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1.
J Neurol Sci ; 444: 120526, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36584558

RESUMO

Secondary parkinsonism induced by exposure to dopamine (DA) receptor antagonists as first and second generation antipsychotics, DA storage depleters, calcium channel blockers, benzamides substituted and other classes of drugs is traditionally believed to be completely reversible in most of patients following withdrawal of the offending drug even though after a variable time delay. The lack of recovery or initial full recovery with subsequent development of progressive parkinsonism has been regarded to result from an underlying subclinical degenerative process like PD unmasked by the inducing drug. These well-recognized clinical outcomes of drug-induced parkinsonism (DIP) have disregarded the existence of another outcome, characterized by permanent non-progressive parkinsonism. This syndrome may fullfil the criteria of tardive parkinsonism, a controversial entity currently referred to as a persistent condition without indication of its long-term course and clinical features. On reviewing the published literature on DIP, we have identified two prospective long-term follow-up of elderly patients in which parkinsonism induced by the calcium channel antagonists cinnarizine and flunarizine became permanent and non-progressive following drug discontinuation in a non-negligible proportion of patients, consistent with the clinical concept of a true tardive syndrome, according to currently accepted criteria. The authors hypothesize that the development of tardive parkinsonism might be due to a neurotoxic effect of the pharmacodynamic proprieties of the calcium channel blockers and their metabolites, exerted on post-synaptic striatal neurons and/or a neurotoxic damage on presynaptic DA neurons in patients without an underlying subclinical degenerative parkinsonism, so accounting for the stable and non-progressive course over time.


Assuntos
Antipsicóticos , Cinarizina , Doença de Parkinson Secundária , Transtornos Parkinsonianos , Humanos , Idoso , Flunarizina/efeitos adversos , Cinarizina/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Estudos Prospectivos , Transtornos Parkinsonianos/induzido quimicamente , Doença de Parkinson Secundária/induzido quimicamente , Antagonistas de Dopamina/efeitos adversos , Antipsicóticos/efeitos adversos , Síndrome
2.
Int J Nanomedicine ; 17: 5641-5660, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36452306

RESUMO

Purpose: Cinnarizine (CIN) is a class II BSC drug, suffering from erratic bioavailability due to its pH-dependent solubility. It has preferential absorption in the stomach. In this study, new chitosan (CS) coated niosomes of CIN (CIN-loaded chitosomes) have been developed to extend the gastric retention and ameliorate CIN oral bioavailability. Methods: Various CIN-loaded niosomes were fabricated by thin-film hydration technique and fully characterized. Based on the predetermined criteria of low particle size (PS) and high entrapment efficiency percent (EE%), niosomal formulation F1 was selected and further coated with different CS concentrations. The optimized chitosomal formulation (C2) was evaluated through solid state characterization and mucoadhesive efficiency testing. It was also subjected to cytotoxicity study on Caco-2 cells; besides, in vitro drug release, stability and pharmacokinetic studies were assessed. Results: The optimized chitosomal formulation (C2) exhibited an EE% of 58.30±2.75%, PS of 440 ±13.03 nm, PDI of 0.335±0.21 and ZP of +28.1±0.10 mv. Solid state characterization results revealed the compatibility between the vesicle components and the entrapment of CIN within niosomal vesicles. C2 formulation demonstrated favorable mucoadhesive efficiency. The cytotoxicity study on Caco-2 cells manifested the safety of the optimized chitosomal formulation (C2) over the free drug. Additionally, it displayed a remarkable sustaining of CIN in vitro release up to 8 h and exhibited a good stability at the refrigerated temperature up to 3 months. In vivo pharmacokinetic assessment revealed that the CIN bioavailability from the optimized chitosomal formulation C2 was enhanced by 2.79 and 1.92 folds compared to the free drug and uncoated niosomal formulation F1, respectively. The priority of the chitosomal formulation (C2) over the niosomal one (F1) was also conferred. Conclusion: Novel formulation of chitosan coated niosomes (chitosomes) could be presented as a promising platform to improve the oral bioavailability of drugs with narrow absorption window.


Assuntos
Quitosana , Cinarizina , Humanos , Disponibilidade Biológica , Células CACO-2 , Lipossomos
3.
Biomed Pharmacother ; 155: 113779, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36271560

RESUMO

Microwave is commonly used in the life, manufacturing and military fields, which may induce body injuries. Brain is the major target organ of microwave radiation and microwave-induced brain injury (MIBI) can lead to insomnia, dreaminess, and a decline in learning and memory. However, there is no clinical medications are available currently. Calcium channel blockers may protect the brain tissue from microwave but most of them cannot enter the brain. Here, we selected a calcium channel blocker-cinnarizine to prepare its dissolving microneedles (MNs) for the therapy of MIBI. The cinnarizine MNs was composed of polyvinyl pyrrolidone (PVP) K90 as the tip, the photopolymerized PVP as the base and the drug, which owned high mechanical strength, leading to easily piecing the skin on the neck and high drug release in vivo. The cinnarizine MNs markedly improved the recovery of spatial memory and spontaneous exploratory behavior of the rats after microwave radiation by inhibiting the expression of calcineurin and calpain-1. The dissolving MN technique is a promising method to improve drugs into the body and perform the anti-microwave radiation action.


