Current updates on the epidemiology,pathogenesis and development of small molecule therapeutics for the treatment of Ebola virus infections

Ebola virus disease(EVD)is a rare,highly contagious and a deadly disease with a variable fatality rate ranging from 30%to 90%.Over the past two decades,Ebola pandemic has severely affected the sub-Sahara region including Democratic Republic of the Congo(DRC),and Uganda.The causative agents of the most EVD cases are three distinct species out of six Ebolaviruses namely Zaire Ebolavirus(ZEBOV),Sudan Ebolavirus(SUDV)and Bundibugyo Ebolavirus(BDBV).In recent years,significant strides have been made in therapeutic interventions.Notably,the US Food and Drug Administration has approved two monoclonal antibodies:InmazebTM(REGN-EB3)and Ansuvimab or EbangaTM.Additionally,many small molecules are currently in the developmental stage,promising further progress in medical treatment.Addressing the critical need for preventive measures,this review provides an in-depth analysis of the licensed Ebola vaccines-Ervebo and the combination of Zabdeno(Ad26.ZEBOV)and Mvabea(MVA-BN-Filo)as well as the vaccines which are currently being tested for their efficacy and safety in clinical studies.These vaccines might play an important role in curbing the spread and mitigating the impact of this lethal disease.The current treatment landscape for EVD encompasses both nutritional(supportive)and drug therapies.The review comprehensively details the origin,pathogenesis,and epidemiology of EVD,shedding light on the ongoing efforts to combat this devastating disease.It explores small molecules in various stages of the development,discusses patents filed or granted,and delves into the clinical and supportive therapies that form the cornerstone of EVD management.This review aims to provide the recent developments made in the design and synthesis of small molecules for scientific community to facilitate a deeper understanding of the disease and fostering the development of effective strategies for prevention,treatment,and control of EVD.

A review on therapeutic potential of Nigella sativa:A miracle herb

Nigella sativa(N.sativa)(Family Ranunculaceae)is a widely used medicinal plant throughout the world.It is very popular in various traditional systems of medicine like Unani and Tibb,Ayurveda and Siddha.Seeds and oil have a long history of folklore usage in various systems of medicines and food.The seeds of N.saliva have been widely used in the treatment of different diseases and ailments.In Islamic literature,it is considered as one of the greatest forms of healing medicine.It has been recommended for using on regular basis in Tibb-e-Nabwi(Prophetic Medicine).It has been widely used as antihypertensive,liver tonics,diuretics,digestive,anti-diarrheal,appetite stimulant,analgesics,anti-bacterial and in skin disorders.Extensive studies on N.sativa have been carried out by various researchers and a wide spectrum of its pharmacological actions have been explored which may include antidiabetic,anticancer,immunomodulator,analgesic,antimicrobial,anti-inflammatory,spasmolytic,bronchodilator,hepato-protective,renal protective,gaslro-prolective,antioxidant properties,etc.Due to its miraculous power of healing,N.sativa has got the place among the top ranked evidence based herbal medicines.This is also revealed that most of the therapeutic,properties of this plant are due to the presence of thymoquinone which is major bioactive component of the essential oil.The present review is an effort to provide a detailed survey of the literature on scientific researches of pharmacognostical characteristics,chemical composition and pharmacological activities of the seeds of this plant.

Quantification of total phenol,flavonoid content and pharmacognostical evaluation including HPTLC fingerprinting for the standardization of Piper nigrum Linn fruits

Objective:To carry out the physicochemical and phytochemical standardization with high performance thin layer chromatography fingerprinting of Piper nigrum L.(P.nigrum)fruits in order to ascertain the standard pharmacognostical parameters of this king of spices.Methods:Many standardization parameters like extractive values,total ash value,water soluble ash value and acid insoluble ash,moisture content,loss on drying and pH values of P.nigrum L.fruits were analyzed.The method of Harborne was adopted for the preliminary phytochemicals screening.Analysis of total phenolic and flavonoid contents,pesticides residues,aflatoxin and heavy metals were also performed.CAMAG-high performance thin layer chromatography system was used for fingerprinting of methanolic extract of P.nigrum L.fruits.Results:The results of phytochemicals testing indicated the presence of carbohydrates,phenolic compounds,flavonoids,alkaloids,proteins,saponins,lipids,sterols and tannins in various solvent extracts.Total phenolic and flavonoid contents in methanolic extract were found to be 1.728 1 mg/g and 1.087 ug/g,respectively.Heavy metals concentrations were found to be within standard limits.Aflatoxins and pesticides residues were absent.Conclusions:The outcome of this study might prove beneficial in herbal industries for identification,purification and standardization of P.nigrum L.fruits.

