Drug Repositioning: A Monetary Stratagem to Discover a New Application of Drugs.

Drug repurposing, also referred to as drug repositioning or drug reprofiling, is a scientific approach to the detection of any new application for an already approved or investigational drug. It is a useful policy for the invention and development of new pharmacological or therapeutic applications of different drugs. The strategy has been known to offer numerous advantages over developing a completely novel drug for certain problems. Drug repurposing has numerous methodologies that can be categorized as target-oriented, drug-oriented, and problem-oriented. The choice of the methodology of drug repurposing relies on the accessible information about the drug molecule and like pharmacokinetic, pharmacological, physicochemical, and toxicological profile of the drug. In addition, molecular docking studies and other computer-aided methods have been known to show application in drug repurposing. The variation in dosage for original target diseases and novel diseases presents a challenge for researchers of drug repurposing in present times. The present review critically discusses the drugs repurposed for cancer, covid-19, Alzheimer's, and other diseases, strategies, and challenges of drug repurposing. Moreover, regulatory perspectives related to different countries like the United States (US), Europe, and India have been delineated in the present review.

Global Trends of Cosmeceutical in Nanotechnology: A Review.

Nanotechnology suggests different innovative solutions to augment the worth of cosmetic products through the targeted delivery of content that manifests scientific innovation in research and development. Different nanosystems, like liposomes, niosomes, microemulsions, solid lipid nanoparticles, nanoform lipid carriers, nanoemulsions, and nanospheres, are employed in cosmetics. These nanosystems exhibit various innovative cosmetic functions, including site-specific targeting, controlled content release, more stability, improved skin penetration and enhanced entrapment efficiency of loaded compounds. Thus, cosmeceuticals are assumed as the highest-progressing fragment of the personal care industries that have progressed drastically over the years. In recent decades, cosmetic science has widened the origin of its application in different fields. Nanosystems in cosmetics are beneficial in treating different conditions like hyperpigmentation, wrinkles, dandruff, photoaging and hair damage. This review highlights the different nanosystems used in cosmetics for the targeted delivery of loaded content and commercially available formulations. Moreover, this review article has delineated different patented nanocosmetic formulation nanosystems and future aspects of nanocarriers in cosmetics.

A comparative study on the cardioprotective potential of atorvastatin and simvastatin in hyperhomocysteinemic rat hearts.

The present study has been deliberated in order to compare the cardioprotective potential of 3-hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, Atorvastatin and Simvastatin in hyperhomocysteinemic rat hearts. L-methionine (1.7 g/kg/day orally) was administered to rats for 4 weeks to produce experimental hyperhomocysteinemia (Hhcy). Isolated Langendorff-perfused normal and hyperhomocysteinemic rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 120 min. The extent of myocardial damage was assessed in terms of myocardial infarct size using triphenyltetrazolium chloride (TTC) staining, and release of creatine kinase (CK) and lactate dehydrogenase (LDH) in the coronary effluent; whereas the oxidative stress in the heart was assessed by measuring lipid peroxidation, superoxide anion generation and reduced glutathione. Ischemia-reperfusion (I/R) was noted to produce myocardial injury in normal and hyperhomocysteinemic rat hearts, assessed in terms of increase in myocardial infarct size, LDH and CK in coronary effluent and oxidative stress. Treatment with Atorvatstain (50 µM) and Simvastatin (10 µM) afforded cardioprotection against I/R-induced myocardial injury in normal and hyperhomocysteinemic rat hearts as assessed in terms of reductions in myocardial infarct size, LDH and CK levels in coronary effluent and oxidative stress. It may be concluded that reductions in the high degree of oxidative stress may be responsible for the observed cardioprotective potential of Atorva-and Simvastatin, and both statins can be used interchangeably to afford cardioprotection against I/R-induced myocardial injury in normal and hyperhomocysteinemic rat hearts.

