 for Cinnarizine and 25 for transdermal scopolamine) underwent a battery of computerized and paper and pencil performance tests, and filled out a questionnaire on side-effects and well-being self-assessment. Dimenhydrinate significantly impaired decision reaction time and auditory digit span. Most of the subjects who took dimenhydrinate also reported a subjective decrease in well-being and general performance abilities. Cinnarizine and transdermal scopolamine did not affect performance abilities. Cinnarizine was free of significant side-effects. Dry mouth was the only significant side-effect of transdermal scopolamine. These findings could be explained by the well-known sedative properties of dimenhydrinate and not by a specific effect on any particular cognitive or motor function. Our results suggest that dimenhydrinate, 100 mg, adversely affects psychomotor function, whereas single doses of Cinnarizine, 50 mg, and transdermal scopolamine appear to be free of side-effects on performance and seem to be a preferable anti-seasickness drug for use by a naval crew.