A novel polyherbal formulation containing thymoquinone attenuates carbon tetrachloride-induced hepatorenal injury in a rat model

Objective:To evaluate a novel polyherbal formulation(BSVT)containing the standardized extracts from the leaves of Boerhavia diffusa,Solidago virgaurea,Vitex negundo,and thymoquinone in CCl4 induced hepatorenal toxicity in rats.Methods:A total of 36 rats were divided into six groups including normal control,CCl4(2 mL/kg,i.p.),CCl4(2 mL/kg,i.p.)+Cystone?(750 mg/kg p.o.),CCl4(2 mL/kg,i.p.)+BSVT(25 mg/kg,p.o.),CCl4(2 mL/kg,i.p.)+BSVT(50 mg/kg,p.o.),and CCl4(2 mL/kg,i.p.)+BSVT(100 mg/kg,p.o.).All treatments were given for four weeks.Serum levels of aspartate transaminase,alanine transaminase,alkaline phosphatase,cholesterol,total protein,serum urea,blood urea nitrogen and creatinine were assessed.Superoxide dismutase,malondialdehyde,and glutathione peroxidase were evaluated in tissue homogenate.The histopathological study of liver and kidney tissues was also done.Results:Aspartate transaminase,alanine transaminase,alkaline phosphatase,cholesterol,serum urea,blood urea nitrogen and creatinine were significantly elevated(P<0.001)while total protein was considerably reduced in the CCl4 group as compared to the normal control(P<0.001),which indicated hepatorenal toxicity.In addition,superoxide dismutase and glutathione peroxidase activities were significantly decreased(P<0.001)while malondialdehyde levels were increased markedly(P<0.001).Treatment with BSVT formulation recovered these parameters towards a normal level in a dose-dependent manner.Conclusions:BSVT formulation ameliorates the hepatorenal toxicity in a dose-dependent manner.Furthermore,clinical studies are required to confirm its efficacy.

Phytochemistry and potential therapeutic actions of Boswellic acids:A mini-review

The pentacyclic triterpenic acids isolated from the oleo gum resin of various Boswellia species are collectively called as Boswellic acids(BA).The oleo gum resin obtained from Indian variety i.e.Boswellia serrata(Family – Burseraceae) is commonly known as Salai guggal.The resin fraction of Salai guggal is rich in Boswellic acids and its essential oil is composed of a mixture of mono,di and sesquiterpenes while gum fraction chiefly contains pentose and hexose sugars.This oleo-gum resin is quite popular among traditional practitioners of traditional Chinese and Indian Systems of medicine owing to their wide range of useful biological properties such as anti-inflammatory,anti-arthritic,antirheumatic,anti-diarrheal,anti-hyperlipidemic,anti-asthmatic,anti-cancer,anti-microbial anti-fungal,anti-complementary and analgesic activity,etc.It has been used as a herbal medicine since the prehistoric time to cure acute and chronic ailments including inflammatory diseases.Phytochemical investigation of this herbal medicine lead to identification of Boswellic acids which are found to be novel,potent,specific antiinflammatory agents due to non-redox inhibition of 5-lipoxygenase(5-LO) enzyme.However,the other important targets of Boswellic acids also include topoisomerases,angiogenesis,and cytochrome p450 enzymes.This review is a sincere attempt to discuss and present the current status of therapeutic potential,phytochemical as well as pharmacological profile of Boswellic acids primarily obtained from B.serrata.

Application of LC–MS/MS for quantitative analysis of glucocorticoids and stimulants in biological fuids

Liquid chromatography tandem mass chromatography （LC-MS/MS） is an important hyphenated technique for quantitative analysis of drugs in biological fluids. Because of high sensitivity and selectivity, LC-MS/MS has been used for pharmacokinetic studies, metabolites identification in the plasma and urine. This manuscript gives comprehensive analytical review, focusing on chromatographic separation approaches （column packing materials, column length and mobile phase） as well as different acquisition modes （SIM, MRM） for quantitative analysis of glucocorticoids and stimulants. This review is not meant to be exhaustive but rather to provide a general overview for detection and confirmation of target drugs using LC-MS/MS and thus useful in the doping analysis, toxicological studies as well as in pharmaceutical analysis.