Assuntos
Lesões Encefálicas , Cinarizina , Ratos , Animais , Administração Cutânea , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Agulhas , Sistemas de Liberação de Medicamentos/métodos , Calcineurina , Calpaína , Polivinil , Povidona
4.
Cochrane Database Syst Rev ; 10: CD012715, 2022 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-36250781

RESUMO

BACKGROUND: Motion sickness is a syndrome that occurs as a result of passive body movement in response to actual motion, or the illusion of motion when exposed to virtual and moving visual environments. The most common symptoms are nausea and vomiting. Antihistamines have been used in the management of motion sickness for decades, however studies have shown conflicting results regarding their efficacy. OBJECTIVES: To assess the effectiveness of antihistamines in the prevention and treatment of motion sickness in adults and children. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials; Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 7 December 2021. SELECTION CRITERIA: Randomised controlled trials (RCTs) in susceptible adults and children in whom motion sickness was induced under natural conditions such as air, sea and land transportation. We also included studies in which motion sickness was induced under experimental conditions (analysed separately). Antihistamines were included regardless of class, route or dosage and compared to no treatment, placebo or any other pharmacological or non-pharmacological interventions. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1) the proportion of susceptible participants who did not experience any motion sickness symptoms; 2) the proportion of susceptible participants who experienced a reduction or resolution of existing symptoms. Secondary outcomes were 1) physiological measures (heart rate, core temperature and gastric tachyarrhythmia (electrogastrography)) and 2) adverse effects (sedation, impaired cognition, blurred vision). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included nine RCTs (658 participants). Studies were conducted across seven countries, with an overall age range of 16 to 55 years. Motion sickness was induced naturally in six studies and experimentally in four studies (rotating chair). All the naturally induced studies only evaluated first-generation antihistamines (cinnarizine and dimenhydrinate). Risk of bias across the studies varied, with mostly low risk for random sequence generation and allocation concealment, and mostly high risk for selective reporting. Only the experimentally induced studies measured physiological parameters and only the naturally induced studies evaluated adverse effects. There were no studies that clearly assessed the paediatric population. Antihistamines versus placebo or no treatment Antihistamines are probably more effective than placebo at preventing motion sickness symptoms under natural conditions (symptoms prevented: 25% placebo; 40% antihistamines) (risk ratio (RR) 1.81, 95% confidence interval (CI) 1.23 to 2.66; 3 studies; 240 participants) (moderate-certainty). The evidence is very uncertain about the effect of antihistamines on preventing motion sickness under experimental conditions (standardised mean difference (SMD) 0.32, 95% CI -0.18 to 0.83; 2 studies; 62 participants) (very low-certainty). No studies reported results on the resolution of existing motion sickness symptoms. Antihistamines may result in little or no difference in gastric tachyarrhythmia under experimental conditions (mean difference (MD) -2.2, 95% CI -11.71 to 7.31; 1 study; 42 participants) (low-certainty). No studies reported results for any other physiological measures. When compared to placebo, antihistamines may be more likely to cause sedation (sedation: 44% placebo; 66% antihistamines) (RR 1.51, 95% CI 1.12 to 2.02; 2 studies; 190 participants) (low-certainty); they may result in little or no difference in blurred vision (blurred vision: 12.5% placebo; 14% antihistamines) (RR 1.14, 95% CI 0.53 to 2.48; 2 studies; 190 participants) (low-certainty); and they may result in little or no difference in terms of impaired cognition (impaired cognition: 33% placebo; 29% antihistamines) (RR 0.89, 95% CI 0.58 to 1.38; 2 studies; 190 participants) (low-certainty). Antihistamines versus scopolamine The evidence is very uncertain about the effect of antihistamines on preventing motion sickness under natural conditions when compared to scopolamine (symptoms prevented: 81% scopolamine; 71% antihistamines) (RR 0.89, 95% CI 0.68 to 1.16; 2 studies; 71 participants) (very low-certainty). No studies were performed under experimental conditions. No studies reported results on the resolution of existing motion sickness symptoms. The evidence is very uncertain about the effect of antihistamines on heart rate under natural conditions (narrative report, 1 study; 20 participants; "No difference in pulse frequency"; very low-certainty). No studies reported results for any other physiological measures. When compared to scopolamine, the evidence is very uncertain about the effect of antihistamines on sedation (sedation: 21% scopolamine; 30% antihistamines) (RR 0.82, 95% CI 0.07 to 9.25; 2 studies; 90 participants) (very low-certainty) and on blurred vision (narrative report: not a significant difference; 1 study; 51 participants; very low-certainty). No studies evaluated impaired cognition. Antihistamines versus antiemetics Antihistamines may result in little or no difference in the prevention of motion sickness under experimental conditions (MD -0.20, 95% CI -10.91 to 10.51; 1 study; 42 participants) (low-certainty). The evidence is of low certainty due to imprecision as the sample size is small and the confidence interval crosses the line of no effect. No studies assessed the effects of antihistamines versus antiemetics under natural conditions. No studies reported results on the resolution of existing motion sickness symptoms. Antihistamines may result in little or no difference in gastric tachyarrhythmia (MD 4.56, 95% CI -3.49 to 12.61; 1 study; 42 participants) (low-certainty). No studies reported results for any other physiological measures. No studies evaluated sedation, impaired cognition or blurred vision. One study reported physiological data for this outcome, evaluating gastric tachyarrhythmia specifically. Antihistamines may result in little or no difference in gastric tachyarrhythmia (MD 4.56, 95% CI -3.49 to 12.61; 1 study; 42 participants; low-certainty evidence). This evidence is of low certainty due to imprecision as the sample size is small and the confidence interval crosses the line of no effect. Antihistamines versus acupuncture The evidence is very uncertain about the effects of antihistamines on the prevention of motion sickness under experimental conditions when compared to acupuncture (RR 1.32, 95% CI 1.12 to 1.57; 1 study; 100 participants) (very low-certainty). This study did not assess the prevention of motion sickness under natural conditions, nor the resolution of existing motion sickness symptoms. There was no study performed under natural conditions. Physiological measures and adverse effects were not reported. AUTHORS' CONCLUSIONS: There is probably a reduction in the risk of developing motion sickness symptoms under naturally occurring conditions of motion when using first-generation antihistamines, in motion sickness-susceptible adults, compared to placebo. Antihistamines may be more likely to cause sedation when compared to placebo. No studies evaluated the treatment of existing motion sickness, and there are few data on the effect of antihistamines in children. The evidence for all other outcomes and comparisons (versus scopolamine, antiemetics and acupuncture) was of low or very low certainty and we are therefore uncertain about these effects of antihistamines.