Cardioprotective potential of simvastatin in the hyperhomocysteinemic rat heart.

The present study investigated the probable role of simvastatin, 3-hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, in abrogated cardioprotection in hyperhomocysteinemic (Hhcy) rat hearts. Isolated Langendorff's perfused normal and Hhcy rat hearts were subjected to 30-min global ischemia (I) followed by 120-min reperfusion (R). Assessment of myocardial damage was done by measuring infarct size and analyzing the release of lactate dehydrogenase (LDH) and creatine kinase (CK-MB) in coronary effluent. In addition, the oxidative stress in the heart was assessed by measuring lipid peroxidation and superoxide anion generation. I/R produced myocardial injury in normal and Hhcy rat hearts by increasing myocardial infarct size, LDH and CK in coronary effluent and oxidative stress. Hhcy rat hearts showed enhanced myocardial injury and high oxidative stress as compared to normal hearts. Treatment with Simvastatin (10 µMol) afforded cardioprotection against I/R-induced myocardial injury in normal and hyperhomocysteinemic rat hearts as assessed in terms of reductions in myocardial infarct size, LDH and CK levels in coronary effluent and oxidative stress. The reductions in the high degree of oxidative stress may be responsible for the observed cardioprotection afforded by simvastatin against I/R-induced myocardial injury in normal and hyperhomocysteinemic rat hearts.

Myocardial postconditioning: next step to cardioprotection.

Myocardial ischemia is a condition in which lack of blood flow to the cardiac muscle occurs resulting in deficient oxygen and nutrient supply to the heart. The restoration of blood flow to an organ or tissue is termed reperfusion. Brief episodes of ischemia and reperfusion given after prolonged ischemia and at the onset of reperfusion denotes postconditioning. Myocardial postconditioning is a phenomenon in which myocardium from lethal ischemia-reperfusion injury is protected. However, numerous experimental studies reveal that the cardioprotective effects of postconditioning are suppressed in various pathological states. This review critically discusses the mechanisms involved in the cardioprotective effects of postconditioning and factors affecting the cardioprotective potential of myocardial postconditioning.

Pleiotropic actions of fenofibrate on the heart.

Fenofibrate is a third-generation fibric acid derivative employed clinically as a hypolipidemic agent to lessen the risk caused by atherosclerosis. Dyslipidemia is a condition associated with elevated levels of low-density lipoproteins (LDL), very low-density lipoproteins (VLDL) and triglycerides, and reduced levels of high-density lipoproteins (HDL) in the circulation. Fenofibrate has an ability to diminish LDL, VLDL and triglycerides and pertinently augment HDL, and thus it is used to manage dyslipidemia. The lipid lowering effects of fenofibrate are classically mediated via an activation of peroxisome proliferator-activated receptor-alpha (PPAR-α). Recent studies demonstrated numerous pleiotropic effects of fenofibrate on the heart that afford direct myocardial protection besides its lipid lowering effects. Fenofibrate has an additional potential to prevent the induction and progression of hypertensive heart damage, cardiac hypertrophy, heart failure, myocarditis, lipotoxic cardiomyopathy and vascular endothelial dysfunction-associated cardiovascular abnormalities. In this review, we critically discussed recently identified pleiotropic actions of fenofibrate on the heart. Moreover, the novel cardioprotective effects of fenofibrate against various cardiac disorders have been delineated.

Gentamicin-induced nephrotoxicity: Do we have a promising therapeutic approach to blunt it?

Aminoglycoside antibiotics are employed clinically because of their potent bactericidal activities, less bacterial resistance, post-antibiotic effects and low cost. However, drugs belong to this class are well-known to cause nephrotoxicity, which limits their frequent clinical exploitation. Gentamicin, a commonly used aminoglycoside, is associated with an induction of tubular necrosis, epithelial oedema of proximal tubules, cellular desquamation, tubular fibrosis, glomerular congestion, perivascular edema and inflammation, which ultimately show the way to renal dysfunction. It is a matter of debate whether we have promising agents to prevent the incidence of gentamicin-induced nephrotoxicity. The present review critically discussed the pathogenesis of gentamicin-induced nephrotoxicity. In addition, based on the experimental and clinical studies, the possible therapeutic approach to prevent gentamicin-induced nephrotoxicity has been discussed.

