A note on higher-order nondifferentiable symmetric duality in multiobjective programming

AbstractIn this work, we establish a strong duality theorem for Mond–Weir type multiobjective higher-order nondifferentiable symmetric dual programs. This fills some gaps in the work of Chen [X. Chen, Higher-order symmetric duality in nondifferentiable multiobjective programming problems, J. Math. Anal. Appl. 290 (2004) 423–435]

A COMPREHENSIVE REVIEW ON MICRONEEDLES - AN ARCHETYPE SWING IN TRANSDERMAL DRUG DELIVERY

Transdermal drug delivery is the non-invasive delivery of medications through the skin surface into the systemic circulation. The advantage of transdermal drug delivery system is that it is painless technique of administration of drugs. The advantage of transdermal drug delivery system is that it is painless technique of administration of drugs. Transdermal drug delivery system can improve the therapeutic efficacy and safety of the drugs because drug delivered through the skin at a predetermined and controlled rate. Due to the various biomedical benefits, it has attracted many researches. The barrier nature of stratumcorneum poses a danger to the drug delivery. By using microneedles, a pathway into the human body can be recognized which allow transportation of macromolecular drugs such as insulin or vaccine. These microneedles only penetrate outer layers of the skin, exterior sufficient not to reach the nerve receptors of the deeper skin. Thus the microneedles supplement is supposed painless and reduces the infection and injuries. Researches from the past few years showed that microneedles have emerged as a novel carrier and considered to be effective for safe and improved delivery of the different drugs. Microneedles development is created a new pathway in the drug delivery field. This review focus on new advances in transdermal drug delivery system using various carriers emphasizing mostly on the potential role of microneedles as transdermal system

A study on pattern of initial and acquired drug resistance for isoniazid and rifampicin in A.F.B. positive sputum smears of pulmonary tuberculosis patients at a Medical College in North Eastern Uttar Pradesh, India

Background: Despite availability of good quality anti-tubercular drugs and its administration through Directly Observed Therapy Short Course (DOTS) strategy of Revised National Tuberculosis Control Programme (RNTCP), tuberculosis remains a major cause of morbidity and mortality in India. The emergence of drug resistance necessitates the timely detection of susceptibility of anti-TB drugs. This can help in appropriate modification in treatment strategies.Methods: A total of 50 patients of pulmonary TB with AFB positive sputum smears attending the OPD of TB and Chest department of B.R.D. Medical College, Gorakhpur were included. Patients were grouped based on history into new (cat-I) and previously treated patients (cat-II). Cat-II patients were further subdivided into defaulter, treatment failure and relapse groups. The culture and DST of AFB positive sputum smears of these patients was done in VersaTREK™®. At the end of study, patients were grouped according to age, sex, category and drug sensitivity pattern for Isoniazid (INH) and Rifampicin (RIF) viz mono resistance (resistance to either INH or RIF) or multi drug resistance (M.D.R.) and the resultant data were analysed.Results: Of the total 50 patients included in this study, 18 (36%) patients were sensitive to both the drugs INH and RIF, of which 11 (22%) were of cat-I and 7 (14%) of category-II. Twenty-two (44%) patients were resistant to INH only of which 8 (16%) were of cat-I and 14 (28%) of cat-II. One (2%) case of cat-I showed resistance to RIF only, while M.D.R. type of resistance is seen in 1 (2%) patient of cat-I and 8 (16%) patients of cat-II. Pattern of resistance to both INH and RIF together (i.e. M.D.R. type) showed significant difference between cat-I and cat-II.Conclusions: Most of the patients showing resistance to INH, RIF or both INH and RIF (M.D.R.) belonged to category-II (previously treated) patients

The Core Collapse Supernova Rate from the SDSS-II Supernova Survey

We use the Sloan Digital Sky Survey II Supernova Survey (SDSS-II SNS) data to measure the volumetric core collapse supernova (CCSN) rate in the redshift range (0.03<z<0.09). Using a sample of 89 CCSN we find a volume-averaged rate of (1.06 +/- 0.19) x 10**(-4)/(yr Mpc**3) at a mean redshift of 0.072 +/- 0.009. We measure the CCSN luminosity function from the data and consider the implications on the star formation history.Comment: Minor corrections to references and affiliations to conform with published versio

