Protective effects of MCR-1329, a dual α1 and angII receptor antagonist, in mineralocorticoid-induced hypertension.

BACKGROUND: With the prototypical structures of losartan and prazosin as the axis of our research, MCR-1329 emerged as a potential designed multiple ligand from a series of compounds designed to possess dual antagonistic activity on the α1 and AT1 receptor. After confirming the activity of MCR-1329 in in vitro and acute in vivo models, the present study was undertaken to determine the efficacy of MCR-1329 in a mammalian test system. METHODS: A rat model of deoxycorticosterone acetate (DOCA)-salt induced renal hypertension following unilateral nephrectomy was utilized to determine the effect of MCR-1329. For mechanistic evaluations, MCR-1329 was evaluated on rat aortic strips in vitro and on rat aortic smooth muscle cells to determine the role of MCR-1329 on phosphoinositide 3 kinase (PI3K) signaling. RESULTS: Results of the study showed that MCR-1329 prevents development of arterial hypertension. It was also observed that MCR-1329 upheld the intimal structures of major arteries like the thoracic aorta. Acetylcholine (Ach)-mediated relaxation remained intact in arteries from MCR-1329 treated animals. It was observed that MCR-1329 partially prevents Thr-308 phosphorylation of Akt following ligand-mediated receptor stimulation in vascular smooth muscle cells. Addition of LY294002 to the reaction medium caused a near-complete inhibition of Akt-phosphorylation. This suggested that MCR-1329 elicits its antihypertensive role by blocking activation of receptor-mediated PI3K-Akt downstream signaling as well as through preservation of arterial integrity. CONCLUSIONS: MCR-1329 has the potential to be evaluated further for clinical development as a potential antihypertensive agent with multiple mechanisms of action.

Enhancing Skin Permeation of Biphenylacetic Acid (BPA) Using Salt Formation with Organic and Alkali Metal Bases.

In the present study, a series of organic and alkali metal salts of biphenylacetic acid (BPA) have been prepared and evaluated in vitro for percutaneous drug delivery. The physicochemical properties of BPA salts were determined using solubility measurements, DSC, and IR. The DSC thermogram and FTIR spectra confirmed the salt formation with organic and alkali metal bases. Among the series, salts with organic amines (ethanolamine, diethanolamine, triethanolamine, and diethylamine) had lowered melting points while the alkali metal salt (sodium) had a higher melting point than BPA. The in vitro study showed that salt formation improves the physicochemical properties of BPA, leading to improved permeability through the skin. Amongst all the prepared salts, ethanolamine salt (1b) showed 7.2- and 5.4-fold higher skin permeation than the parent drug at pH 7.4 and 5.0, respectively, using rat skin.

Management of Hypertension-Journey from Single Drug Therapy to Multitargeted Ligand Therapy: A Clinical Overview.

Hypertension is recognized as one of the leading risk factors for human morbidity and mortality. It is a major risk factor for myocardial infarction, congestive heart failure, stroke, and endstage renal disease. The difficulty in controlling hypertension is related, at least in part, to the complex pathogenesis of hypertension. In spite of the availability of variety of antihypertensive agents, the control of blood pressure in the general population is at best inadequate. It is being recognized that a balanced modulation of several targets can provide a superior therapeutic effect to side effect profile compared to the use of a selective ligand. Fixed combinations of drugs and multitargeted ligands provide answers to the problem of hypertension. This review provides a status report of current antihypertensive drug therapy with fixed combination of drugs and evolvement of multitargeted ligands for better management of the disease.

Extraction and structural studies of an unexplored monoamide, N,N'-dioctyl, α-hydroxy acetamide with lanthanide(III) and actinide(III) ions.

A monoamide, N,N'-dioctyl, α-hydroxy acetamide, shows unusual extraction properties towards trivalent lanthanide and actinide ions above 3 M HNO3. The extracted ions could be quantitatively back extracted using 0.5 M HNO3. This amide shows negligible extraction towards Sr(II) and Ru(III) ions, making it advantageous over other reported extractants. The structures of Sm(III) and Eu(III) nitrate compounds show that the metal ion is surrounded by three of the ligands, one nitrate and one water molecule. The ligand acts as a neutral bidentate ligand and bonds through the amido and hydroxyl oxygen atoms.

Redefining the R1 resection for pancreatic ductal adenocarcinoma: tumour lymph nodal burden and lymph node ratio are the only prognostic factors associated with survival.