The multifaceted therapeutic potential of benfotiamine.

Thiamine, known as vitamin B(1), plays an essential role in energy metabolism. Benfotiamine (S-benzoylthiamine O-monophoshate) is a synthetic S-acyl derivative of thiamine. Once absorbed, benfotiamine is dephosphorylated by ecto-alkaline phosphatase to lipid-soluble S-benzoylthiamine. Transketolase is an enzyme that directs the precursors of advanced glycation end products (AGEs) to pentose phosphate pathway. Benfotiamine administration increases the levels of intracellular thiamine diphosphate, a cofactor necessary for the activation transketolase, resulting in the reduction of tissue level of AGEs. The elevated level of AGEs has been implicated in the induction and progression of diabetes-associated complications. Chronic hyperglycemia accelerates the reaction between glucose and proteins leading to the formation of AGEs, which form irreversible cross-links with many macromolecules such as collagen. In diabetes, AGEs accumulate in tissues at an accelerated rate. Experimental studies have elucidated that binding of AGEs to their specific receptors (RAGE) activates mainly monocytes and endothelial cells and consequently induces various inflammatory events. Moreover, AGEs exaggerate the status of oxidative stress in diabetes that may additionally contribute to functional changes in vascular tone control observed in diabetes. The anti-AGE property of benfotiamine certainly makes it effective for the treatment of diabetic neuropathy, nephropathy and retinopathy. Interestingly, few recent studies demonstrated additional non-AGE-dependent pharmacological actions of benfotiamine. The present review critically analyzed the multifaceted therapeutic potential of benfotiamine.

Possible involvement of PKC-delta in the abrogated cardioprotective potential of ischemic preconditioning in hyperhomocysteinemic rat hearts.

The present study has been designed to investigate the possible role of protein kinase C-delta (PKC-delta) in hyperhomocysteinemia-induced attenuation of cardioprotective potential of ischemic preconditioning (IPC). Rats were administered L-methionine (1.7 g/kg/day, p.o.) for 4 weeks to produce hyperhomocysteinemia. Isolated Langendorff perfused normal and hyperhomocysteinemic rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 120 min. Myocardial infarct size was assessed macroscopically using triphenyltetrazolium chloride (TTC) staining. Coronary effluent was analyzed for lactate dehydrogenase (LDH) and creatine kinase (CK) release to assess the degree of cardiac injury. Moreover, the oxidative stress in heart was assessed by measuring lipid peroxidation and superoxide anion generation. The ischemia-reperfusion (I/R) was noted to produce myocardial injury as assessed in terms of increase in myocardial infarct size, LDH and CK in coronary effluent and oxidative stress in normal and hyperhomocysteinemic rat hearts. In addition, the hyperhomocysteinemic rat hearts showed enhanced I/R-induced myocardial injury with high degree of oxidative stress as compared with normal rat hearts subjected to I/R. Four episodes of IPC (5 min each) afforded cardioprotection against I/R-induced myocardial injury in normal rat hearts as assessed in terms of reduction in myocardial infarct size, LDH, CK and oxidative stress. On the other hand, IPC mediated myocardial protection against I/R-injury was abolished in hyperhomocysteinemic rat hearts. Treatment with rottlerin (10 microM), a selective inhibitor of PKC-delta did not affect the cardioprotective effects of IPC in normal rat hearts; but its treatment significantly restored the cardioprotective potentials of IPC in hyperhomocysteinemic rat hearts. The high degree of oxidative stress produced in hyperhomocysteinemic rat hearts during reperfusion may activate PKC-delta, which may be implicated in the observed paradoxically abrogated cardioprotective potentials of IPC in hyperhomocysteinemic rat hearts.

