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Background and Aims Diabetes is a risk factor for exacerbated outcome after acute myocardial infarction (AMI) and doubles the risk of mortality after MI. Increased levels of MMP-2 and MMP-9 in diabetes cause vascular remodelling, which leads to cardiovascular complications of diabetes. We hypothesized that inhibition of MMP-2 and MMP-9 can reduce worsening of myocardial ischemia in diabetic patients. Further, we hypothesized that minocycline induced MMP-2 and MMP-9 inhibition will be potentiated by aspirin and the combination of both drugs will prevent worsening of MI in diabetic patients. In the present study, efficacy of combination of minocycline and aspirin to attenuate exacerbation of myocardial ischemia/reperfusion (I/R) injury in diabetic rats was evaluated. Methods Diabetes was induced in male Wistar rats by streptozotocin (55 mg/kg i.p.). Three weeks after diabetes induction, rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of 3 weeks. At the end of week 6, I/R injury was induced by ligating the left anterior descending coronary artery for 30 min followed by 2 h reperfusion. Results Percentage infarct volume, arrhythmias, mortality, collagen level and MMP-2 and MMP-9 level were significantly increased in vehicle-treated diabetic group when compared with normoglycemic rats. Treatment with a combination of minocycline and aspirin decreased percentage infarct volume, arrhythmias, mortality and collagen level when compared with vehicle-treated diabetic controls and showed reduced levels of MMP-2 and MMP-9. Conclusions Results of the present study suggest that the combination of minocycline and aspirin prevent worsening of AMI in diabetic rats.

Despite an incessant advancement in the treatment of Colorectal Cancer (CRC), 40% of individuals suffer from disease relapse which marks the need for new treatment options. In this study we report synergistic antitumor activity of Laccaic acid (LA) and Phenethyl isothiocyanate (PEITC) combination in colorectal cancer via dual inhibition of DNA methyltransferase-1 and Histone deacetylase-1. Efficacy of combination was evaluated in both in-vitro and in-vivo experiments using human colon carcinoma cell line HT29 and 1,2-dimethyl hydrazine induced colon cancer rat model, respectively. In the cell line studies treatment with combination showed reduced cell viability with apoptotic cell death compared to individual treatment groups which showed necrotic cell death. IC50 value for combination (0.478 μM) was much lower than LA (6.08 μM), PEITC (11.88 μM) and 5-Fluorouracil (9.88 μM). In the in-vivo study combination group significantly attenuated number of aberrant crypt foci, fecal consistency score, IL-6, TNF-α, DNMT1 and HDAC1 levels, histological findings and mortality as compared to negative control. Further, toxic effects produced by combination were significantly less. Results suggest potent synergistic efficacy of Laccaic acid and Phenethyl isothiocyanate combination in colorectal cancer.

Hyperglycemia induced oxidative stress is a prime factor for cardiovascular dysfunction (CVD) in diabetic patients. In this process matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) play important roles. Nobiletin, a polymethoxy citrus flavone, has potent MMP-2 and MMP-9 inhibitory activity in addition to antioxidant activity. We hypothesized that nobiletin due to its MMP-2 & MMP-9 inhibitory and antioxidant effects may ameliorate the cardiovascular dysfunction of diabetes. Diabetes was induced using streptozotocin (50 mg kg(-1) i.p.) in male wistar rats. Four weeks after the induction of diabetes, the rats were treated with nobiletin (10 mg kg(-1), and 25 mg kg(-1)) for a period of the following four weeks. At the end of eight weeks, hemodynamic parameters were recorded, cardiac hypertrophy was measured, and antioxidant assays, and gelatin zymography for MMP-2 & MMP-9 analysis and histopathology were performed. The vascular reactivity of the aorta was measured by recording the contractile response to phenylephrine and relaxation responses to acetylcholine. Treatment with 25 mg kg(-1) nobiletin ameliorated the hemodynamic parameters, oxidative stress, collagen level, MMP-2 and MMP-9 levels, and vascular reactivity significantly compared with vehicle treated diabetic group. Thus, this study suggests that nobiletin ameliorates the CVD of diabetes by inhibiting oxidative stress, MMP-2 & MMP-9 and can be used as a potential therapeutic approach.

