An architecturally rational hemostat for rapid stopping of massive bleeding on anticoagulation therapy.

Hemostatic devices are critical for managing emergent severe bleeding. With the increased use of anticoagulant therapy, there is a need for next-generation hemostats. We rationalized that a hemostat with an architecture designed to increase contact with blood, and engineered from a material that activates a distinct and undrugged coagulation pathway can address the emerging need. Inspired by lung alveolar architecture, here, we describe the engineering of a next-generation single-phase chitosan hemostat with a tortuous spherical microporous design that enables rapid blood absorption and concentrated platelets and fibrin microthrombi in localized regions, a phenomenon less observed with other classical hemostats without structural optimization. The interaction between blood components and the porous hemostat was further amplified based on the charged surface of chitosan. Contrary to the dogma that chitosan does not directly affect physiological clotting mechanism, the hemostat induced coagulation via a direct activation of platelet Toll-like receptor 2. Our engineered porous hemostat effectively stopped the bleeding from murine liver wounds, swine liver and carotid artery injuries, and the human radial artery puncture site within a few minutes with significantly reduced blood loss, even under the anticoagulant treatment. The integration of engineering design principles with an understanding of the molecular mechanisms can lead to hemostats with improved functions to address emerging medical needs.

Comparative effectiveness of metoprolol, ivabradine, and its combination in the management of inappropriate sinus tachycardia in coronary artery bypass graft patients.

BACKGROUND: Inappropriate sinus tachycardia (IST) is an arrhythmic complication observed after coronary artery bypass graft (CABG) surgery which left untreated, commonly increases chances of postoperative stroke. The primary study objective was comparing effectiveness of beta blocker-metoprolol; a specific If blocker-ivabradine and its combination in patients who develop IST as a complication following CABG. MATERIALS AND METHODS: An open-labeled, investigator initiated, clinical study was conducted on 150 patients who developed IST (heart rate [HR] >100 beats/min) following elective CABG surgery. The patients were randomized into three treatment groups. Group I - received ivabradine (5 mg), Group II - metoprolol (25 mg), and Group III - ivabradine (5 mg) and metoprolol (25 mg). Treatment was given orally, twice a day for 7 days in all the three groups postoperatively. Primary endpoints were comparative effectiveness in HR and blood pressure reduction following treatment. RESULTS: IST was diagnosed by an electrocardiogram (12-lead) considering morphological features of P-wave and with 32% increase from baseline HR in all the three groups. Compared to IST arrthymic rate, HR was reduced in all groups following respective treatment (P = 0.05). Reduction in HR was significant (P < 0.05) in combination group followed by ivabradine which was significantly greater than metoprolol treated group. None of the treatments clinically changed the systolic, diastolic and mean blood pressure till discharge. No surgery/treatment-related complications were observed in any groups. CONCLUSION: Ivabradine stands as a pharmacological option for controlling HR and rhythm without associated side effects in postoperative CABG patients with IST.

Late coronary stent infection: a difficult to diagnose rare complication after percutaneous coronary intervention.

Percutaneous transluminal coronary angioplasty (PTCA) with drug-eluting stent placement is a well-established treatment modality for coronary stenotic lesions. Although infection involving implanted stent is rare, it can occur at any point of time, leading to high morbidity and mortality. We describe a rare case of infected coronary stents complicated with recurrent stent thrombosis, sepsis, and myocardial abscess formation after 2 years of percutaneous cornary intervention (PCI). Using multi-modality imaging final diagnoses to evaluate the precise location, extent and morphology of myocardial abscess (MA) was done. "On pump" coronary artery bypass graft (CABG) was performed, left anterior descending (LAD) artery intramyocardially was opened up, about 7-10 ml of pus was evacuated, and two drug-eluting stents (DES) were removed. The isolated identified organism was Pseudomonas aeruginosa which had remained dormant and restricted to the stent area for almost 2 years thinning the myocardium; an unusual trait of a very virulent bacterium which otherwise spreads fast to cause septicemia. The present case exemplifies the high index of clinical sensitivity with early multi-modality diagnosis, aggressive medical therapy, multidisciplinary care, and timely surgical intervention saving the patient's life in otherwise fatal condition.