Eslicarbazepine acetate:A therapeutic agent of paramount importance in acute anticonvulsant therapy

Eslicarbazepine acetate (ESL) is a new, once daily, orally administered, third generation antiepileptic drug which is indicated in the treatment of partial-onset seizures. ESL is known to exert it's anticonvulsant effect by blocking the voltage-gated sodium channels. Several clinical trials and pharmacological studies have revealed that seizure control was better with ESL monotherapy (1 200 or 1 600 mg once daily) following a switch from other antiepileptic drugs in comparison with pseudo-placebo patients. The studies have indicated the ESL to be well tolerated and produced only mild to moderate emergent adverse events with the therapy. Being a dibenzazepine family member, structure and chemistry of ESL resembles more or less to carbamazepine and oxcarbazepine. ESL differs structurally from carbamazepine and oxcarbazepine at the 10, 11 position of dibenazepine nucleus. This molecular variation results in differences in metabolism and thus helps to prevent the formation of toxic epoxide metabolites. ESL following oral administration is rapidly metabolised to active metabolite namely S-licarbazepine which is responsible for its pharmacological activity. ESL exhibits acceptable pharmacokinetic profile and shows insignificant drug-drug interactions. In phase III clinical program, ESL was found to be efficacious and well tolerated in adult patients with partial onset seizures previously not controlled with treatment with one or two other antiepileptic drugs.

PI3K signaling pathway targeting by using different molecular approaches to treat cancer

Recent evidence of research has been proposed that the phosphoinositide 3-kinase(PI3K) pathway is noticeable target for searching novel anticancer agents. The phosphoinositide 3-kinase(PI3K) is accountable for harmonizing a diverse range of cell functions, such as transcription, proliferation, cell survival, cell growth, degranulation, vesicular trafficking and cell migration, which are mostly involved in carcinogenesis. Particularly, PI3K-mediated signaling molecules and its effects on gene expression contribute to tumorigenesis. PI3Ks generally are grouped into three distinct classes: Ⅰ, Ⅱ and Ⅲ according to their structure and function. The class IA of PI3K includes an alpha, beta or delta p110 catalytic subunit(p110α, p110β, or p110γ), which are associated with the activation of RTKs. Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, have just been recognized as novel mechanisms of inducing oncogenic PI3K signaling. Therefore, the class IA PI3K is the only one of most evidently implicated in cancer. The PI3K pathway is mostly mutated in more cancer patients compared with normal person, making it an eyecatching molecular target for analyses based on inhibitor molecule. In this article, we highlighted the signaling effects and regulation pathway of PI3K involved in the development and survival of tumor cells. The consequence and intricacy of PI3K pathway made it an essential beneficial target for cancer treatment.

Chemical modification of acetaminophen：PASS assisted in vivo antiinflammatory activity of chalcones,flavanones and Schiff bases

In the present study,synthetic chalcones,flavanones and Schiff bases were prepared starting from paraceamol,and evaluated their anticipated anti-inflammatory activity.Chalcones were synthesized by reacting 3-acetyl-4-hydroxy acetanilide and aromatic aldehydes in alcoholic potassium hydroxide(KOH) solution under Claisen-Schmidt condensation conditions.The chalcones were cyclized in the presence of piperidine in isoamyl alcohol to obtain flavonone derivatives.Schiff bases were synthesized by condensing 3-acetyl-4-hydroxy anilines with aromatic aldehydes in the presence of HCl.These Schiff bases were further reacted with other aromatic aldehydes in alcoholic KOH solution.PASS cheminformatics software was used to predict the anti-inflammatory activity of synthesized compounds.PASS software predicted that chalcone-based Schiff bases 6a–d contained structural features that can exhibit anti-inflammatory activity.All the prepared derivatives of acetaminophen exhibited moderate to excellent in vivo anti-inflammatory activity in carrageenan-induced edema in rat paw.All the Schiff bases coupled chalcones showed good anti-inflammatory activity compared with the reference drug,diclofenac.Further evaluation of their therapeutic potential and safety profile is required in the future study.