Pancytopenia is a health condition in which there is a reduction in the amount of leucocytes, erythrocytes and thrombocytes. If more than one of the blood cells is low then the condition is called as bicytopenia. The pancytopenic condition is observed in treatment of diseased conditions like thalassemia and hepatitis C. Iatrogenically pancytopenia is caused by some antibiotics and anti-HCV drugs. Medical conditions like aplastic anaemia, lymphoma, copper deficiency, and so forth can also cause pancytopenia. Pancytopenia can in turn decrease the immunity of the person and thereby can be fatal. Current therapies for pancytopenia include bone marrow stimulant drugs, blood transfusion and bone marrow transplant. The current therapies are very excruciating and have long-term side-effects. Therefore, treating these condition using herbal drugs is very important. Herbs like wheatgrass, papaya leaves and garlic are effective in treating single lineage cytopenias. The present review is focused on the potential effects of natural herbs for the treatment of pancytopenia.

Zaltoprofen, a non-steroidal anti-inflammatory drug, has potent inhibitory action against nociceptive responses. However, gastrointestinal ulcer accompanied with anemia due to the bleeding are most cited side effects associated with it. Due to this, administration of Zaltoprofen is not suitable for individuals with gastric ulcer. Thus, there is unmet need to develop an alternative delivery system that will be easy to administer and can avoid ulcerogenic side effects associated with it.Present study was aimed to prepare and evaluate microemulsion (ME) and microemulsion-based gel formulation of Zaltoprofen for transdermal delivery.Pseudo-ternary phase diagrams were utilized to prepare ME formulations. Effect of surfactant and co-surfactant mass ratio on the ME formation and permeation of ME were evaluated and formulation was optimized. Permeation studies were performed using excised pigskin was studied. Efficacy of optimized formulations was evaluated in rat model of inflammation and pain.Composition of optimized formulation was 1% (w/w) Zaltoprofen, 20% (w/w) Capryol 90, 50% (w/w) Smix (2:1, Cremophor RH 40 and Transcutol P). Optimized formulation showed globule size of 22.11 nm, polydispersity index of 0.251 and zeta potential of -11.4 mV. ME gel was found safe in skin irritation study. Significant analgesic activity and anti-inflammatory activity of ME gel was observed in hot plate test and rat paw edema test, respectively.In conclusion, results of present study suggest that ME could be a promising formulation for transdermal administration of Zaltoprofen.

The efficacy of lamotrigine in the treatment of focal epilepsies have already been reported in several case reports and open studies, which is thought to act by inhibiting glutamate release through voltage-sensitive sodium channels blockade and neuronal membrane stabilization. However, recent findings have also illustrated the importance of lamotrigine in alleviating the depressive symptoms of bipolar disorder, without causing mood destabilization or precipitating mania. Currently, no mood stabilizers are available having equal efficacy in the treatment of both mania and depression, two of which forms the extreme sides of the bipolar disorder. Lamotrigine, a well established anticonvulsant has received regulatory approval for the treatment and prevention of bipolar depression in more than 30 countries worldwide. Lamotrigine, acts through several molecular targets and overcomes the major limitation of other conventional antidepressants by stabilizing mood from “below baseline” thereby preventing switches to mania or episode acceleration, thus being effective for bipolar I disorder. Recent studies have also suggested that these observations could also be extended to patients with bipolar II disorder. Thus, lamotrigine may supposedly fulfill the unmet requirement for an effective depression mood stabilizer.