Temporal trends in pharmacology publications by pharmacy institutes: A deeper dig.

OBJECTIVE: Publications in Indian Journal of Pharmacology (IJP) are the face of contemporary pharmacology practices followed in health-care profession - a knowledge-based profession. It depicts trends in terms of quantity (proportions), quality, type (preclinical/clinical), thrust areas, etc., of pharmacology followed by biomedical community professions both nationally and internationally. This article aims to establish temporal trends in pharmacology research by pharmacy institutes in light of its publications to IJP from 2010 to 2015. METHODOLOGY: The website of IJP was searched for publications year and issue wise for contributing authors from pharmacy institutions and analyzed for types of publications, their source and the categories of research documented in these publications. RESULTS: A total of 1034 articles were published, of which 189 (18%) articles were published by pharmacy institutes, of which 90% (n = 170) were contributed from pharmacy institutes within India whereas 10% (n = 19) from international pharmacy institutes. 75% of these were research publication, the majority of which (65%) were related to preclinical screening of phytochemical constituents from plants. CONCLUSION: With multi and interdisciplinary collaborations in pharmacy profession the trend needs to improve toward molecular and cellular pharmacology and clinical studies.

Unique Aspects of Coronary Artery Disease in Indian Women.

PURPOSE: Epidemiologic and clinical research suggests important gender-related differences in the prevalence, presentation, associated conventional and non-conventional risk factors, management and outcomes of coronary heart disease (CHD) patients. Adequate data is not available for Indian population where prevalence of CHD and depression is high. METHOD: We conducted an observational, single-center, study from January 2010 to December 2011 on 10450 consecutive patients visiting a tertiary care center, Ahmedabad, Gujarat, India who presented with complaints related to CHD. RESULTS: Of these, 6867 patients had coronary artery disease (CAD) as confirmed by angiographic investigation; 5678 were males, and 1189 were females with similar mean age. As compared to males, females had higher prevalence of hypertension, diabetes and obesity while males had higher prevalence of smoking. Invasive treatment options like Coronary Artery Bypass Grafting (p < 0.001) and Percutaneous Coronary Intervention (p = 0.001) were used less often to treat females, and medical therapy (p < 0.001) was the preferred treatment option irrespective of the contributing risk factors/extent of CAD. Depression was observed in 39.8% of acute coronary syndrome patients (n = 1648) as assessed by MARDS scale. It was higher in female patients and in low socioeconomic strata (p < 0.001).At 12 and 36 months, rates of revascularization (p < 0.001) and mortality (p < 0.005) were higher with poor quality of life (QoL) (P < 0.001) in depressed CAD patients. CONCLUSION: In India, women appear to have a higher prevalence of hypertension, diabetes, obesity, and family history of CHD. Yet women get invasive treatments less often than men. Depression is also more common in women and is associated with poor QoL and early mortality than men.

Long-term safety and performance of the orbital atherectomy system for treating calcified coronary artery lesions: 5-Year follow-up in the ORBIT I trial.