Assuntos
Antieméticos , Cinarizina , Dimenidrinato , Enjoo devido ao Movimento , Adolescente , Adulto , Criança , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Enjoo devido ao Movimento/tratamento farmacológico , Derivados da Escopolamina , Adulto Jovem
5.
Pain Pract ; 22(8): 733-745, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36148684

RESUMO

OBJECTIVE: To investigate and analyze the available data on the prophylactic effectiveness of cinnarizine in migraine disorder. BACKGROUND: Cinnarizine has demonstrated encouraging potential in preventing the attacks of migraine. Therefore, we opted to evaluate whether its sole administration leads to positive outcomes. METHODS: The PubMed, Scopus, Web of Science, and Embase databases were searched for English-only original interventional studies published until April 2022, then screened for relevancy and eligibility. The resulting data from the included studies, including the primary (ie, headache episode frequency, intensity, duration, monthly timing, and analgesic intake frequency) and secondary (ie, reported adverse events, quality of life, and activities of daily living) outcome changes compared to placebo and active controls (e.g., sodium valproate and propranolol) were then recorded by two independent assessors. Ultimately, these data were synthesized qualitatively and quantitatively (achieved by determining the mean difference via the random-effects model). RESULTS: A total of 10 studies comprising seven randomized controlled trials and three quasi-experimental studies were included. Compared to placebo, cinnarizine demonstrated significant improvements in migraine episode frequency (Mean difference = -3.10; Confidence interval = [-3.33, -2.88]; p-value < 0.001; I2  < 0.001%), and intensity (Mean difference = -1.54; Confidence interval = [-2.08, -0.99]; p-value < 0.001; I2  < 37.97%). Moreover, cinnarizine led to similar or better results when compared to active controls, including sodium valproate, topiramate, and propranolol. CONCLUSIONS: Cinnarizine can be considered a safe and effective medication for migraine prophylaxis. However, the relatively small sample size made reaching a definite conclusion impossible. Therefore, a higher number of randomized controlled trials are recommended to be taken place to clarify the situation further.