Enhanced production of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in diabetes leads to degradation of extracellular matrix in blood vessels and leads to complications of diabetes. In the present study, we have targeted MMP-2 and MMP-9 overactivation in diabetic neuropathy using a known MMP-2 and MMP-9 inhibitor, minocycline, with a non-selective COX inhibitor, aspirin. Streptozotocin-induced diabetic neuropathy was carried out in male Wistar rats and monitored by measuring the sensory nerve conduction velocity (SNCV), motor nerve conduction velocity (MNCV), tail flick latency and hot plate latency. Three weeks of treatment with a combination of minocycline and aspirin showed significant improvement in SNCV, MNCV, hot plate latency and tail flick latency when compared with diabetic control. The results of the present study suggest that MMP-2 and MMP-9 inhibition in the presence of COX inhibitor prevents the development of experimental diabetic neuropathy in rats and can be a potential approach for the treatment.

Lokesh K Bhatt,1 Jyotika Bansal,2 Poonam Piplani,2 SL Bodhankar,3 A Veeranjaneyulu11Department of Pharmacology, School of Pharmacy and Technology Management, NMIMS University, Mumbai, India; 2University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India; 3Department of Pharmacology, Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Erandawane, Pune, IndiaAbstract: The present study was performed to evaluate the cardioprotective effects and pharmacological characterization of newly synthesized β-adrenoreceptor antagonists 3-(3-tertbutylamino- 2-hydroxypropoxy)-4-methoxybenzaldehyde (PP-36) in the rat model of coronary artery occlusion and reperfusion. Pre-ischemic administration (20 minutes before coronary occlusion) of PP-36 showed cardioprotective effects against ischemia/reperfusion injury in rats. PP-36 (6 mg kg-1) significantly reduced arrhythmia score (6.33 ± 0.55, P< 0.05), infarct size/left ventricle size (38.9 ± 3.2, P< 0.05) and no mortality compared to vehicle-treated control group (14.17 ± 1.83, 44.9 ± 4.6 and 17% respectively). In-vitro studies in rat isolated right atria, guinea-pig trachea and rat distal colon preparations, were carried out to investigate the potency of PP-36 towards different β-adrenoceptor subtypes. pA2/pKB values of PP-36 for β1- β2- and β3-adrenoceptors were 6.904 ± 0.190, 6.44 ± 0.129 and 5.773 ± 0.129, respectively. In conclusion, PP-36 is a β-adrenoceptor antagonist possessing potent anti-arrhythmic and cardioprotective effects against ischemia/reperfusion injury in rats.Keywords: β-adrenoreceptors blocker, ischemia/reperfusion injury, arrhythmias, infarct area

Mutual azo prodrug of 5-aminosalicylic acid with L-tryptophan was synthesized by coupling L-tryptophan with salicylic acid, for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. The structure of synthesized prodrug was confirmed by elemental analysis, IR and NMR spectroscopy. In vitro kinetic studies in HCl buffer (pH 1.2) showed negligible release of 5-aminosalicylic acid, whereas in phosphate buffer (pH 7.4) 18% release was observed over a period of 7 h. In rat fecal matter, 87.9% of 5-aminosalicylic acid was released with a half-life of 143.6 min, following first order kinetics. The azo conjugate was evaluated for its ulcerogenic potential by Rainsford's cold stress method. The ameliorating effect of the azo conjugate and therapeutic efficacy of the carrier system was evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model. The synthesized prodrug was found to be equally effective in mitigating the colitis in rats as that of sulfasalazine without the ulcerogenicity of 5-amino-salicylic acid.

Mutual azo prodrug of 5-aminosalicylic acid with d-phenylalanine was synthesized by coupling D-phenylalanine with salicylic acid, for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. The structure of synthesized prodrug was confirmed by elemental analysis, IR and NMR spectroscopy. In vitro kinetic studies in HCl buffer (pH 1.2) showed negligible release of 5-aminosalicylic acid, whereas in phosphate buffer (pH 7.4) only 15% release was observed over a period of 7h. In rat fecal matter the release of 5-aminosalicylic acid was almost complete (85%), with a half-life of 160.1 min, following first order kinetics. The azo conjugate was evaluated for its ulcerogenic potential by Rainsford's cold stress method. Therapeutic efficacy of the carrier system and the mitigating effect of the azo conjugate were evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model. The synthesized prodrug was found to be equally effective in mitigating the colitis in rats as that of sulfasalazine without the ulcerogenicity of 5-aminosalicylic acid.