BACKGROUND/PURPOSE: The ORBIT I trial, a first-in-man study, was conducted to evaluate the safety and performance of the orbital atherectomy system (OAS) in treating de novo calcified coronary lesions. METHODS/MATERIALS: Fifty patients were enrolled between May and July 2008 based on several criteria, and were treated with the OAS followed by stent placement. The safety and performance of the OAS were evaluated by procedural success, device success, and overall major adverse cardiovascular event (MACE) rates, including cardiac death, myocardial infarction (MI) and need for target lesion revascularization (TLR). Our institution enrolled and treated 33 of the 50 patients and continued follow-up for 5 years. RESULTS: Average age was 54 years and 91% were males. Mean lesion length was 15.9 mm. Device success was 100%, and average number of orbital atherectomy devices (OAD) used per patient was 1.3. Stents were placed directly after OAS in 31/32 patients (96.9%). All stents (average stent per lesion 1.1) were successfully deployed with 0.3% residual stenosis. The overall cumulative MACE rate was 6.1% in-hospital, 9.1% at 30 days, 12.1% at 6 months, 15.2% at 2 years, 18.2% at 3 years and 21.2% at 5 years (4 total cardiac deaths). None of the patients had Q-wave MIs. Angiographic complications were observed in 5 patients. No flow/slow flow due to distal embolization was observed. CONCLUSIONS: The ORBIT I trial suggests that OAS treatment continues to offer a safe and effective method to change compliance of calcified coronary lesions to facilitate optimal stent placement in these difficult-to-treat patients.

Orbital atherectomy system in treating calcified coronary lesions: 3-Year follow-up in first human use study (ORBIT I trial).

BACKGROUND/PURPOSE: The ORBIT I trial evaluated the safety and performance of an orbital atherectomy system (OAS) in treating de novo calcified coronary lesions. Severely calcified coronary arteries pose ongoing treatment challenges. Stent placement in calcified lesions can result in stent under expansion, malapposition and procedural complications. OAS treatment may be recommended to facilitate coronary stent implantation in these difficult lesions. MATERIALS/METHODS: Fifty patients with de novo calcified coronary lesions were enrolled in the ORBIT I trial. Patients were treated with the OAS followed by stent placement. Our institution treated 33/50 patients and continued follow-up for 3 years. RESULTS: Average age was 54.4 years and 90.9% were males. Mean lesion length was 15.9mm. The average number of OAS devices used per patient was 1.3. Procedural success was achieved in 97% of patients. Angiographic complications were observed in five patients (two minor dissections, one major dissection and two perforations). The cumulative major adverse cardiac event (MACE) rate was 6.1% in-hospital, 9.1% at 30 days, 12.1% at 6 months, 15.2% at 2 years, and 18.2% at 3years. The MACE rate included two in-hospital non Q-wave myocardial infarctions (MI), one additional non Q-wave MI at 30 days leading to target lesion revascularization (TLR), and three cardiac deaths. CONCLUSIONS: The ORBIT I trial suggests that OAS treatment may offer an effective method to modify calcified coronary lesion compliance to facilitate optimal stent placement in these difficult-to-treat patients with acceptable levels of safety up to 3 years post-index procedure.

Evaluation of antidepressant and anxiolytic activity of phosphodiesterase 3 inhibitor - cilostazol.

BACKGROUND: Cyclic nucleotide Phosphodiesterases (PDEs) are ubiquitously distributed in mammalian tissues and play a major role in cell signaling by hydrolyzing cyclic Adenosine Monophosphate (cAMP) and cyclic Guanosine Monophosphate (cGMP). Impairments in signal transduction have been implicated as possible mechanism of reduced plasticity and neuronal survival in major depressive disorders. PDE inhibitors possess a potentially powerful means to manipulate secondary messengers involved in learning, memory and mood. Cilostazol is an antiplatelet agent indicated for the treatment of intermittent claudication with peripheral artery occlusion and for the prevention of ischemic stroke worldwide. Various animal studies have reported neuroprotective, anti apoptotic, cognition and cerebral blood flow improvement properties of cilostazol. MATERIALS AND METHODS: In this study, the antidepressant and anxiolytic effects of cilostazol were evaluated in mice using behavioral tests sensitive to clinically effective antidepressant compound. RESULTS: Cilostazol, administered intraperitoneally (20 mg/kg), decreased immobility time of mice when subjected to forced swim test and tail suspension test as compared to standard fluoxetine (20 mg/kg). Cilostazol also produced significant decrease in the number of marbles buried as compared to fluoxetine in marble burying model. CONCLUSION: The present study suggests that cilostazol possesses potential antidepressant and anxiolytic activity, which could be of therapeutic interest for use in patients with depressive disorders.