Assuntos
Cinarizina , Transtornos de Enxaqueca , Humanos , Cinarizina/uso terapêutico , Ácido Valproico/uso terapêutico , Propranolol/uso terapêutico , Qualidade de Vida , Atividades Cotidianas , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle
6.
Clin Drug Investig ; 42(9): 705-720, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35864302

RESUMO

BACKGROUND AND OBJECTIVE: The source data of four individual randomised, double-blind, reference- and/or placebo-controlled clinical trials with virtually identical study design were pooled for the present meta-analysis. The main objective was to further evaluate the efficacy and safety of the fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg in comparison to various other antivertigo treatments in patients suffering from central and/or peripheral vestibular vertigo. METHODS: Adult male and female outpatients were subjected to a 4-week treatment with the fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg, cinnarizine (20 mg, 50 mg), dimenhydrinate (40 mg, 100 mg), betahistine dimesylate (12 mg), betahistine dihydrochloride (16 mg) and placebo, respectively. The primary efficacy endpoint was the reduction of a validated mean vertigo score (MVS), a composite score of 12 individual vertigo symptoms, the intensities of which were each evaluated by the patients on a 5-point visual analogue scale. For analysis of primary and further secondary efficacy endpoints, baseline-adjusted analysis of covariance (ANCOVA) was used to calculate adjusted least squares means (LSM) with associated two-sided 95% confidence intervals (CIs) for the difference in MVS reductions between treatment groups. Moreover, various sensitivity analyses, responder and subgroup analyses as well as descriptive analyses with respect to safety/tolerability of the treatments were conducted. RESULTS: Of 795 randomised patients, 779 belonged to the intent-to treat (ITT) and 723 to the per-protocol (PP) population. The main efficacy analysis was based on the ITT population (mean age 52.1 years, 61% female). The mean decrease of the MVS from baseline to Week 4 in the cinnarizine/dimenhydrinate group (-1.10) proved to be significantly larger than in any of the comparator groups. LSM differences for comparators versus the fixed combination ranged between 0.16 (95% confidence interval (CI) 0.03; 0.30, p = 0.017) for cinnarizine 20 mg and 0.60 (95% CI 0.42; 0.78; p < 0.001) for betahistine dimesylate 12 mg in favour of the fixed combination. Furthermore, after 4 weeks of treatment, 74 patients (24.7%) in the cinnarizine/dimenhydrinate group were completely symptom free (MVS = 0), a significantly greater proportion than in any of the comparator groups. Sensitivity analyses showed that baseline characteristics such as age, sex, duration of vertigo and antivertigo pretreatment had only a very minor and clinically non-relevant impact on the efficacy results regarding the primary efficacy outcome. Subgroup analyses with respect to age groups (< 65 years/≥ 65 years) and sex showed no significant differences in efficacy within any of the treatment groups. All treatments were well tolerated. A total of 55 patients (6.9%) reported 75 non-serious adverse events (AEs), and 19 patients (2.4%) discontinued the study prematurely because of AEs. Nearly 95% of the patients (cinnarizine/dimenhydrinate group: 97.9%) rated the tolerability of the study medications as either "good" or "very good". CONCLUSION: The findings of the present meta-analysis indicate that the fixed combination of cinnarizine and dimenhydrinate is a safe and potentially superior treatment option for patients suffering from central and/or peripheral vestibular vertigo, as compared to current standard treatments such as cinnarizine, dimenhydrinate or betahistine given alone in monotherapy.


Assuntos
Cinarizina , Dimenidrinato , Adulto , Idoso , beta-Histina/efeitos adversos , Cinarizina/efeitos adversos , Dimenidrinato/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Vertigem/tratamento farmacológico
7.
J Chem Inf Model ; 62(12): 3008-3022, 2022 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-35696534

RESUMO

The transient receptor potential vanilloid 1 (TRPV1) receptor is a nonselective cation channel, known to be involved in the regulation of many important physiological and pathological processes. In the last few years, it has been proposed as a promising target to develop novel anticonvulsant compounds. However, thermoregulatory effects associated with the channel inhibition have hampered the path for TRPV1 antagonists to become marketed drugs. In this regard, we conducted a structure-based virtual screening campaign to find potential TRPV1 modulators among approved drugs, which are known to be safe and thermally neutral. To this end, different docking models were developed and validated by assessing their pose and score prediction powers. Novobiocin, montelukast, and cinnarizine were selected from the screening as promising candidates for experimental testing and all of them exhibited nanomolar inhibitory activity. Moreover, the in vivo profiles showed promising results in at least one of the three models of seizures tested.


