Increase in the effectiveness of somatodendritic 5-HT-1A receptors in a rat model of tardive dyskinesia

The present study concerns responsiveness of pre- and postsynaptic 5-hydroxytryptamine (5-HT)-1A receptors in a rat model of tardive dyskinesia (TD). Vacuous chewing movements (VCMs) in rats are widely accepted as an animal model of TD. Results show that haloperidol injected at a dose of 1 mg/kg twice a day for 5 weeks elicited VCMs, which increased in a time dependent manner following the drug administration for 3-5 weeks. Tolerance was produced in motor coordination during the potentiation of VCMs. Exploratory activity in an open field and in an activity box decreased in haloperidol treated animals. The effects of 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT; 0.5 mg/kg) were monitored 48-h after withdrawal from repeated administration of haloperidol. 8-OH-DPAT-induced locomotion was greater in haloperidol treated rats. 5-HT synthesis increased in haloperidol treated animals, while 8-OH-DPAT-induced decreases of 5-HT synthesis were greater in repeated haloperidol than repeated saline injected animals. The results suggest that an increase in the effectiveness of somatodendritic 5-HT-1A receptors may decrease the inhibitory influence of 5-HT on the activity of dopaminergic neurons to precipitate VCMs. The 5-HT-1A agonist may help to alleviate neuroleptic-induced TD.     

Adaptation of Quality by Design-Based Development of Isradipine Nanostructured–Lipid Carrier and Its Evaluation for In Vitro Gut Permeation and In Vivo Solubilization Fate

The present study demonstrated the systematic adaptation of quality by design-integrated approach for the development of novel nanostructured lipid carrier (NLC) of an anti-hypertensive drug isradipine (ISD) to address the inherent challenges such as low solubility and low oral bioavailability. Plackett-Burman design was used for preliminary screening of significant process and formulation variables (p <0.05), which were further processed using Box-Behnken design for the attainment of optimization goal that is, mean particle size (85.7 ± 7.3 nm), drug entrapment efficiency (87.4 ± 3.29%), and in vitro drug release characteristics (92.89 ± 5.47%). The optimized ISD-NLC formulation also demonstrated well-dispersed uniform-shaped particles (polydispersity index 0.207 ± 0.029), high gastrointestinal fluid stability (zeta potential ?10.17 ± 0.59 mV), and higher in vitro gut permeation (21.69 ± 2.38 μg/cm² of ISD-NLC as compared to 11.23 ± 1.74 μg/cm² in ISD suspension). Furthermore, lipolysis studies were performed for the purpose of in vivo fate, and significantly higher drug content of ISD from ISD-NLC in aqueous phase was found (72.34 ± 4.62%) as compared to drug suspension (3.01 ± 0.91%). Relative bioavailability of ISD-NLC and ISD suspension was increased by 4.2-fold and 1.78-fold in the absence and presence of cycloheximide which is a lymphatic uptake inhibitor revealing lymphatic uptake of ISD-NLC in bioavailability improvement. Hence, systematic adaptation of quality by design integrated approach improved gut permeation and potential solubilizaton fate (dynamic lipolysis) of ISD-NLC, which further improved the lymphatic uptake and biodistribution of drug thereby promisingits in vivo prospect and clinical efficacy.     

Beyond bone biology: Lessons from team science

Today, research in biomedicine often requires the knowledge and technologies in diverse fields. Therefore, there is an increasing need for collaborative team science that crosses traditional disciplines. Here, we discuss our own lessons from both interdisciplinary and transdisciplinary teams, which ultimately ushered us to expand our research realm beyond bone biology.     

l-Proline catalyzed one-pot synthesis of polysubstituted pyridine system incorporating benzothiazole moiety via sustainable sonochemical approach

The efficient, highly convenient synthesis of polysubstituted pyridine derivatives was established via the reaction of N-(benzothiazol-2-yl)-2-cyanoacetamides with an assortment of arylidene malononitriles and arylidene ethyl cyanoacetates in the presence of l-proline as an efficient organocatalyst for this type of ultrasonic-mediated Michael addition. The mechanistic pathway and factors affecting this reaction were also established. The main characteristics of this procedure are high yields, use of a cost-effective catalyst, and easy work-up and purification.