Comparative evaluation of adverse drug reaction reporting forms for introduction of a spontaneous generic ADR form.

Despite comprehensive and stringent phases of clinical trials and surveillance efforts, unexpected and serious adverse drug reactions (ADRs) repeatedly occur after the drug is marketed. ADR reporting is an important aspect of an efficient and effective pharmacovigilance program. Although Medwatch, Yellow Card, CDSCO form, etc. are the protocol forms of ADR collection and reports, a number of countries design and use their respective ADR forms. This review compares similarities and dissimilarities of 13 ADR forms of countries representing their geographical location. This study extracted 73 data elements mentioned in 13 different ADR forms. Only 13 elements were common. An ADR form of Malaysia and Canada covers the highest number of data 43, while Brazil falls to the opposite end with a number of 17 data elements in lieu with the Generic ADR Form. The result of this review highlights 58 data elements of the proposed generic ADR form which ensures that requisite reporting information essential for correct causality assessment of ADRs are included. The proposed "Generic ADR form" could be adopted worldwide mandatorily for reporting any/all ADRs associated with marketed drugs.

Association between altered thyroid state and insulin resistance.

OBJECTIVE: To determine the association between altered thyroid hormones and insulin resistance (IR). MATERIALS AND METHODS: Eight euthyroid (EU), eight hypothyroid (HO), and eight hyperthyroid (HR) patients with no past medical history were studied in this cross-sectional study at the Care Institute of Medical Sciences, Ahmedabad, India, The fasting blood sample were analyzed for thyroid stimulating hormone (TSH), lipid profile, insulin, and glucose. Homeostatic model assessment (HOMA) was calculated for assessing IR. RESULTS: HOMA values were significantly higher in HR and HO groups as compared to the EU group (P < 0.05). Insulin levels were also found to be significantly increased in HR and HO groups as compared to the EU group (P < 0.05). Cholesterol, triglycerides (TG), and low density lipoprotein (LDL) were significantly raised in HO as compared to EU and HR groups (P < 0.05) whereas high density lipoprotein levels (HDL) were lower. HOMA and insulin were found to be positively correlated with TSH in HO and negatively in HR. CONCLUSION: Thyroid disorder, including both hypo- and hyper have been associated with IR due to various mechanisms such as altered insulin secretion and lipid levels. IR was comparable in patients with both HO and HR. Although HO and HR constitute an IR state, more studies need to be done in order to clarify the underlying pathogenic mechanism. Thus, an altered thyroid state can lead to IR leading to glucose-related disorder such as diabetes dyslipidemia.

Drug-eluting stents in multivessel coronary artery disease: cost effectiveness and clinical outcomes.

Multivessel coronary artery disease is more often treated either with coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI) with stenting. The advent of drug-eluting stent (DES) has changed the revascularization strategy, and caused an increase in the use of DES in multivessel disease (MVD), with reduced rate of repeat revascularization compared to conventional bare metal stent. The comparative studies of DES-PCI over CABG have shown comparable safety; however, the rate of major adverse cerebrovascular and cardiac events and repeat revascularization was significantly higher with DES-PCI at long term. In diabetic patients with MVD, concern of repeat revascularization with DES-PCI is persistent. More recent, one-year economic outcomes have reported that the CABG is favored among patients with high angiographic complexity. The higher rate of repeat revascularization with DES-PCI in MVD would lead to increased economic burden on patient at long term besides bearing high cost of DES. In diabetic MVD patients, CABG is associated with having better clinical outcomes and being more cost-effective approach when compared to DES-PCI at long term.

Hepatoprotective activity of punarnavashtak kwath, an Ayurvedic formulation, against CCl4-induced hepatotoxicity in rats and on the HepG2 cell line.