Assuntos
Anticonvulsivantes , Cinarizina , Acetatos , Anticonvulsivantes/farmacologia , Ciclopropanos , Novobiocina , Quinolinas , Sulfetos , Canais de Cátion TRPV
8.
Int J Pharm ; 622: 121856, 2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35618175

RESUMO

To elucidate the critical parameters affecting drug dissolution in the human stomach, the intrinsic dissolution rate (IDR) of cinnarizine was determined in aspirated and simulated human gastric fluids (HGF). Fasted aspirated HGF (aspHGF) was collected from 23 healthy volunteers during a gastroscopic examination. Hydrochloric acid (HCl) pH 1.2, fasted state simulated gastric fluid (FaSSGF), and simulated human gastric fluid (simHGF) developed to have rheological, and physico-chemical properties similar to aspHGF, were used as simulated HGFs. The IDR of cinnarizine was significantly higher in HCl pH 1.2 (952 ± 27 µg/(cm2·min)) than in FaSSGF pH 1.6 (444 ± 7 µg/(cm2·min)), and simHGF pH 2.5 (49 ± 5 µg/(cm2·min)) due to the pH dependent drug solubility and viscosity differences of the three simulated HGFs. The shear thinning behavior of aspHGF had a significant impact on the IDR of cinnarizine, indicating that the use of FaSSGF, with viscosity similar to water, to evaluate gastric drug dissolution, might overestimate the IDR by a factor of 100-10.000, compared to the non-Newtonian, more viscous, fluids in the human stomach. The developed simHGF simulated the viscosity of the gastric fluids, as well as the IDR of the model drug, making it a very promising medium to study gastric drug dissolution in vitro.


Assuntos
Cinarizina , Humanos , Concentração de Íons de Hidrogênio , Reologia , Solubilidade , Estômago , Viscosidade
10.
AAPS PharmSciTech ; 23(3): 80, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35233687

RESUMO

Generally, supersaturation of weakly basic drug solution in the gastrointestinal tract can be followed by precipitation, and this can compromise the bioavailability of drugs. The purpose of this study was to evaluate the effect of Eudragit® S100 on the pH-induced supersaturation of cinnarizine and to examine the preserving mechanism of cinnarizine supersaturation by Eudragit®. Variables, including pH of media, ionic strength, and degree of supersaturation, were studied to investigate the effects of these parameters on cinnarizine supersaturation in the presence and absence of Eudragit®. The size of the Eudragit® aggregate in solution using dynamic light scattering was determined. The effect of Eudragit® on the transport of cinnarizine through the Caco-2 membrane was also investigated. The particle size study of Eudragit® aggregates showed that the size of these aggregates become large when the pH was lowered. Supersaturation experiments also demonstrated that Eudragit® preserved higher cinnarizine supersaturation with increasing ionic strength of the solution. The phase separation behavior of cinnarizine solution as a function of the degree of the supersaturation could be readily explained by considering the drug amorphous solubility. In vitro permeation studies revealed that the rate of cinnarizine permeation across Caco-2 cells increased in the presence of Eudragit®. According to the obtained results, the aggregation status of Eudragit® and nonspecific hydrophobic cinnarizine-Eudragit® interactions seemed to be essential in determining the effect of Eudragit® on cinnarizine supersaturation.


Assuntos
Cinarizina , Células CACO-2 , Cinarizina/química , Humanos , Ácidos Polimetacrílicos/química , Solubilidade
11.
Dermatol Ther ; 35(5): e15365, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35137498

RESUMO

During SARS-CoV-2 pandemic, an outbreak of chilblain-like lesions has been developed, even if the relationship with the virus infection is still debated. We report the good results obtained in 12 patients with chilblain lesions and the use of oral cinnarizine, a piperazine derivative with many pharmacological properties among whom antihistaminic and calcium channel blocking activities.


Assuntos
Pérnio , Cinarizina , Pérnio/diagnóstico , Pérnio/tratamento farmacológico , Pérnio/epidemiologia , Humanos , Pandemias , SARS-CoV-2
12.
J Chromatogr Sci ; 60(9): 832-839, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34875682

RESUMO

From evolution, thin-layer chromatography (TLC) attracts attention as a versatile technique for efficient separation and identification of many drug substances and chemicals. Owing to its simplicity and other outstanding advantages, TLC is extensively used by chromatographers in quantification and purity profiling objectives. In the present study two TLC-Densitometric methods are established and validated for the synchronous estimation of Cinnarizine (Cinn) and Acefyline Heptaminol (Acef) in the presence of Cinn/Acef reported degradation products and Thoephylline (Theo) as Acef potential impurity. The proposed methods are based on densitometric measurements of the spots of Cinn and Acef after separation from their degradation products. Separation is attained on silica gel sheet with dichloromethane: methanol: formic acid as a developing system in ratio: (15, 1, 0.5, by volume) and (15, 0.75, 0.4, by volume) for Cinn (method 1) and Acef (method 2) degradation, consecutively. Quantification is done at 254 nm over concentration ranges of 0.2-1.8 and 2-18 µg/spot for Cinn and Acef; respectively, with mean percentage recoveries of 99.18 ± 0.60/99.84 ± 0.53 and 99.19 ± 0.93/99.66 ± 0.58 for method 1 and method 2; consecutively. The two methods are fully validated and proven to be selective, robust and retained their accuracy in up to 50% of Cinn/Acef reported degradation products and Theo. Moreover, the two methods are applied to a coformulated drug product comprising Cinn and Acef showing satisfactory results. Comparison of the obtained results by the proposed methods with that of the reference ones statistically shows no significant differences.