The l-proline catalyzed ultrasonic-mediated synthesis of polysubstituted pyridone derivatives through the reaction of N-(benzothiazol-2-yl)-2-cyanoacetamides with an assortment of arylidenes has demonstrated as an efficient protocol.     

Saphenous vein grafts: to use or not to use?

The choice of the graft conduit is crucial to the success of coronary artery bypass grafting (CABG) because the patency of a coronary conduit is closely associated with an uneventful postoperative course and better long-term patient survival. From the beginning of coronary bypass surgery venous conduits particularly the great saphenous vein (GSV) has been the most frequently used coronary conduit. However, over the last decade or so, coronary bypass graft surgery with arterial revascularization of all diseased coronaries has shown to be efficient because arterial grafts have better long-term patency, especially left internal mammary artery (LIMA), compared with venous grafts. Early vein graft failure coupled with occlusion is the most important limitation of saphenous vein grafts. Nevertheless, vein grafting is still an integral part of cardiac surgical practice. This review provides a summary of the patency rates, technical features and certain characteristics of the venous conduits. It also examines the current understanding and knowledge of venous histology, vein graft pathology and the associated endothelial and smooth muscle cell physiology and pharmacology. In addition, the existing and the emerging strategies to combat and control vein graft intimal hyperplasia and accelerated atherosclerosis are reviewed in detail.     

Coronary arterial disease in systemic lupus erythematosus: Quantification of degrees of narrowing in 22 necropsy patients (21 women) aged 16 to 37 years

The degrees of cross-sectional area luminal narrowing by atherosclerotic plaques of each 5 mm long segment of each of the four major (right, left main, left anterior descending and left circumflex) epicardial coronary arteries in 22 necropsy patients (age 16 to 37 years, 21 women) with systemic lupus erythematosus (SLE) was determined, and the findings were compared to those in 13 control subjects. Of 623 coronary segments (5 mm long) in the patients with SLE, 80 (13 percent) were narrowed 76 to 100 percent (controls = 0 of 431 segments); 125 (20 percent), 51 to 75 percent (controls = 6 percent); 273 (44 percent), 26 to 50 percent (controls = 63 percent) and 145 (23 percent), 0 to 25 percent (controls = 31 percent). Of the 22 patients with SLE, 10 had one or more of the four major coronary arteries narrowed 76 to 100 percent in cross-sectional area, and 12 patients had lesser degrees of narrowing similar to that in the 13 control subjects. The 10 patients with SLE and severe coronary narrowing compared to the 12 patients with SLE and no severe (> 75 percent) coronary narrowing had significantly higher (1) mean values of total serum cholesterol (382 versus 290 mg/dl), (2) mean systolic/diastolic systemic arterial pressures (175/119 versus 151/93 mm Hg), (3) frequencies of mitral valvular disease (seven of 10 patients versus none of 12 patients) and (4) frequencies of pericardial adhesions (seven of 10 patients versus three of 12 patients).     

Normal coronary angiograms: financial victory from the brink of clinical defeat?

OBJECTIVE: To examine the hypothesis that, in patients undergoing coronary angiography for suspected ischaemic heart disease, a normal angiographic result is associated with a fall in consumption of health care resources following the angiogram. DESIGN: Retrospective cost-benefit analysis comparing the 12 month periods before and after coronary angiography. SETTING: Tertiary cardiac referral centre. SUBJECTS: 69 consecutive patients investigated in the financial year 1991-92 whose angiograms were normal. MAIN OUTCOME MEASURES: Drug and hospital admission costs in the 12 month periods before and after angiography; urgent and elective consultations with general practitioner in that time. RESULTS: The mean cost of care per patient in the year before investigation was 656.89 pounds. A highly significant fall in all indices of resource consumption was observed in the year following investigation, the mean resulting difference in the cost of care being 35.15 pounds per month. The cost of coronary angiography would, if this fall were maintained, be recouped in a mean time of 18 months. CONCLUSIONS: Patients suspected on clinical grounds to have coronary atherosclerosis who are found at angiography to have normal coronary arteries are heavy consumers of health care resources. Early investigation for these patients is safe and has beneficial resource consequences in the medium term.