Care of patients undergoing day case inguinal hernia repair.

Inguinal hernia repair is a common operation often performed as a day case procedure. Day surgery is popular with patients and offers many benefits. This article outlines the most common forms of hernia repair and discusses the need for general or local anaesthesia. Basic principles of day surgery management, including patient selection criteria, pain relief, post-operative information, nurse-led discharge and subsequent aftercare are described, many of which are applicable to other day surgery procedures.

Prolonged inhibition of glycogen phosphorylase in livers of Zucker Diabetic Fatty rats models human glycogen storage diseases.

The preclinical efficacy and safety of GPi921, a glycogen phosphorylase inhibitor, was assessed following twenty-eight days of administration to Zucker Diabetic Fatty (ZDF) rats. The ZDF rat is an animal model of type 2 diabetes mellitus (TTDM) which develops severe hyperglycemia. Inhibition of glycogen phosphorylase throughout the duration of the study was demonstrated by reductions in twenty-four-hour glucose profiles and glycated hemoglobin levels. In addition, progression towards hyperglycemia was halted in treated but not control animals, which developed hyperglycemia over the twenty-eight days of the study. Biochemical and histopathological analysis revealed large increases in hepatic glycogen, which closely paralleled the development of hepatomegaly and ultimately resulted in increases in hepatic lipids. Furthermore, prolonged glycogen phosphorylase inhibition resulted in an increased incidence and severity of other adverse pathological findings in the liver, such as inflammation, fibrosis, hemorrhage, and necrosis. The observed biochemical and histopathological phenotype of the liver closely resembled that seen in severe cases of human glycogen storage diseases (GSD) and hepatic glycogenosis in poorly controlled diabetes mellitus. These findings revealed that although glycogen phosphorylase inhibitors are efficacious agents for the control of hyperglycemia, prolonged treatment might have the potential to cause significant clinical hepatic complications that resemble those seen in GSD and hepatic glycogenosis.

Kinetics of the time-dependent inactivation of CYP2D6 in cryopreserved human hepatocytes by methylenedioxymethamphetamine (MDMA).

Methylenedioxymethamphetamine (MDMA) was investigated in cryopreserved human hepatocytes as a time-dependent inactivator (TDI) of CYP2D6 using dextromethorphan (DEX) as a probe substrate. Inhibition kinetic parameters k(inact), the maximal rate of inactivation, and K(I), the inhibitor concentration at half the maximal activation rate, were determined. Time- and concentration-dependent inhibition were confirmed, and the influence of different elements of study design (e.g. cell number, stability of hepatocytes, dilution after preincubation) on estimated kinetic parameters were evaluated. Dilution factors (DF) of 1.2, 5 or total removal of inhibitor (by washing cells after preincubation, WR) resulted in k(inact) and K(I) (+/-S.E.) values of 0.02+/-0.002 min(-1) and 0.88+/-0.31 microM, 0.01+/-0.001 min(-1) and 1.23+/-0.70 microM, and 0.01+/-0.001 min(-1) and 2.10+/-1.32 microM, respectively; indicating that insufficient dilution may lead to overestimation of CYP2D6 inactivation. Accounting for MDMA depletion during the preincubation, corrected K(I) values were significantly lower (0.11+/-0.05 microM, 0.15+/-0.09 microM, 0.24+/-0.16 microM for DF of 1.2, 5, and WR, respectively). Inactivation efficiency in hepatocytes, as measured by k(inact)/K(I), was 10-fold less than that previously reported in human liver microsomes or recombinantly expressed systems. Possible causes for the observed differences between in vitro systems warrant further investigation. These may include differences in metabolic consumption of MDMA in each system, non-specific binding and presence of active efflux in hepatocytes.

Indazole-6-phenylcyclopropylcarboxylic Acids as Selective GPR120 Agonists with in Vivo Efficacy.

GPR120 agonists have therapeutic potential for the treatment of diabetes, but few selective agonists have been reported. We identified an indazole-6-phenylcyclopropylcarboxylic acid series of GPR120 agonists and conducted SAR studies to optimize GPR120 potency. Furthermore, we identified a (S,S)-cyclopropylcarboxylic acid structural motif which gave selectivity against GPR40. Good oral exposure was obtained with some compounds displaying unexpected high CNS penetration. Increased MDCK efflux was utilized to identify compounds such as 33 with lower CNS penetration, and activity in oral glucose tolerance studies was demonstrated. Differential activity was observed in GPR120 null and wild-type mice indicating that this effect operates through a mechanism involving GPR120 agonism.

Temporary sympathectomy in the treatment of chronic refractory angina.