Assuntos
Cinarizina , Heptaminol , Cromatografia em Camada Delgada/métodos , Cinarizina/análise , Densitometria/métodos , Reprodutibilidade dos Testes
13.
J Sep Sci ; 45(4): 968-975, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34889052

RESUMO

Cinnarizine is a weak base, which can produce supersaturation and precipitation during gastrointestinal transit, affecting its absorption in vivo. Therefore, it is necessary to investigate whether the oral bioavailability of cinnarizine can be improved after co-administration with precipitation inhibitors or not. In order to evaluate the pharmacokinetic behavior of cinnarizine in rats, a simple, rapid, sensitive, and environmentally friendly supercritical fluid chromatography-tandem mass spectrometric method was established and validated. In this method, flunarizine, a structural analogue of cinnarizine, was selected as the internal standard, and cinnarizine was extracted from rat plasma using evaporation-free liquid-liquid extraction method. The analytes were separated on a Torus 1-AA column (3.0 mm × 100 mm, 1.7 µm) within 2.0 min, using a gradient elution procedure. The transitions of cinnarizine and flunarizine were m/z 369.1 → 167.1 and m/z 405.1 → 203.1, respectively. Cinnarizine showed good linear correlation in the range of 1-500 ng/ml with a lower limit of quantification of 1 ng/ml. The intra- and interday precision and accuracy of all quality control samples were within ±15%. This high-throughput, accurate, sensitive, and reproducible method has been successfully applied to study the effects of the precipitation inhibitor cinnarizine on the pharmacokinetics in rats.


Assuntos
Cromatografia com Fluido Supercrítico , Cinarizina , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia com Fluido Supercrítico/métodos , Extração Líquido-Líquido , Ratos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
14.
Braz. J. Pharm. Sci. (Online) ; 58: e19859, 2022. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1383996

RESUMO

To overcome the problems associated with bioavailability and systemic side effects of the drug by oral administration, monolithic matrix type transdermal patches containing cinnarizine (CNZ) were developed. For this purpose, films based on hydroxypropyl methylcellulose and polyvinylpyrrolidone as matrix-forming polymers were designed. Physical characteristics of transdermal films and drug-excipient compatibility were investigated. Factors affecting in vitro drug release and ex vivo skin penetration and permeation of the drug were studied. It was confirmed that films displayed sufficient flexibility and mechanical strength for application onto the skin for a long time period. Ex vivo penetration experiments gave satisfactory results for transdermal drug delivery through rat skin. The parameters determining good skin penetration were also evaluated. The highest drug permeation rate was obtained with incorporation of Transcutol® (0.102 mg/cm2/h) into the base CNZ formulation, followed by propylene glycol (0.063 mg/cm2/h), menthol (0.045 mg/cm2/h), and glycerin (0.021 mg/cm2/h) as penetration enhancers (p < 0.05). As a result, the developed transdermal patches of CNZ may introduce an alternative treatment for various conditions and diseases such as idiopathic urticarial vasculitis, Ménière's disease, motion sickness, nausea, and vertigo. Thus, the risk of systemic side effects caused by the drug can be reduced or eliminated


Assuntos
Administração Oral , Cinarizina , Agonistas dos Receptores Histamínicos/efeitos adversos , Antagonistas Colinérgicos , Anestésicos/classificação , Pele , Técnicas In Vitro/métodos , Preparações Farmacêuticas/análise , Derivados da Hipromelose/efeitos adversos , Liberação Controlada de Fármacos
15.
Molecules ; 26(22)2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34834144