INTRODUCTION: The presence of positive nodal disease (LND) and the number of lymph nodes involved (LNB) are known to be significant prognostic markers for resected adenocarcinoma of the pancreas. In addition, the ratio of the number of involved nodes to the number of nodes resected known as the lymph node ratio (LNR) is emerging as an important prognostic marker. The role of the resection margin (RM) as presently defined (R1 ≤ 1 mm) is unclear as results differ based on the dataset. The aim of this study was to assess the impact of nodal disease and a redefined RM on outcome. MATERIAL AND METHODS: Retrospective analysis of pancreatic head resections for adenocarcinomas from 2003-2009. The RM was re-analysed based on tumour clearance and categorized into: histopathological evidence of a tumour; ≤ 0.5 mm, ≤ 1 mm, ≤ 1.5 mm, or ≤ 2.0 mm of the actual surgical resection margin. The impact of histopathological variables on cancer-specific survival (CSS) and disease-free survival (DFS) was analysed. RESULTS: LND, LNB and LNR were independent prognostic markers for CSS (P = 0.048, 0.003, 0.016) but, did not influence DFS. A LNR < 0.143 was associated with a higher CSS [38.16 ± 4.69 versus 20.59 ± 2.20 months, P = 0.0042, hazard ratio (HR) 3.74 (95% confidence interval (CI) 1.52-9.23)]. An R1 RM was not associated with CSS or DFS on multivariate analysis, irrespective of the distance. LNB and LNR maintained independent significance irrespective of the size of the RM. CONCLUSION: LNB and LNR are the only prognostic factors for CSS in patients with pancreatic head adenocarcinoma, but do not predict recurrence. Microscopic RMs does not seem to influence the outcome even when redefined. Further prospective studies are indicated to substantiate these findings.

Falcipain inhibitors as potential therapeutics for resistant strains of malaria: a patent review.

INTRODUCTION: There is an urgent need to discover new antimalarial drugs due to emergence of resistance in the parasite to the existing drugs. Malarial cysteine proteases falcipin-2 (FP-2) and falcipain-3 (FP-3) are attractive targets for antimalarial chemotherapy. The structures and functions of FP-2/3, their binding domains and their interactions with small- and macro-molecules are well studied. These studies could provide important insight into rational designing of FP inhibitors as potential antimalarial drugs. AREAS COVERED: This review is focused on a selection of interesting patents published during 1999 - 2011 on peptidic and nonpeptidic chemotypes of the FP-2/FP-3 inhibitors. EXPERT OPINION: It is a known fact that malaria is a serious health problem worldwide due to the emergence of resistant strains. Hence, development of novel, potent and affordable antimalarial drugs devoid of side effects is of great significance and in great demand. FPs, the malarial cysteine proteases are potential targets for development of new antimalarial drugs. Assessing the available literature on FP-2/3 and their inhibitors it could be speculated that these inhibitors have the potential to enter the clinical stages of development for the treatment of malaria in the years to come.

Finlay-Marks syndrome: report of two siblings and review of literature.

Finlay-Marks syndrome (scalp-ear-nipple syndrome), is the infrequently reported association of scalp aplasia, malformed ears, and breast abnormalities varying from small nipples to complete absence of breasts. Other manifestations are variable and some of them resemble ectodermal dysplasia and include dystrophy of nails and teeth, sparse hair, decreased sweating, and cutaneous syndactyly of digits. Renal anomalies have been reported in some patients leading to hypertension and renal insufficiency. Most reported patients have been sporadic but familial occurrences following an autosomal dominant pattern of inheritance have been reported. We report on two affected siblings, of whom one died in the neonatal period due to renal failure. Two affected siblings born to non-affected parents may suggest an autosomal recessive inheritance.

Techniques of flushing and reperfusion for liver transplantation.