Repurposing Lansoprazole and Posaconazole to treat Leishmaniasis: Integration of in vitro Testing, Pharmacological Corroboration, and Mechanisms of Action

Leishmaniasis remains a serious public health problem in many tropical regions of the world. Among neglected tropical diseases, the mortality rate of leishmaniasis is second only to malaria. All currently approved therapeutics have toxic side effects and face rapidly increasing resistance. To identify existing drugs with antileishmanial activity and predict the mechanism of action, we designed a drug-discovery pipeline utilizing both in-silico and in-vitro methods. First, we screened compounds from the Selleckchem Bio-Active Compound Library containing ~1622 FDA-approved drugs and narrowed these down to 96 candidates based on data mining for possible anti-parasitic properties. Next, we completed preliminary in-vitro testing of compounds against Leishmania amastigotes and selected the most promising active compounds, Lansoprazole and Posaconazole. We identified possible Leishmania drug targets of Lansoprazole and Posaconazole using several available servers. Our in-silico screen identified likely Lansoprazole targets as the closely related calcium-transporting ATPases (LdBPK_352080.1, LdBPK_040010.1, and LdBPK_170660.1), and the Posaconazole target as lanosterol 14-alpha-demethylase (LdBPK_111100.1). Further validation showed LdBPK_352080.1 to be the most plausible target based on induced-fit docking followed by long (100ns) MD simulations to confirm the stability of the docked complexes. We present a likely ion channel-based mechanism of action of Lansoprazole against Leishmania calcium-transporting ATPases, which are essential for parasite metabolism and infectivity. The LdBPK_111100.1 interaction with Posaconazole is very similar to the known fungal orthologue. Herein, we present two novel anti-leishmanial agents, Posaconazole and Lansoprazole, already approved by the FDA for different indications and propose plausible mechanisms of action for their antileishmanial activity

In Silico Binding of 2-Aminocyclobutanones to SARS-CoV-2 Nsp13 Helicase and Demonstration of Antiviral Activity

The landscape of viral strains and lineages of SARS-CoV-2 keeps changing and is currently dominated by Delta and Omicron variants. Members of the latest Omicron variants, including BA.1, are showing a high level of immune evasion, and Omicron has become a prominent variant circulating globally. In our search for versatile medicinal chemistry scaffolds, we prepared a library of substituted α-aminocyclobutanones from an α-aminocyclobutanone synthon (11). We performed an in silico screen of this actual chemical library as well as other virtual 2-aminocyclobutanone analogs against seven SARS-CoV-2 nonstructural proteins to identify potential drug leads against SARS-CoV-2, and more broadly against coronavirus antiviral targets. Several of these analogs were initially identified as in silico hits against SARS-CoV-2 nonstructural protein 13 (Nsp13) helicase through molecular docking and dynamics simulations. Antiviral activity of the original hits as well as α-aminocyclobutanone analogs that were predicted to bind more tightly to SARS-CoV-2 Nsp13 helicase are reported. We now report cyclobutanone derivatives that exhibit anti-SARS-CoV-2 activity. Furthermore, the Nsp13 helicase enzyme has been the target of relatively few target-based drug discovery efforts, in part due to a very late release of a high-resolution structure accompanied by a limited understanding of its protein biochemistry. In general, antiviral agents initially efficacious against wild-type SARS-CoV-2 strains have lower activities against variants due to heavy viral loads and greater turnover rates, but the inhibitors we are reporting have higher activities against the later variants than the wild-type (10–20X). We speculate this could be due to Nsp13 helicase being a critical bottleneck in faster replication rates of the new variants, so targeting this enzyme affects these variants to an even greater extent. This work calls attention to cyclobutanones as a useful medicinal chemistry scaffold, and the need for additional focus on the discovery of Nsp13 helicase inhibitors to combat the aggressive and immune-evading variants of concern (VOCs)