Identification of hit compounds with anti-schistosomal activity on in vitro generated juvenile worms in cell-free medium

Background Anthelminthic treatment options against schistosomiasis are limited. The current treatment relies almost exclusively on a single drug, praziquantel (PZQ). As a consequence, the development of resistance to PZQ and limited activity of PZQ against earlier development stages are respectively a risk and a limitation to achieving the goals of the new WHO roadmap towards elimination. For the discovery of new chemical starting points, the in vitro drug screening on Schistosoma mansoni (S. mansoni) against newly transformed schistosomula (NTS) is still the most predominant approach. The use of only NTS in the initial screening limits sensitivity to potential new compounds which are predominantly active in later developmental stages. Using our recently described highly standardized, straightforward and reliable culture method that generates high rates of juvenile worms, we aimed to repurpose a subset of the NCATS Pharmaceutical Collection (340 compounds) to identify new hits with an in vitro worm culture assay. Methodology/Principal findings Cercariae were mechanically transformed into skin-stage (SkS) schistosomula and continuously cultured for 3–6 weeks to the liver stage (LiS). A commercial source of serum was identified, and decrease of NTS/well along with optimal drug testing conditions was established to test compounds on early and late LiS worms. The library was screened in 96-well format assays using praziquantel (PZQ) as a positive control. Primary screening allowed a 5.9% hit rate and generated two confirmed hits on adult worms; a prophylactic antianginal agent and an antihistaminic drug. Conclusion With this standardized and reliable in vitro assay, important S. mansoni developmental stages up to LiS worms can be generated and cultured over an extended period. When exposed to a subset of the National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection, 3 compounds yielded a defined anti-schistosomal phenotype on juvenile worms. Translation of activity on perfused adult S. mansoni worms was achieved only for perhexiline (a prophylactic antianginal agent) and astemizole (an antihistaminic drug).

Genotoxic Impurities in Ranitidine Containing Products: An Overview

Ranitidine is a well known H2 blocker antihistaminic drug used for symptomatic relief of heartburn, indigestion, acid indigestion, peptic ulcer and hyperacidity. However, On 13th September 2019, the United States Food and Drug Administration (USFDA) has given an alerting statement regarding the presence of nitrosamine impurity called N-nitrosodimethylamine (NDMA) in ranitidine containing products. Recently, some pharmaceutical companies have also recalled their ranitidine containing products from the market. Thus, there is a need to understand about these impurities in ranitidine containing products. The first part of this article highlights the mechanism of action of ranitidine in established therapeutic indications along with its adverse drug reactions and contraindications. Further, the introduction of genotoxic impurities in pharmaceutical products along with its types and mechanism of toxicity of ranitidine containing genotoxic impurity have been discussed.

Assessment of efficacy of promethazine on seizure activity and its interactions with antiepileptic drugs lorazepam and sodium valproate in rats

Background: Presently available antiepileptic drugs are effective in controlling seizures in more than half of patients of all epilepsy but use is often limited by adverse effects. H1 receptor antagonists, have a controversial status in patients of epilepsy. Both pro and antiepileptic effect has been documented in various animal studies. Hence, this study was designed to see the effect of promethazine, an H1 antihistaminic drug and its interactions with antiepileptic drugs lorazepam and sodium valproate in rats.Methods: The effect of promethazine (10 mg/kg) and its interactions with antiepileptic drugs lorazepam and sodium valproate was assessed by using maximal electroshock seizures (MES) and chemoshock pentylenetetrazol (PTZ) method.Results: Promethazine along with lorazepam and sodium valproate in subtherapeutic doses exerted significant protection against MES induced seizures whereas no such protection was observed with PTZ method rather the seizure threshold was reduced.Conclusions: Subtherapeutic doses of promethazine alone and in combination with lorazepam and sodium valproate showed protection against seizures in MES method. However, proconvulsant effect was seen with PTZ method. This shows dual behavior of promethazine on MES and PTZ induced seizures.