The infarct size-limiting effect of ischemic postconditioning (IPOC) is suppressed in isolated hyperhomocysteinemic (Hhcy) rat hearts: the reasonable role of PKC-delta.

BACKGROUND: Recently we have demonstrated that the cardioprotective potential of ischemic postconditioning (IPOC) against ischemia and reperfusion (I/R)-induced myocardial injury was markedly suppressed in hyperhomocysteinemic (Hhcy) rat hearts. The present study investigated the possible role of PKC-delta in Hhcy-induced suppression of myocardial infarct size-limiting effect of IPOC. METHODS: Isolated Langendorff's perfused normal and Hhcy rat hearts were subjected to 30-min global ischemia (I), followed by 120-min reperfusion (R). The myocardial damage was assessed by measuring the infarct size, and analyzing the release of LDH and CK-MB in coronary effluent. The oxidative stress in the heart was assessed by measuring lipid peroxidation and superoxide anion generation. RESULTS: The I/R produced myocardial injury in normal and Hhcy rat hearts by increasing myocardial infarct size, LDH and CK in coronary effluent and oxidative stress. Hhcy rat hearts exhibited enhanced I/R-induced myocardial injury and high oxidative stress as compared to normal rat hearts subjected to I/R. The IPOC (six brief episodes of I/R, 10s each) afforded cardioprotection against I/R-induced myocardial injury in normal rat hearts; but IPOC-mediated cardioprotection was abolished in Hhcy rat hearts. Treatment with rottlerin (10 microM), a selective inhibitor of PKC-delta, did not affect the cardioprotective effect of IPOC in normal rat hearts; but its treatment significantly restored the myocardial infarct size-limiting effect of IPOC in Hhcy rat hearts. CONCLUSION: The high oxidative stress produced in Hhcy rat hearts during reperfusion may activate PKC-delta, which may be responsible for impairing the infarct size-limiting potential of IPOC in Hhcy rat hearts.

Modulation of cardioprotective effect of ischemic pre- and postconditioning in the hyperhomocysteinemic rat heart.

The present study was designed to investigate the effect of hyperhomocysteinemia (Hhcy) on cardioprotective potentials of ischemic preconditioning (IPC) and postconditioning (IPost). Rats were administered L-methionine (1.7 g/kg/day orally) for 4 weeks to produce Hhcy. Isolated Langendorff-perfused normal and hyperhomocysteinemic rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 120 min. Myocardial infarct size was assessed macroscopically by volume method using triphenyltetrazolium chloride staining. Coronary effluent was analyzed for the release of lactate dehydrogenase (LDH) and creatine kinase (CK) to assess the degree of cardiac injury. Moreover, oxidative stress in the heart was assessed by measuring lipid peroxidation, superoxide anion generation and reduced glutathione. Ischemia-reperfusion (I/R) was noted to produce myocardial injury, as assessed in terms of increase in myocardial infarct size, LDH and CK in coronary effluent and oxidative stress in normal and hyperhomocysteinemic rat hearts. In addition, the hyperhomocysteinemic rat hearts showed enhanced I/R-induced myocardial injury with a high degree of oxidative stress in comparison with normal rat hearts subjected to I/R. Four episodes of IPC (5 min each) and six episodes of IPost (10 s each) afforded cardioprotection against I/R-induced myocardial injury in normal rat hearts, as assessed in terms of reduction in myocardial infarct size, LDH, CK and oxidative stress. However, surprisingly, IPC- and IPost-mediated myocardial protection against I/R injury was abolished in the hyperhomocysteinemic rat heart. It may be concluded that Hhcy may make the heart susceptible to oxidative stress induced by I/R, and that the high degree of oxidative stress produced in the hyperhomocysteinemic rat heart in response to reperfusion may be responsible for abolishing the cardioprotective potential of IPC and IPost against I/R injury.

