A review of the evidence to explain pharmacological basis of injection (ab)use of buprenorphine–naloxone tablets

Opioid use disorder is a major public health problem, and opioid replacement therapy with buprenorphine (BPN) is a clinically effective and evidence-based treatment for it. To deter misuse of the tablet through the injecting route, BPN coformulated with naloxone (BNX) in 4:1 ratio is available in many countries. Despite this, significant diversion and injecting use of the BNX combination has been reported from across the world. In this article, the pharmacological properties of BPN and BNX and the evidence for their diversion are reviewed. Also, a critical examination is made of the evidence supporting the role of naloxone in reducing the agonist effects of BPN when used through the injecting route. Based on this evidence, a hypothesis explaining the continued diversion of BNX has been proposed.

DRUG REPURPOSING: IN SILICO BASED STUDY ON REPURPOSING PHYTOCHEMICALS ON INFLUENZA

By and by, the world is in a battle with the novel Influenza and with no prompt medicines accessible the scourge brought about by the disease is expanding step by step. A ton of researchers are continuing for the potential medication up-and-comer that could help the medical care framework in this battle. In recent years, studies of phytoconstituents have gradually increased worldwide because the natural sources and variety of such plants allow them to complement modern pharmacological approaches. As computer technology has developed, in silico approaches such as virtual screening and network analysis have been widely utilized in efforts to elucidate the pharmacological basis of the functions of phytoconstituents. We present a docking?based screening using a quantum mechanical scoring of a library built from approved drugs and compounds that Curcumin, Gallic Acid, Phenethyl Isothiocyanate, Piperine, with Proteins Neuraminidase, Hemagglutinin, M1 and M2 Matrix proteins having PDB IDs 3BEQ, 4WE8, 5V6G, 6BKL respectively, could display antiviral activity against Influenza. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against the disease. We hope that these findings may contribute to the rational drug design against Influenza. Keywords: PDB IDs 3BEQ, 4WE8, 5V6G, 6BKL

Chemistry, Cyclophosphamide, Cancer Chemotherapy, and Serendipity: Sixty Years On

Cambridge Dictionary: serendipity | noun | the phenomenon of finding interesting or valuable things by chance. The year 2019 marked the 60th anniversary of the approval of cyclophosphamide (CP) as an anticancer by the U.S. Food & Drug Administration in 1959 for the treatment of lymphoma. Between 1959 and 2019 there were ~50,000 publications listed in PubMed that have CP in the title and/or abstract, with these annual numbers showing a continual increase, and over 1,800 such articles in 2019 alone. The discovery of CP is a prime example of serendipity in science, which also applies to key elements of the metabolism and pharmacological basis for the specificity of the cytotoxicity of CP toward cancer cells. Phosphoramide mustard (PM), HO(H2N)P(O)N(CH2CH2Cl)2, the principal metabolite of CP with DNA alkylating activity, was synthesized and reported by Friedman and Seligman in 1954 prior to the discovery of CP. Interestingly, the original drug design premise for synthesizing PM, which was based on elevated phosphamidase enzyme activity in cancer cells proved to be incorrect. While this wrong premise also led to the synthesis of CP, as a six-membered ring cyclic phosphamidase-activated precursor of PM, the actual metabolic conversion of CP to PM was subsequently found to involve a surprisingly complex array of metabolites and metabolic pathways, all completely unrelated to phosphamidase. Although the molecular structure of CP has an asymmetrically substituted, i.e. chiral phosphorus center, the racemic mixture of the Rp and Sp enantiomers of CP was used throughout its initial investigations and subsequent clinical trials despite the involvement of an initial enzyme-mediated metabolic activation step, which could, in principle, be stereoselective for only one of the enantiomers of CP. Stereochemical investigations along those lines were eventually carried out, but the results did not warrant replacement of racemic CP with either enantiomer in the clinic. Amazingly, there are now ~4,000 structural congeners of PM listed Chemical Abstracts, but none have led to an anticancer drug superior to CP. This account provides a synopsis of the key chemistry and stereochemistry investigations that comprise this story of CP, as a remarkable instance of serendipity in science, and my chance involvement in the unfolding of this fascinating story.