Calcium oxalate nephrolithiasis in rats was induced by intraperitoneal injection of sodium oxalate (7 mg/100 g) daily for 7 days. A significant increase in the level of oxalate in urine and kidney with a decrease in urinary volume, pH, creatinine clearance, and lipid peroxide level was observed in animals receiving sodium oxalate as compared with saline-treated animals. Administration of petroleum ether extract (50 and 100 mg/kg, p.o.) of Crataeva adansonii. DC. along with sodium oxalate (prophylactically) and after 7 days of sodium oxalate injection (therapeutically) significantly decreased calcium oxalate content in urine and kidney and lipid peroxide level in liver and kidney compared with vehicle-treated group. Animals treated with petroleum ether extract (50 and 100 mg/kg, p.o.) of Crataeva adansonii. showed improved creatinine clearance as compared with vehicle group. Histological estimation of kidney treated with petroleum ether extract (50 and 100 mg/kg, p.o.) along with sodium oxalate str...

Cardiovascular complications in the diabetic population are the foremost cause of death and impose a huge economic burden. Despite recent advances in our understanding of diabetic complications, there is an unmet need for treatment. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes that are involved in the remodeling of several components of the extracellular matrix. Upregulation of MMP-2 and MMP-9 in diabetes leads to disruption of extracellular matrix and thus causes complications of diabetes. Matrix metalloproteinase 2 and 9 can be potential targets to treat cardiovascular complications of diabetes.

Cerebrovascular disease is a major cause of mortality and disability in adults. Diabetes mellitus increases the risk of cerebral ischaemia and is associated with worse clinical outcome following an event. Upregulation of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in diabetes appears to play a role in vascular complications of diabetes. We hypothesised that inhibition of MMP-2 and MMP-9 by minocycline can be potentiated by aspirin through inhibition of cyclooxygenase-2 and tissue plasminogen activator, resulting in amelioration of clinical cerebral ischaemia in diabetes. In the present study, cerebral ischaemia/reperfusion injury was induced in streptozotocin diabetic rats by 1 h middle cerebral artery occlusion and 24 h reperfusion. Infarct volume, cerebral oedema, neurological severity score and blood–brain barrier disruption were significantly increased in diabetic animals compared with the normoglycemic control group. The combination of aspirin and minocycline treatment significantly improved these parameters in diabetic animals. Moreover, this therapy was associated with significantly lower mortality and reduction in MMP-2 and MMP-9 levels. Our data indicate that combination of aspirin and minocycline therapy protects from the consequences of cerebral ischaemia in animal models of diabetes and is associated with inhibition of MMP-2 and MMP-9. Therefore, this combination therapy may represent a novel strategy to reduce the neurological complications of cerebral ischaemia in diabetes.

Degradation of extracellular matrix (ECM) by enhanced production of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in diabetes leads to nephropathy. Cyclooxygenases (COX) further increase levels of these MMPs. The objective of present study was to inhibit MMP-2 and MMP-9 by combination of minocycline and aspirin to treat diabetic nephropathy. Diabetes was induced in male Wistar rats by streptozotocin (STZ, 55 mg/kg i.p.). Four weeks after diabetes induction, the rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of 4 weeks. At the end of eighth week fluid input, urine output, and renal function tests were carried out for diagnosis of diabetic nephropathy. Renal hypertrophy was measured and histopathology was done to evaluate renal damage. Diabetes produced significant loss of body weight, polyuria, polydipsia, hyperglycemia, and increase in blood pressure. Serum creatinine, urea, and blood urea nitrogen levels were found to be increased significantly in the STZ group diabetic rats. Treatment with combination of minocycline and aspirin significantly prevented the rise in creatinine, urea, and blood urea nitrogen levels and increased creatinine clearance. Image analysis of kidneys revealed that collagen level was significantly decreased in combined treated group when compared with control. Results of present study suggest that MMP-2 and MMP-9 inhibition in presence of COX inhibitor prevents the development of experimental diabetic nephropathy in rats and can be a potential approach for the treatment.