Possible role of JAK-2 in attenuated cardioprotective effect of ischemic preconditioning in hyperhomocysteinemic rat hearts.

The present study investigated the possible role of Janus kinase-2 (JAK-2) in hyperhomocysteinemia-induced attenuation of the cardioprotective effects of ischemic preconditioning (IPC). Rats were administered L-methionine (1.7 g/kg/day, p.o.) for 4 weeks to produce hyperhomocysteinemia. Isolated Langendorff's perfused normal and hyperhomocysteinemic rat hearts were subjected to global ischemia for 30 min, followed by reperfusion for 120 min. Myocardial infarct size was assessed macroscopically using triphenyltetrazolium chloride staining. Coronary effluent was analyzed for lactate dehydrogenase (LDH) and creatine kinase (CK) release to assess the extent of cardiac injury. The oxidative stress in the heart was assessed by measuring thiobarbituric acid-reactive substances (TBARS), superoxide anion generation and the reduced form of glutathione. Ischemia-reperfusion (I/R) induced oxidative stress by increasing TBARS, superoxide anion generation and decreasing reduced form of glutathione in normal and hyperhomocystenemic rat hearts. Moreover, I/R produced myocardial injury, which was assessed in terms of the increase in myocardial infarct size, LDH and CK release in coronary effluent, and decrease in coronary flow rate in normal and hyperhomocysteinemic rat hearts. The hyperhomocysteinemic rat hearts showed enhanced I/R-induced myocardial injury with a high degree of oxidative stress as compared with normal rat hearts subjected to I/R. Four episodes of IPC (5 min each) afforded cardioprotection against I/R-induced myocardial injury in normal rat hearts as assessed in terms of improvement in coronary flow rate and reduction in myocardial infarct size, levels of LDH, CK, and oxidative stress. On the other hand, IPC-mediated myocardial protection against I/R-injury was abolished in hyperhomocysteinemic rat hearts. Tyrphostin AG490 (5 microM), a selective inhibitor of JAK-2, did not affect the cardioprotective effects of IPC in normal rat hearts, but its administration markedly restored the cardioprotective potential of IPC in hyperhomocysteinemic rat hearts. Administration of diazoxide (30 microM), an ATP-sensitive potassium (K(ATP)) channel opener, also restored the cardioprotective effects of IPC in hyperhomocysteinemic rat hearts. In conclusion, it is suggested that the high degree of oxidative stress produced in hyperhomocysteinemic rat hearts during reperfusion and consequent activation of JAK-2 and closure of K(ATP) channels may be responsible for abolishing the cardioprotective potential of IPC against I/R-induced myocardial injury.

Pre-conditioning and postconditioning to limit ischemia-reperfusion-induced myocardial injury: what could be the next footstep?

Myocardial ischemia is a condition in which the coronary blood flow to the heart is reduced, which results in deficient oxygen and nutrients supply to the heart. Reperfusion to an ischemic myocardium often results in lethal myocardial injury. The brief episodes of ischemia and reperfusion given before prolonged ischemia and reperfusion denote pre-conditioning. On the other hand, brief episodes of ischemia and reperfusion given after prolonged ischemia and at the onset of reperfusion denotes postconditioning. Pre- and postconditioning are anti-jeopardized phenomenons in which both forms have been shown to protect the myocardium from lethal ischemia-reperfusion injury. However, numerous experimental studies reveal that the cardioprotective effects of these phenomenons have been suppressed in presence of some pathological factors such as hyperglycemia, obesity, hypercholesterolemia, etc. In this review, we have critically discussed the mechanisms involved in the cardioprotective effects of pre- and postconditioning to limit ischemia-reperfusion-induced myocardial injury. Moreover, the clinical relevance and factors affecting the cardioprotective potentials of pre- and postconditioning have been delineated.