RESUMO

Between 293.2 and 313.2 K and at 0.1 MPa, the solubility of the weak base, cinnarizine (CNZ) (3), in various {Transcutol-P (TP) (1) + water (2)} combinations is reported. The Hansen solubility parameters (HSP) of CNZ and various {(TP) (1) + water (2)} mixtures free of CNZ were also predicted using HSPiP software. Five distinct cosolvency-based mathematical models were used to link the experimentally determined solubility data of CNZ. The solubility of CNZ in mole fraction was increased with elevated temperature and TP mass fraction in {(TP) (1) + water (2)} combinations. The maximum solubility of CNZ in mole fraction was achieved in neat TP (5.83 × 10-2 at 313.2 K) followed by the minimum in neat water (3.91 × 10-8 at 293.2 K). The values of mean percent deviation (MPD) were estimated as 2.27%, 5.15%, 27.76%, 1.24% and 1.52% for the "Apelblat, van't Hoff, Yalkowsky-Roseman, Jouyban-Acree, and Jouyban-Acree-van't Hoff models", respectively, indicating good correlations. The HSP value of CNZ was closed with that of neat TP, suggesting the maximum solubilization of CNZ in TP compared with neat water and other aqueous mixtures of TP and water. The outcomes of the apparent thermodynamic analysis revealed that CNZ dissolution was endothermic and entropy-driven in all of the {(TP) (1) + water (2)} systems investigated. For {(TP) (1) + water (2)} mixtures, the enthalpy-driven mechanism was determined to be the driven mechanism for CNZ solvation. TP has great potential for solubilizing the weak base, CNZ, in water, as demonstrated by these results.


Assuntos
Cinarizina/química , Etilenoglicóis/química , Termodinâmica , Água/química , Solubilidade
16.
Artigo em Inglês | MEDLINE | ID: mdl-33946152

RESUMO

Vertigo is not itself a disease, but rather a symptom of various syndromes and disorders that jeopardize balance function, which is essential for daily activities. It is an abnormal sensation of motion that usually occurs in the absence of motion, or when a motion is sensed inaccurately. Due to the complexity of the etiopathogenesis of vertigo, many pharmacological treatments have been tested for efficacy on vertigo. Among these drugs, cinnarizine, usually given together with dimenhydrinate, appears to be the first-line pharmacotherapy for the management of vertigo and inner ear disorders. Based on these considerations, the present non-interventional study aimed to investigate the clinical efficacy and tolerability of a fixed combination of cinnarizine (20 mg) and dimenhydrinate (40 mg) in patients suffering from vertigo-related symptoms. To this end, we enrolled 120 adults-70 males, and 50 females-with an average age of 64 years. Before beginning pharmacological treatment, all patients were screened for the intensity of vertigo, dizziness, and concomitant symptoms through the Visual Scale of Dizziness Disorders and Dizziness Handicap Inventory scales. At the end of the anamnestic evaluation, patients received the fixed-dose combination of cinnarizine (20 mg) plus dimenhydrinate (40 mg) 3 times daily, for 60 days. The results of this study provide further insight regarding the efficacy of the fixed combination when used to reduce symptoms of vestibular vertigo of central and/or peripheral origin, after both the 15- and 60-day therapies. Independent of the type of vertigo, the fixed combination was able to reduce dizziness- and vertigo-associated symptoms in more than 75% of all patients treated, starting from 15 days of therapy, and improving 60 days after starting the therapy. Interestingly, we also found differences between male and female patients in the framework of the pharmacological effects of therapy. This study provides further details concerning the therapeutic efficacy of the fixed combination of cinnarizine and dimenhydrinate, and also focuses attention on the possibility that these drugs could act in a gender-specific manner, paving the way for further research.


Assuntos
Cinarizina , Dimenidrinato , Adulto , Cinarizina/uso terapêutico , Dimenidrinato/uso terapêutico , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Vertigem/tratamento farmacológico , Vertigem/etiologia
17.
Int J Pharm ; 597: 120292, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33581479

RESUMO

Lipid based formulations (LBFs) can enhance oral bioavailability, however, their utility may be restricted by low drug loading in the formulation. Converting drugs to drug-ionic liquids (drug-ILs) or lipophilic salts can significantly increase lipid solubility but this approach is complicated in some cases by salt disproportionation, leading to a reduction in solubility and physical instability. Here we explore the physical stability of the weakly basic model drug, cinnarizine (CIN), when paired with a decanoate counterion (Dec) to form the drug-IL, cinnarizine decanoate (CIN.Dec). Consistent with published studies of salt disproportionation in aqueous solution, weakly acidic counterions such as Dec lead to the generation of drug-IL lipid solutions with pHs below pHmax. This leads to CIN deprotonation to the less soluble free base and precipitation. Subsequent studies however, show that these effects can be reversed by acidification of the formulation (either with excess decanoic acid or other lipid soluble acids), stimulating a pH shift to the salt plateau of CIN.Dec and the formation of stable lipid solutions of CIN.Dec. Altering formulation pH to more acidic conditions, therefore stabilises drug-ILs formed using weakly acidic lipophilic counterions, and is a viable method to promote formulation stability via inhibition of disproportionation of some drug-ILs.