Diabetes greatly increases risk of cardiovascular dysfunction and interruptions of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) have been shown to reduce the risk by alteration in extracellular matrix. We hypothesized that minocycline induced MMP-2 and MMP-9 inhibition can be enhanced by aspirin (through its COX and tPA inhibitory action) and this combination can reduce cardiovascular dysfunction of diabetes. Four weeks after diabetes induction (streptozotocin, 55 mg/kg, i.p.), rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of next four weeks. At the end of eighth week arterial pressure, heart rate and left ventricular pressure were recorded. Contractile response to phenylephrine (10 −5 M) and relaxation responses to acetylcholine (10 −9 –10 −4 M) were obtained from aortic rings of diabetic rats. Gel zymography was performed to evaluate MMP-2 and MMP-9 levels. Heart rate, mean arterial pressure, d p /d t max and d p /d t min were found significantly decreased in STZ diabetic rats when compared with normoglycemic group. Treatment with combination of minocycline and aspirin significantly ameliorate these compared to vehicle treated diabetic group. Endothelium-dependent relaxation responses induced by acetylcholine were decreased in diabetic rats and significantly higher in combination treated group. Collagen, MMP-2 and MMP-9 levels were significantly decreased in combined treated group when compared with diabetic control. Present study revealed that aspirin potentate minocycline induced MMP-2 and MMP-9 inhibition to ameliorate cardiovascular dysfunction of diabetes and this combination can be an approach for the treatment.

Interruptions of Matrix Metalloproteinase-2 (MMP-2) and Matrix Metalloproteinase-9 (MMP-9) have been shown to reduce the ensuing threatening risk factors of vascular complications of diabetes by alteration in Extracellular Matrix (ECM). We hypothesized that minocycline induced MMP-2 and MMP-9 inhibition can be enhanced by aspirin, a non-selective COX and tPA inhibitor and this combination can reduce progression of diabetic retinopathy. Diabetes was induced in male Wistar rats by streptozotocin (55 mg/kg i.p.). Four weeks after diabetes induction rats were treated with minocycline (50 mg/kg, p.o.) per se, aspirin (50 mg/kg, p.o.) per se, or minocycline in combination with aspirin for a period of four weeks. At the end of eighth week rats were anesthetized and electroretinograms were recorded. B-wave latency, B-wave amplitude and retinal permeability were measured. Histology was done and retinal thickness was measured. Zymography was carried out for MMP-2 and MMP-9 level determinations. B-wave amplitude was significantly decreased while B- wave latency was significantly increased in diabetic group when compared with normo-glycemic rats. Treatment with combination of minocycline and aspirin significantly reversed B-wave amplitude and latency compared with vehicle-treated diabetic controls. Blood retinal permeability and retinal thickness were also significantly attenuated by the treatment of minocycline in combination with aspirin. Results of the present study suggest that MMP-2 and MMP-9 inhibition in presence of COX inhibitor prevents the development of experimental diabetic retinopathy in rats and can be a potential approach for the treatment.

Colon-specific mutual azo prodrugs of 5-aminosalicylic acid with essential amino acids were synthesized for the management of inflammatory bowel disease. The structures were confirmed by elemental and spectral analyses. 85-88% release of 5-aminosalicylic acid was achieved in rat fecal matter with half-lives ranging from 140 to 160 min, following first order kinetics. The prodrugs exhibited comparable ameliorating effect as that of sulfasalazine on trinitrobenzenesulfonic acid-induced experimental colitis in rats with a better safety profile.