Neil Butkow

Effects of systemic non-steroidal anti-inflammatory drugs on nociception during tail ischaemia and on reperfusion hyperalgesia in rats.

1 We have investigated the effects of five non‐steroidal anti‐inflammatory drugs (NSAIDs) on nociception during ischaemia and on reperfusion hyperalgesia in rats. 2 We induced tail ischaemia in conscious rats by applying a tourniquet at the base of the tail until the rats exhibited co‐ordinated escape behaviour when we released the tourniquet. 3 We assessed hyperalgesia by measuring the tail flick latency following tail immersion in water at 49°C, before applying and immediately after releasing the tourniquet, and then at 30 min intervals for 2 h. 4 Intraperitoneal injection of NSAIDs prior to applying the tourniquet had no effect on the co‐ordinated escape behaviour during ischaemia, nor on tail flick latency in the absence of prior ischaemia. However all the drugs attenuated reperfusion hyperalgesia in a log dose‐dependent manner. Doses required to abolish hyperalgesia, were indomethacin 5 mg kg−1, diclofenac sodium 42 mg kg−1, ibuprofen 54 mg kg−1, dipyrone 168 mg kg−1 and paracetamol 170 mg kg−1. 5 We conclude that the mechanisms underlying nociception during ischaemia are not the same as those underlying reperfusion hyperalgesia. Moreover our procedure provides a rapid and more humane method for measuring the antinociceptive potency of NSAIDs.

Injectable aspirin and mepyramine abolish post-ischaemic hyperalgesia in rats

&NA; We have investigated the effects of mepyramine, an H1 receptor antagonist, and lysine acetylsalicylate, a cyclo‐oxygenase inhibitor, on post‐ischaemic hyperalgesia in rats. We induced tail ischaemia in conscious rats by applying a tourniquet until the rats exhibited coordinated escape behaviour, when we released the tourniquet. We assessed hyperalgesia, by measuring tail flick latency following tail immersion in water at 49 °C, immediately after releasing the tourniquet and then at 30 min intervals for 2 h. After pretreatment with the drug vehicles, tail flick latency decreased significantly following ischaemia. Pretreatment with mepyramine maleate (3 mg/kg), or lysine acetylsalicylate (400 mg/kg), injected subcutaneously, abolished the decrease. We conclude that both histamine release and prostanoid synthesis are involved in the post‐ischaemic hyperalgesia.

Lithium blocks 45Ca2+ uptake into platelets in bipolar affective disorder and controls.

The basal uptake of radiolabelled 45Ca2+ into platelets and the effect of 1 mM lithium on uptake was measured in manic (n = 13) and depressed (n = 15) patients with bipolar disorder and in controls (n = 13). Lithium was significantly associated with inhibition of uptake of 45Ca2+ into platelets in all three groups. There were no significant intergroup differences in either basal levels of calcium uptake or the effects of lithium on calcium uptake (analysis of variance).

Augmented platelet calcium uptake in response to serotonin stimulation in patients with major depression measured using Mn2+ influx and 45Ca2+ uptake.

There is an augmented platelet intracellular calcium response to serotonin stimulation in major depression. The role that calcium influx has in this process is not known. The objective of this study was to determine platelet calcium influx in response to serotonin by two methods, Mn2+ influx and 45Ca2+ uptake, in order to observe if the uptake response to serotonin was augmented in major depression by comparing the response to normal controls. The use of the two methods of calcium influx showed that serotonin stimulates calcium uptake into platelets. Furthermore, patients with major depression have significantly augmented platelet calcium uptake in response to serotonin. The interesting finding was that calcium uptake into platelets is biphasic, occurring immediately and after five minutes. These results may support the two pool model for calcium oscillations within cells whereby extracellular calcium is needed for intracellular calcium release, and for replenishment of depleted stores once intracellular calcium is released.

The augmented platelet intracellular calcium response to serotonin in anorexia nervosa but not bulimia may be due to subsyndromal depression

Objective Serotonergic dysregulation is associated with both bulimia and anorexia nervosa. This study attempted to measure the levels of basal and serotonin-stimulated intra-cellular calcium in patients with bulimia and anorexia Nervosa. Method: In this study, basal levels of platelet intracellular calcium as well as the effects of serotonin on intracellular calcium were studied using the Fura-2 method in subjects with bulimia (N = 11), anorexia nervosa (N = 12), and in matched normal controls (N = 17). Depressed patients, defined as meeting DSM-IV criteria for major depression or having a Hamilton Depression Scale score over 16 were excluded from the study. Results: An enhanced serotonin-mediated mobilization of intracellular calcium was found in anorexia compared to both bulimics and controls at serotonin concentrations of 100 nM (p < .002), 500 nM (p < .001), and 1 μM (p < .001, ANOVA), respectively. However, when the anorexic group was subdivided into high and low Hamilton Depression scale groups, only the high Hamilton group demonstrated an augmented intracellular response to serotonin, with the low Hamilton group not differing from controls. Discussion: These results suggest that the augmented intracellular calcium response to serotonin in anorexia may be due to subsyndromal depression in that group rather than to a primary eating disorder.