Assuntos
Cinarizina , Líquidos Iônicos , Lipídeos , Sais , Solubilidade
18.
Int J Pharm ; 595: 120266, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33486017

RESUMO

Partitioning tests in water are early-stage standard experiments during the development of pharmaceutical formulations, e.g. of lipid-based drug delivery system (LBDDS). The partitioning behavior of the active pharmaceutical ingredient (API) between the fatty phase and the aqueous phase is a key property, which is supposed to be determined by those tests. In this work, we investigated the API partitioning between LBDDS and water by in-silico predictions applying the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and validated these predictions experimentally. The API partitioning was investigated for LBDDS comprising up to four components (cinnarizine or ibuprofen with tricaprylin, caprylic acid, and ethanol). The influence of LBDDS/water mixing ratios from 1/1 up to 1/200 (w/w) as well as the influence of excipients on the API partitioning was studied. Moreover, possible API crystallization upon mixing the LBDDS with water was predicted. This work showed that PC-SAFT is a strong tool for predicting the API partitioning behavior during in-vitro tests. Thus, it allows rapidly assessing whether or not a specific LBDDS might be a promising candidate for further in-vitro tests and identifying the API load up to which API crystallization can be avoided.


Assuntos
Lipídeos/química , Preparações Farmacêuticas/química , Água/química , Caprilatos/química , Química Farmacêutica/métodos , Cinarizina/química , Cristalização , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Etanol/química , Excipientes/química , Ibuprofeno/química , Solubilidade , Termodinâmica , Triglicerídeos/química
19.
Drug Deliv Transl Res ; 11(3): 1236-1244, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32935235

RESUMO

Delamanid is a poorly water-soluble drug currently being used for the treatment of tuberculosis. The high frequency of dosing leads to poor adherence for patients who live in lower economic and nomadic populations. Non-digestible self-assembling lipids as a formulation approach for poorly water-soluble drugs have previously been shown to extend the window of absorption through gastric retention. We hypothesise that this approach could lead to the reduction of dosing frequency for delamanid and thereby has potential to improve adherence. Formulations of delamanid were prepared in selachyl alcohol and phytantriol as non-digestible self-assembling lipid vehicles, and their behaviour was compared with reconstituted milk powder, as a digestible lipid-based formulation, and an aqueous suspension. The self-assembly of selachyl alcohol and phytantriol in aqueous media in the presence of delamanid was studied using small angle X-ray scattering and produced the inverse hexagonal (H2) and inverse bicontinuous cubic (V2) liquid crystal structures, respectively. The times at which maximum delamanid levels in plasma were observed (Tmax) after oral administration of the phytantriol, selachyl alcohol and reconstituted milk powder formulations of delamanid to rats were 27 ± 3, 20 ± 4 and 6.5 ± 1.0 h, respectively, compared with the aqueous suspension formulation with a Tmax of 3.4 ± 1 h, which confirms the hypothesis of an extended duration of absorption after administration in non-digestible self-assembling lipids. The digestion products of the triglycerides in the milk formulation increased the solubilisation of delamanid in the gastrointestinal tract, leading to an increase in exposure compared with the aqueous suspension formulation but did not significantly extend Tmax. Overall, the non-digestible nanostructured lipid formulations extended the duration of absorption of delamanid well beyond that from milk or suspension formulations. Graphical abstract.


Assuntos
Cinarizina , Cristais Líquidos , Administração Oral , Animais , Cinarizina/química , Humanos , Cristais Líquidos/química , Nitroimidazóis , Oxazóis , Ratos , Solubilidade
20.
Artigo em Russo | MEDLINE | ID: mdl-35041315

RESUMO

OBJECTIVE: Neuroprotective and nootropic drugs often exhibit complementary, «synergistic¼ effects, the consideration of which is important for choosing the most effective and safe drug combinations. MATERIAL AND METHODS: Chemoinformatic analysis of vinpocetine, piracetam and cinnarizine on neuron cultures, on model organisms (mice, rats) based on modern data mining and machine learning methods. RESULTS: The paper presents the results of the chemoreactom analysis of vinpocetine, piracetam, and cinnarizine. Estimates of various biological activities of molecules on neuronal cultures, on model organisms (mice, rats) and estimates of modulation of the activity of target proteins in rats and humans were obtained. The data obtained made it possible to quantify the value of the synergism score for the combination «vinpocetine + piracetam¼ (54 points) compared with the combination «piracetam + cinnarizine¼ (25 points). CONCLUSIONS: The combination of «vinpocetine + piracetam¼ in the fixed combination (Vinpotropil) is thus more preferable for combined use than for the combination of «piracetam + cinnarizine¼.


Assuntos
Cinarizina , Nootrópicos , Piracetam , Alcaloides de Vinca , Animais , Camundongos , Nootrópicos/farmacologia , Piracetam/farmacologia , Ratos , Alcaloides de Vinca/farmacologia
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