OBJECTIVE: Punarnavashtak kwath (PNK) is a classical Ayurvedic formulation, mentioned in Ayurvedic literature Bhaishajya Ratnavali, for hepatic disorders and asthma. This study investigated the hepatoprotective activity of PNK to validate the traditional use of this formulation. MATERIALS AND METHODS: PNK was prepared in the laboratory according to the method given in Ayurvedic literature. Phytochemical screening was performed to determine the presence of phytoconstituents. Hepatoprotective activity was evaluated against CCl(4)-induced hepatotoxicity in rats and by its effect on the HepG2 cell line. RESULTS: Preliminary phytochemical screening revealed the presence of alkaloids, tannins, flavonoids, saponins, and a bitter principle in PNK. Administration of PNK produced significant hepatoprotective effect as demonstrated by decreased levels of serum liver marker enzymes such as aspartate transaminase, serum alanine transaminase, serum alkaline phosphatase, and serum bilirubin and an increase in protein level. Thiopentone-induced sleeping time was also decreased in the PNK-treated animals compared with the CCl(4)-treated group. It also showed antioxidant activity by increase in activity of glutathione, superoxide dismutase, and catalase and by a decrease in thiobarbituric acid reactive substance level compared with the CCl(4)-treated group. Results of a histopathological study also support the hepatoprotective activity of PNK. Investigation carried out on the HepG2 cell line depicted significant increase in viability of cells exposed to PNK as compared with CCl(4)-treated cells. DISCUSSION AND CONCLUSION: It can be concluded that PNK protects hepatocytes from CCl(4)-induced liver damages due to its antioxidant effect on hepatocytes. An in vitro study on HepG2 cell lines also supports its protective effect.

Determination of penciclovir in human plasma by liquid chromatography-electrospray ionization tandem mass spectrometry: application to a clinical pharmacokinetic study.

A rapid, specific and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for the determination of penciclovir in human plasma. The method involved simple, one-step SPE procedure coupled with a C(18) , 75 × 4.mm, 3 µm column with a flow-rate of 0.5 mL/min, and acyclovir was used as the internal standard. The Quattro Micro mass spectrometry was operated under the multiple reaction-monitoring mode using the electrospray ionization technique. Using 250 µL plasma, the methods were validated over the concentration range 52.555-6626.181 ng/mL, with a lower limit of quantification of 52.55 ng/mL. The intra- and inter-day precision and accuracy values were found to be within the assay variability limits as per the FDA guidelines. The developed assay method was applied to a clinical pharmacokinetic study in human volunteers.

Development and validation of a high-throughput and robust LC-MS/MS with electrospray ionization method for simultaneous quantitation of oseltamivir phosphate and its oseltamivir carboxylate metabolite in human plasma for pharmacokinetic studies.

A rapid, sensitive and rugged solid-phase extraction ultraperformance liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for determination of oseltamivir phosphate (OP) and oseltamivir carboxylate (OC) in human plasma. The procedure for sample preparation includes a simple SPE extraction procedure coupled with a Chromatopack C(18) column (50 × 3.0 mm, i.d., 3.0 µm) with isocratic elution at a flow-rate of 0.600 mL /min and acyclovir was used as the internal standard. The analysis was performed on a triple-quadrupole tandem mass spectrometer by multiple reaction monitoring mode via electrospray ionization. Using 500 µL plasma, the methods were validated over the concentration ranges 0.92-745.98 and 5.22-497.49 ng/mL for OP and OC, with a lower limit of quantification of 0.92 and 5.22 ng/mL. The intra- and inter-day precision and accuracy of the quality control samples were within 10.1%. The recovery was 68.72, 70.66 and 71.59% for OP, OC and IS, respectively. Total run time was only 1.0 min. The method was highly reproducible with excellent chromatography properties.

Comparative influence of propranolol and verapamil on glycemic control and histamine sensitivity associated with L-thyroxine-induced hyperthyroidism - an experimental study.