Eco-Friendly Green Liquid Chromatographic Determination of Azelastine in the Presence of its Degradation Products: Applications to Degradation Kinetics

Background: Green solvents such as microemulsion were used in the proposed method because they play a vital role in the analytical method’s influence on the environment. Objective: A highly sensitive, specific, and validated stability-indicating eco-friendly green microemulsion liquid chromatography (MELC) method was developed for separation of the antihistaminic drug Azelastine HCl (AZL) from its degradation products with application to degradation kinetics. Methods: Chromatographic separation was operated on a C18 column with a microemulsion mobile phase, which consists of 0.1 M sodium dodecyl sulphate, 10% n-propanol, 1% n-octanol, and 0.3% triethylamine, by using 0.02 M phosphoric acid at pH 3.5 and irbesartan as internal standard. The eluted compounds were monitored at 210 nm with flow rate 1 mL/min at ambient temperature. Results: A linear dependence of the peak area on drug concentration over the concentration range of 0.1 to 25 μg/mL was achieved with an LOD of 0.04 μg/mL and an LOQ of 0.10 μg/mL. Moreover, the proposed method was successfully applied for determination of AZL in eye drops and metered dose nasal inhaler as well as to study the kinetics of alkaline, acidic, neutral, oxidative, and photolytic degradation processes of AZL according to the International Council for Harmonization guidelines. Conclusions: The proposed method could be used as a harmless alternative for quality control analysis of the mentioned drug, without interference from dosage form additives or decomposition products. Highlights: A highly sensitive stability-indicating eco-friendly green MELC method was developed for the separation of the antihistaminic drug AZL from its degradation products.

Effect of promethazine on seizure activity and its interactions with antiepileptic drugs diazepam and phenytoin in Rats

Background: Current antiepileptic drugs (AEDs) are effective in controlling seizures in about 70% patients but use is often limited by adverse effects. Promethazine, H1 receptor antagonist, has a controversial status in patients of epilepsy. Both pro and antiepileptic effect has been documented in various animal studies. Hence, this study was designed to see the effect of promethazine, an H1 antihistaminic drug and its interactions with antiepileptic drugs in rats.Methods: The effect of promethazine (10mg/kg) and its interactions with antiepileptic drugs diazepam and phenytoin was assessed by using maximal electroshock seizures (MES) and chemoshock (PTZ) method.Results: Promethazine along with diazepam in subtherapeutic doses exerted significant protection against MES induced seizures whereas no such protection was observed with PTZ method rather the seizure threshold was reduced.Conclusions: Subtherapeutic doses of Promethazine alone and in combination with diazepam showed protection against seizures in MES method. However, proconvulsant effect was seen with PTZ method suggesting histamine plays a protective role in development of seizures. This shows dual behavior of promethazine on MES and PTZ induced seizures.

Efficacy and Safety of a Combination of Cinnarizine and Dimenhydrinate in the Treatment of Vertigo

Introduction and Background: Vertigo is a medical condition where a person feels as he/ she or the objects around them are moving when they are stable and not moving. Antihistamines, Calcium antagonists, histamine analogs (eg, betahistine derivatives), diuretics, neuroleptics as well as other psychotherapeutic drugs, corticosteroids agents and hemorheologics can be used for the treatment of Vertigo. Combination of Cinnarizine which is a selective calcium-channel blocker and Dimenhydrinate which is an H 1 antihistaminic drug can be used in combination for the treatment of vertigo. This clinical study was conducted to evaluate the efficacy and safety of combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg in patients of vertigo of age group 18 to 65 years. Methodology: Out of total 216 patients, 168 completed the study. Efficacy assessment was made by analysing the reduction in vertigo symptom score (VSS). Safety assessment was made by analysing the adverse events experienced by the patient or observed by the investigator during trial. Results: Reduction in VSS from 7.277 (baseline) to 3.975 (day 3) and 0.987 (day 5). At visit 2 and visit 3 there was reduction of 45.373 % and 86.426 % in mean VSS score. Conclusion: A combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg is safe and efficacious in the treatment of vertigo.