Dose-response relationships of sulfonylureas: will doubling the dose double the response?

type 2 diabetes mellitus is currently a global health problem. Although the armamentarium of oral hypoglycemic agents is continuously expanding, sulfonylureas (SUs) are still extensively used for the management of type 2 diabetes mellitus. However, despite decades of use, there is controversy as to the dosing of SUs. Despite many dose-response relationship studies indicating that SUs should be prescribed at lower doses, their dose recommendations remain unchanged. Moreover, studies have demonstrated that high doses of SUs may result in a deterioration of glycemic control and increased frequency of protracted hypoglycemic episodes. In view of the controversial dose-response relationship of SUs, it is suggested that the dose of SUs be titrated against glycemic parameters of blood glucose and glycated hemoglobin.

Optimal utilisation of sulphonylureas in resource- constrained settings

Summary Abstract Sulphonylureas (SUs) are oral anti-diabetic drugs (OADs) that were introduced more than 60 years ago. Clinicians are familiar with their use and they remain extensively used. However, the SU class is associated with adverse effects of weight gain and hypoglycaemia. In addition, their effects on cardiovascular events remain contentious. Newer classes of anti-diabetic agents have been developed and these agents are weight neutral (di-peptidyl peptidase IV inhibitors), while others reduce weight (glucagon-like peptide analogues and sodium glucose co-transporter inhibitors). Furthermore, the newer agents are less likely to cause hypoglycaemia and have a potentially better cardiovascular safety profile. However, the newer agents are more costly than SUs and their long-term safety is unknown. It is therefore likely that SUs will continue to be used, and more so in resource-limited settings. One may mitigate the adverse effects of weight gain and hypoglycaemia associated with the SU class by using members within this class that are less probable to cause these adverse effects. Furthermore, the specific SU must be used at the lowest effective therapeutic dose. In patients at high risk of SU-induced hypoglycaemic episodes (frail, clinically significant renal impairment), or patients in whom hypoglycaemic episodes may have devastating effects (bus drivers), newer anti-diabetic agents may be a justifiable alternative option.

Glycaemic, blood pressure and cholesterol control in 25 629 diabetics

Objective To examine and compare the extent to which people with type 2 diabetes (T2DM) are achieving haemoglobin A1c (HbA1c), blood pressure (BP) and LDL cholesterol (LDL-C) treatment targets. Methods A review of databases (MEDLINE Ovid, Pubmed and Sabinet) was performed and limited to the following terms: type 2 diabetes mellitus AND guideline AND goal achievement for the years 2009 to 2014 (five years). Results A total of 14 studies (25 629 patients) were selected across 19 different countries. An HbA1c level of 7.0% (or less) was achieved by 44.5% of subjects (range 19.2–70.5%), while 35.2% (range 7.4–66.3%) achieved BP of 130/80 mmHg (or less), and 51.4% (range 20.0–82.9%) had an LDL-C level of either 2.5 or 2.6 mmol/l (100 mg/dl or less). Conclusion Despite guideline recommendations that lowering of HbA1c, BP and lipids to target levels in T2DM will lead to a reduction in morbidity and mortality rates, we found that control of these risk factors remains suboptimal, even across different settings.

Multi-ethnic differences in HbA1c, blood pressure, and low-density-lipid cholesterol control among South Africans living with type 2 diabetes after a 4-year follow-up

Purpose Our study set out to examine if disparities in control of glycated hemoglobin (HbA1c), blood pressure (BP), and low-density-lipoprotein cholesterol (LDL-C) existed among an urban multi-ethnic cohort of South Africans, living with type 2 diabetes mellitus (T2DM). Patients and methods This longitudinal, retrospective study consisted of 261 men and women with previously diagnosed T2DM who attended Charlotte Maxeke Johannesburg Academic Hospital, South Africa across two time periods 2009 and 2013. Demographic and clinical data were extracted from consecutive medical records. The primary outcome was to determine achievements in HbA1c, BP, and LDL-C among ethnic groups using evidence-based goals. Results The mean age of the cohort was 64 (±10.6) years, females represented 55%, and the self-reported diabetes duration was 16 (±10.6) years as at 2013. Black Africans (42.9%, n=112 of 261) were more likely to reach the HbA1c target (<7%) and less likely to have had retinopathy, nephropathy, or cardiovascular disease. Over two-thirds of mixed-ancestry patients attained the BP target (<140/80 mmHg), while 90.2% of Caucasians achieved LDL-C goals (<2.5 mmol/L). Overall, across the ethnic groups studied, we found that HbA1c control deteriorated over time, although BP levels remained the same and LDL-C levels drastically improved. Conclusion There was poor control of HbA1c, BP, and LDL-C across all ethnic groups. Although a minority achieved recommended targets, some ethnic groups appeared to have worse control than others. Timely aggressive actions in particularly high-risk ethnic groups will prevent/delay the complications commonly associated with T2DM.

The platelet intracellular calcium response to serotonin in subsyndromal depression

The relationship of subsyndromal depression to syndromal depression is unclear. Increased sensitivity of platelet serotonin type 2 receptor has been reported in depression using the Fura-2 technique. The sensitivity of the platelet serotonin type 2 receptor was assessed using the Fura-2 method in 16 patients with subsyndromal depression and 14 controls. The patient group had higher numerical values of both basal and serotonin-stimulated levels of platelet intracellular calcium that did not however reach statistical significance.