Protective Effect of Melatonin for Renal Ischemia-Reperfusion Injury: A Systematic Review and Meta-Analysis

Background: Renal ischemia-reperfusion (I/R) injury is one of the major causes related to acute kidney damage. Melatonin has been shown as a powerful antioxidant, with many animal experiments have been designed to evaluate the therapeutic effect of it to renal I/R injury.Objectives: This systematic review aimed to assess the therapeutic effect of melatonin for renal I/R injury in animal models.Methods and Results: The PubMed, Web of Science, Embase, and Science Direct were searched for animal experiments applying melatonin to treat renal I/R injury to February 2021. Thirty-one studies were included. The pooled analysis showed a greater reduction of blood urea nitrogen (BUN) (21 studies, weighted mean difference (WMD) = −30.00 [−42.09 to −17.91], p < 0.00001), and serum creatinine (SCr) (20 studies, WMD = −0.91 [−1.17 to −0.66], p < 0.00001) treated with melatonin. Subgroup analysis suggested that multiple administration could reduce the BUN compared with control. Malondialdehyde and myeloperoxidase were significantly reduced, meanwhile, melatonin significantly improved the activity of glutathione, as well as superoxide dismutase. The possible mechanism for melatonin to treat renal I/R injury is inhibiting endoplasmic reticulum stress, apoptosis, inflammation, autophagy, and fibrillation in AKI to chronic kidney disease.Conclusions: From the available data of small animal studies, this systematic review demonstrated that melatonin could improve renal function and antioxidative effects to cure renal I/R injury through, then multiple administration of melatonin might be more appropriate. Nonetheless, extensive basic experiments are need to study the mechanism of melatonin, then well-designed randomized controlled trials to explore the protective effect of melatonin.

Greater than the Sum: Applying Daily-Dose Equivalents to Antipsychotic Prescription Claims to Study Real-World Effects

Traditional methods to standardize exposures in pharmacoepidemiologic studies, like defined daily-doses, may be inadequate to capture drug class effects when there are many in-class medications, formulations, and administration routes. Antipsychotic medications are one example of a drug class with these complexities. Direct dose conversion methods are pharmacologically-based but often overlooked, potentially for lack of real-world guidance and examples of their implementation. The purpose of this article is to describe a method to implement dose conversion, using an example study that quantifies antipsychotic use among a cohort of older adults with dementia. We identified 45,442 older adults (aged ≥66 years) with dementia initiating antipsychotic therapy between January 1, 2009 and December 31, 2012 in Ontario, Canada using linked administrative healthcare databases. We developed and applied a data cleaning and dose conversion algorithm to quantify antipsychotic exposure in chlorpromazine dose equivalents at initiation, month 6, and month 12 of therapy. Results were stratified by route of administration. At initiation, 14% of patients received multiple antipsychotic prescriptions simultaneously. Patients initiating regular injectable and multiple administration routes received the highest median chlorpromazine equivalent daily-doses. Data cleaning changed 3, 16, 36, and 42% of total equivalent daily-doses in patients initiating oral, regular injectable, long-acting injectable, and multiple administration routes, respectively. Dose conversion of prescription claims data was a feasible method to quantify and present antipsychotic drug exposures. Dose conversion methods can be considered for drug effects studies of antipsychotic therapies and other medication classes with complex use.

Evaluation of the cumulative properties of the drug Delcid 7,5®

Cumulative properties (accumulation of a substance or its effect upon repeated administration in equal doses) is determined on the basis of a quantitative indicator – the cumulation coefficient. Before carrying out chronic toxicological experiments, it is necessary to determine the cumulation index of the pharmacological substance – the ratio of LD50 with a single administration to LD50 with multiple administration. According to the Lim method, the cumulative properties of the drug Delcid 7,5® were studied, the cumulation coefficient of the drug was Kkum = 1,09. In accordance with the classification of chemicals, including pesticides by L.I. For a bear, the drug belongs to a group of substances with pronounced cumulation.

The main results of clinical trials of the efficacy, safety and pharmacokinetics of the perspective anti-tuberculosis drug makozinone (PBTZ169)

Tuberculosis is a chronic infectious disease, usually localized in the respiratory system and representing one of the most important global social and biomedical health problems associated with the spread of therapy-resistant forms (multidrug-resistant and extensively drug-resistant tuberculosis). One of the most promising targets for the development of antimycobacterial drugs is the enzyme DprE1, which is involved in the synthesis of the cell wall of mycobacteria. In the series of DprE1 inhibitor drugs, the most advanced drug is PBTZ169 (INN maсozinone). Clinical trials (CT) of the efficacy and safety of macozinone are conducted by the pharmaceutical company LLC NEARMEDIC PLUS in the Russian Federation, and in other countries (Sponsors: Innovative Medicines for Tuberculosis Foundation, cole polytechnique fdrale de Lausanne and Bill and Melinda Gates Foundation). The publication describes results of completed I, IIa and Ib phases CT, conducted in the Russian Federation. Aim. The goal of phase I CT was to assess the safety, tolerability and pharmacokinetics (PK) of PBTZ169, 40 mg capsule, after single and multiple administration under fasting conditions in increasing doses in healthy volunteers. The goal of phase IIa CT was to study the efficacy (in terms of early bactericidal activity EBA), safety and PK of the drug PBTZ169, 80 mg capsules, in various doses, when used as monotherapy in patients with newly diagnosed respiratory tuberculosis with bacterial excretion and retained sensitivity to isoniazid and rifampicin. The purpose of phase Ib CT was to evaluate the safety, tolerability, PK of PBTZ169, 80 mg capsule, after single, double and multiple administration under fasting conditions in increasing doses, as well as the effect of food on its bioavailability in healthy volunteers. Materials and methods. The data of 100 healthy volunteers and 15 patients with newly diagnosed pulmonary tuberculosis, who received the study medication PBTZ169, capsules 40 mg and 80 mg, in the dose range 40 mg 1280 mg of PBTZ169, obtained during phase I, IIa and Ib CTs were analyzed. During I phases CTs, safety, tolerability, and PK of the drug after a single and multiple administration under fasting condition and after meals at rising doses were evaluated. The safety assessment included evaluation of AE/SAE, vital signs, ECG results, and laboratory tests results in the safety population. In the course of phase IIa CT, in addition to safety, tolerance, and PK evaluation, the efficacy of the drug (in terms of EBA) using sputum culture on agar with CFU/ml counting (main method) and quantitative PCR method (auxiliary method) was evaluated. Results. During all CTs, a high safety and tolerability profile was shown, the main PK parameters of the drug and the efficacy were described. PBTZ169 demonstrated linear PK in the dosage range up to 640 mg after single and multiple administration, a statistically significant of EBA of the drug after monotherapy at the dose of 640 mg/day was demonstrate, and it was concluded that the preferred regimen of the drug PBTZ169 intake is administration after meals. Good tolerability and a favorable safety profile of the drug in the studied doses range were demonstrate during all the CTs. Conclusion. One of the most promising and currently studied drugs-inhibitors of DprE1, a new target for the cell wall of mycobacteria, is PBTZ169 or macozinone, which is being develop by the Russian pharmaceutical company NEARMEDIC PLUS ltd.