The aim of this study was to investigate the safety and efficacy of the two most commonly practiced temporary sympathectomy techniques in the treatment of chronic refractory angina. Fifty-nine consecutive refractory angina patients commencing outpatient temporary sympathectomy from November 1, 2000 to November 1, 2002, were prospectively audited for duration of pain relief and procedural complications over a two-year period. A total of 227 stellate ganglion blockades (SGB) and 100 paravertebral blockades (PVB) were performed on 59 chronic refractory angina (CRA) patients naïve to sympathectomy. The mean period of pain relief obtained following SGB was 3.48 weeks (SD 3.38) and the mean relief following PVB was 2.80 weeks (SD 2.00). Mild, fully reversible complications occurred in 3% of SGB and 3% of PVB procedures, with one patient requiring overnight hospitalization. This study demonstrates that temporary sympathectomy may provide a safe and effective outpatient procedure in refractory angina patients when applied as part of holistic care.

Temporary sympathectomy in chronic refractory angina: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Temporary sympathectomy by injection of bupivacaine at the site of the left stellate ganglion is used in the management of refractory angina at several UK centres. Although patients frequently report significant reduction in symptoms, efficacy has not been established by double-blind, randomised placebo-controlled trial (RCT). OBJECTIVE: To investigate the efficacy of the procedure for the first time by a double-blind RCT. METHODS: Consecutive patients referred to the authors' National Health Service (NHS) angina centre who were candidates for temporary sympathectomy were invited to participate in a trial. A total of 65 patients were randomised to receive either bupivacaine or saline injections. Identical syringes were prepared remotely, blinding patients and staff from randomisation. Cardiac autonomic function was measured 3 hours pre- and post-injection using new heart rate variability (HRV) analyses. Angina episodes were recorded contemporaneously by patients in study diaries in the 7-day periods pre- and post-injection. RESULTS: In 51 patients suitable for analysis, no significant differences between the active and placebo groups were found in patient-recorded frequency or intensity of angina episodes pre- and post-injection. However, across both groups combined, a significant difference was found in the frequency of angina episodes pre- and post-injection. CONCLUSION: The reduction in frequency of angina episodes produced by this procedure may not be due to drug pharmacology. It may be a placebo response or due to the mechanical effects of the injection of fluid. There is a need for further work using a larger patient cohort considering both mechanical and psychological factors.

Long-term benefits of stellate ganglion block in severe chronic refractory angina.

Angina pectoris that is refractory to optimal medication and revascularization is becoming an increasingly common clinical problem. Recently the US Food and Drug Administration (FDA) approved transmyocardial laser revascularization (TMLR) for use in this group of patients and a large numbers of patients have already undergone this therapy. Unfortunately TMLR has is associated with an unacceptably high perioperative mortality (Cooley DA, Frazier OH, Kadipasaoglu KA, Lindenmeir MH, Pehlivanoglu S, KoIff JW, Wilansky S, Moore WH. Transmyocardiai laser revascularisation: clinical experience with twelve-month follow-up. J Thorac Cardiovasc Surg 1996;111:791-799; Horvath KA, Cohn LH, Cooley DA, Crew JR, Frazier GH, Griffith BP, Kadipasaoglu K, Lansing A, Mannting F, March R, Mirhoseini MR, Smith C. Transmyocardial laser revascularisation: results of a multi-centre transmyocardial laser revascularisation used as sole therapy for end-stage coronary artery disease. J Thorac Cardiovasc Surg 1997;113:645-654; Schofield PM, Sharples LD, Caine N, Burns S, Tait S, Wistow T, Buxton M, Wallwork J. Transmyocardial laser revascularisation in patients with refractory angina: a randomised controlled trial. Lancet 1999;353:519-524), and recurrent refractory angina is common (Allen KB, Dowling RD, Fudge TL, Schoettle GP, Selinger SL, Gangahar OM, Angell WW, Petracek MR, Shaar CJ, O'Neill WW. Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina. N Engl J Med 1999;341:1021-1028; Frazier OH, March RJ, Horvath KA, for the Transmyocardial Carbon Dioxide Laser Revascularization Study Group. Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease. N Engl J Med 1999;341:1021-1028). Temporary sympathectomy by stellate ganglion block (SGB) is in widespread use in a variety of chronic pain conditions and has long history of use in the management of angina (Moore DC. Stellate ganglion block. Springfield, IL: CC Thomas, 1954; Wiener L, Cox JW. Influence of stellate ganglion blockade on angina pectoris and the post exercise electrocardiogram. Am J Med Sci 1966;252:289-295). Here we describe a patient with end stage coronary artery disease and chronic refractory angina whose has been successfully treated with repeated unilateral left SGBs following multiple bypass operations, angioplasty procedures and laser therapy. This case report details his progress over a 34 month follow-up period.

Design and optimization of pyrazinecarboxamide-based inhibitors of diacylglycerol acyltransferase 1 (DGAT1) leading to a clinical candidate dimethylpyrazinecarboxamide phenylcyclohexylacetic acid (AZD7687).

A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compound 30 (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, solubility, and preclinical PK profiles. This compound showed the anticipated excellent pharmacokinetic properties in human volunteers.