BACKGROUND: Various techniques of flushing and reperfusion have been advocated to improve outcomes after liver transplantation. There is considerable uncertainty as to which method is superior. OBJECTIVES: To compare the benefits and harms of different methods of flushing and reperfusion during liver implantation in the transplant recipients. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until March 2011. SELECTION CRITERIA: We included all randomised clinical trials that were performed to compare different techniques of flushing and reperfusion during liver transplantation. DATA COLLECTION AND ANALYSIS: Two authors independently identified the trials and extracted the data. We analysed the data with both the fixed-effect model and the random-effects model using RevMan analysis. For each outcome we calculated the hazard ratio (HR), risk ratio (RR), rate ratio, mean difference (MD), or standardised mean difference (SMD) with 95% confidence intervals (CI) based on available case analysis. MAIN RESULTS: We included six trials involving 418 patients for this review. The sample size in the trials varied from 30 to 131 patients. Only one trial involving 131 patients was of low risk of bias for mortality. This trial was at high risk of bias for other outcomes. Four trials excluded patients who underwent liver transplantation for acute liver failure. All the trials included livers obtained from cadaveric donors. The remaining five trials were of high risk of bias for all outcomes. Liver transplantation was performed by the conventional method (caval replacement) in two trials and piggy-back method (caval preservation) in one trial. The method of liver transplantation was not available in the remaining three trials. The comparisons performed included an initial hepatic artery flush versus initial portal vein flush; blood venting via inferior vena cava in addition to venting of storage fluid versus no blood venting; initial hepatic artery reperfusion versus initial portal vein reperfusion; simultaneous hepatic artery and portal vein reperfusion versus initial portal vein reperfusion; and retrograde inferior vena cava reperfusion versus simultaneous hepatic artery and portal vein reperfusion. Only one or two trials could be included under each comparison. There was no significant difference in mortality, graft survival, or severe morbidity rates in any of the comparisons. Quality of life was not reported in any of the trials. AUTHORS' CONCLUSIONS: There is currently no evidence to support or refute the use of any specific technique of flushing or reperfusion during liver transplantation. Due to the paucity of data, absence of evidence should not be confused with evidence of absence of any differences. Further well designed trials with low risk of systematic error and low risk of random errors are necessary.

Cytotoxic potential of novel 6,7-dimethoxyquinazolines.

Herein, we report the synthesis and cytotoxicity of a series of substituted 6,7-dimethoxyquinazoline derivatives. The cytotoxic activity of all synthesized compounds has been evaluated against HCT116p53(+/+) and HCT116p53(-/-) colon cancer cells and a HEY ovarian cancer cell line naturally resistant to cisplatin. Nine of the tested compounds showed significant cytotoxicity in all cell lines at 10µM. The most promising derivative (7c) showed IC(50)values of 0.7 and 1.7µM in the two colon cancer cell lines.

Case report on an infant presenting with hypoglycemia, and milky serum.

A 4-month-old male baby who presented in a moribund condition with seizures was found to have hepatomegaly, hypoglycemia and milky serum. Serum triglycerides were markedly elevated (3 168 mg/dL) with cholesterol being 257 mg/dL and high density lipoprotein levels were low (19 mg/dL). The possibility of glycogen storage disease type I was considered in the diagnosis. Infants with glycogen storage disease type I may present like sepsis. The association of hepatomegaly, hypoglycemia and abnormal lipid profile stated above should alert the physician to consider glycogen storage disease type I in the diagnosis.

Case report on an infant presenting with hypoglycemia, and milky serum

A 4-month-old male baby who presented in a moribund condition with seizures was found to have hepatomegaly, hypoglycemia and milky serum. Serum triglycerides were markedly elevated (3168 mg/dL) with cholesterol being 257 mg/dL and high density lipoprotein levels were low (19 mg/dL). The possibility of glycogen storage disease type I was considered in the diagnosis. Infants with glycogen storage disease type I may present like sepsis. The association of hepatomegaly, hypoglycemia and abnormal lipid profile stated above should alert the physician to consider glycogen storage disease type I in the diagnosis.

Methods of decreasing infection to improve outcomes after liver resections.

BACKGROUND: Infections cause both morbidity and mortality in patients undergoing liver resection. Various methods have been advocated to decrease the infectious complications after liver resection. We do not know if they are of any benefit to the patient or the health-care funder. OBJECTIVES: To determine the benefits and harms of different interventions in decreasing the infectious complications and improving the outcomes after liver resection. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until August 2011. SELECTION CRITERIA: We included all randomised clinical trials that were performed to compare interventions aimed at decreasing the infectious complications after liver resection. DATA COLLECTION AND ANALYSIS: Two authors independently identified the trials and extracted the data. We analysed the data with both the fixed-effect and the random-effects model using RevMan Analysis. For each outcome we calculated the risk ratio (RR), rate ratio, or mean difference (MD) with 95% confidence intervals (CI) based on available patient data analysis. MAIN RESULTS: We included seven trials including 521 patients for this review. The sample size in the trials varied from 12 to 180 patients. All the trials were of high risks of systematic errors and of random errors. Four trials included patients who underwent liver resection only. In the remaining three trials, patients underwent combined liver resection with extrahepatic biliary resection resulting in a biliary enteric anastomosis. Four trials included only major liver resection. The remaining three trials included a mixture of major and minor liver resections. It appears that the proportion of cirrhotic patients in the trials was very low. The comparisons performed included whether antibiotics are necessary routinely during the peri-operative period of liver resection, the duration of antibiotics, the use of prebiotics and probiotics in the perioperative period, use of recombinant bactericidal-permeability increasing protein 21 (rBPI21), and the use of topical povidone iodine gel at the time of wound closure. Only one or two trials were included under each comparison. There was no significant differences in mortality or severe morbidity in any of the comparisons. Quality of life was not reported in any of the trials. AUTHORS' CONCLUSIONS: There is currently no evidence to support or refute the use of any treatment to reduce infectious complications after liver resections. Further well designed trials with low risk of systematic error and low risk of random errors are necessary.