The present investigation was undertaken to study the comparative effectiveness of beta-adrenergic antagonist propranolol and calcium channel blocker verapamil on L-thyroxine-induced alteration on glycemic control and histamine sensitivity on rats and guinea pigs, respectively. Injection of L-thyroxine sodium every alternate day for 3 weeks in guinea pigs (75 microg/kg, i.p.) and rats (75 mg/kg, s.c.) produced a condition similar to thyrotoxicosis. Verapamil and propranolol administered daily in the third week along with L-thyroxine to two separate groups of hyperthyroid animals reversed thyroxine-induced loss in body weight, reduction in serum TSH levels, and rise in body temperature. Effect on glucose metabolism and insulin sensitivity was studied on rats. Compared to normal rats, L-thyroxine-treated animals showed a state of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, and insulin resistance. Propranolol (10 mg/kg, i.p.) treatment significantly decreased fasting serum glucose levels without affecting serum insulin levels, AUC glucose, and K(ITT) values. Treatment with verapamil (5 mg/kg, i.p.) significantly reduced fasting serum glucose and insulin levels, AUC glucose, and significantly increased K(ITT) values. Effect of propranolol (15 mg/kg, orally) and verapamil (20 mg/kg, orally) treatment on histamine sensitivity was studied on L-thyroxine-treated guinea pigs. Compared to normal guinea pigs, L-thyroxine-treated guinea pigs showed an increased sensitivity to histamine-induced asphyxia. Verapamil treatment reversed this increased histamine sensitivity while propranolol aggravated it. In conclusion, compared to propranolol, verapamil has advantageous effects on glucose metabolism, insulin and histamine sensitivity and could therefore be a valuable addition as an adjunctive therapy option currently available for thyrotoxicosis associated with diabetes and/or anaphylaxis.

Comparative effectiveness of carvedilol and propranolol on glycemic control and insulin resistance associated with L-thyroxin-induced hyperthyroidism--an experimental study.

The present study was undertaken to investigate the effectiveness of adrenergic antagonists carvedilol and propranolol on L-thyroxin-induced cardiovascular and metabolic disturbances in rats. Treatment with L-thyroxin sodium (75 mg/kg body mass, s.c., every alternate day for 3 weeks), produced a significant increase in food and water intake, body temperature, heart rate, systolic blood pressure, along with an increase in serum T3, T4, and triglyceride levels. Besides a significant reduction in body mass, serum levels of TSH and cholesterol were also reduced following L-thyroxin treatment. Carvedilol (10 mg/kg body mass, orally) and propranolol (10 mg/kg body mass, i.p.) administered daily in the third week to 2 separate groups of L-thyroxin-treated animals reversed thyroxin-induced loss in body mass and rise in body temperature, blood pressure, and heart rate. Propranolol treatment increased TSH levels and decreased T3 and T4 levels in hyperthyroid animals, whereas carvedilol did not produce any effect on thyroid hormones. Carvedilol treatment reversed thyroxin induced hypertriglyceridemia, whereas propranolol treatment had no effect. Both carvedilol and propranolol prevented decrease in cholesterol levels induced by thyroxine. Compared with normal animals, L-thyroxin-treated animals showed a state of hyperglycemia, hyperinsulinaemia, impaired glucose tolerance, and insulin resistance, as inferred from elevated fasting serum glucose and insulin levels, higher area under the curve over 120 min for glucose, and decreased insulin sensitivity index (KITT). Propranolol and carvedilol treatment significantly decreased fasting serum glucose levels. Treatment with propranolol did not alter serum insulin levels, area-under-the-curve glucose, or KITT values. However, treatment with carvedilol significantly reduced area-under-the-curve glucose, decreased fasting serum insulin levels and significantly increased KITT values. In conclusion, carvedilol appears to produce favorable effects on insulin sensitivity and glycemic control and can therefore be considered as more efficacious adjunctive treatment than propranolol in hyperthyroidism.