Routine drainage for orthotopic liver transplantation.

BACKGROUND: Routine use of abdominal drainage in patients undergoing liver transplantation is controversial. OBJECTIVES: To assess the benefits and harms of routine abdominal drainage after orthotopic liver transplantation versus no drainage and to address different drain types. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and the MetaRegister of Controlled Trials until March 2011 to identify the randomised trials. SELECTION CRITERIA: We planned to include only randomised clinical trials (irrespective of language, blinding, or publication status) addressing this issue. DATA COLLECTION AND ANALYSIS: Two authors identified the trials for inclusion independently. Two authors planned to collect the data independently. We planned to analyse the data with both the fixed-effect and the random-effects model using RevMan Analysis. For each outcome we planned to calculate the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI) based on intention-to-treat analysis whenever possible. MAIN RESULTS: We did not identify any randomised clinical trials addressing this issue. AUTHORS' CONCLUSIONS: There is currently no evidence to conclude whether routine abdominal drainage is useful or harmful in patients undergoing orthotopic liver transplantation. Evidence from non-randomised studies of high risk of bias showed conflicting results on the impact of routine drainage in orthotopic liver transplantation on serious adverse events, showing that this question is an important clinical research question. Well-designed randomised clinical trials with adequate sample size to decrease systematic errors and to decrease random errors are necessary.

Angiotensin II receptor type 1 (AT1) selective nonpeptidic antagonists--a perspective.

Hypertension is a major risk factor for human morbidity and mortality through its effects on target organs like heart, brain and kidneys. More intensive treatment for the effective control of blood pressure significantly reduces the morbidity and mortality. The renin angiotensin system (RAS) is a coordinated hormonal cascade of major clinical importance in the regulation of blood pressure. The principal effector peptide of RAS is angiotensin II, which acts by binding to one of the two major angiotensin II receptors AT(1) and AT(2). Angiotensin II through AT(1) receptor mediates vast majority of biologically detrimental actions. Nonpeptidic angiotensin II (AT(1)) antagonists are the most specific means to block the renin angiotensin enzymatic cascade available presently. Majority of AT(1) antagonists are based on modifications of losartan structure, the first clinically used AT(1) antagonist. In this review, a comprehensive presentation of the literature on AT(1) receptor antagonists has been given.

Opsismodysplasia.

Opsismodysplasia is a rare osteochondrodysplasia with micromelia and platyspondyly. We report on a neonate with opsismodysplasia. During the antenatal period, polyhydramnios was noted. This is the first report of opsismodysplasia from India. Significant observation was antenatal polyhydramnios.

Salicylaldoxime and salen containing imidazolium ionic liquids for biphasic catalysis and metal extractions.

Imidazolium salts containing salicylaldoxime or salen ligands readily form ionic metal complexes with copper and manganese; hence offering applications in metal extractions and biphasic catalysis.

Upregulation of IGF-2 and IGF-1 receptor expression in oral cancer cell lines.

The insulin-like growth factors (IGFs) are a family of mitogenic proteins involved in the regulation of cell growth and differentiation. The presence and role of the IGF system in oral mucosal epithelium is not clear but could influence our understanding of the pathogenesis of oral cancer. We characterised the expression and function of IGF-1, IGF-2 and IGF receptor in human oral squamous carcinoma cell lines and normal oral epithelial cells as well as normal oral and squamous cell carcinoma tissues. Using reverse transcription followed by PCR, IGF-1 mRNA was only detected in normal cells, whereas IGF-2 and IGF-1R mRNA transcripts were highly expressed in tumour cell lines and tissues. Similar observations were seen by Western blot analysis and immunohistochemistry. Exogenous IGF-2, but not IGF-1, caused significant increases in DNA synthesis in the cell lines. IGF-2 also increased cell proliferation which was significantly attenuated in the presence of an IGF-2 neutralizing antibody or one which blocked IGF-1R. Taken together, these studies suggest that autocrine production of IGF-2, together with over-expression of IGF-1R, may be important components controlling the proliferation of oral carcinoma cells.