Over-the-Counter Medicine Utilization by Beneficiaries Under Medical Schemes in South Africa.

BACKGROUND: South African medical insurance schemes (known as medical schemes) cover about 17% of the population. Within these schemes, access to medicines for a defined set of chronic diseases is mandated by legislation. However, much of the responsibility for treatment of minor conditions with non-prescription over-the-counter (OTC) medicines has been transferred to the individuals within the medical schemes. The overall expenditure on pharmacist-assisted therapy (PAT)/OTC medicines in South Africa is considerable and medical schemes endeavor to limit amounts paid out by devising strategies that will limit their financial exposure. AIM: To investigate how benefit design and other factors within two medical schemes influenced access to and payment for OTC medicines and to explore whether access to OTC medicines by individuals impacted on utilization of other health-care services. METHODS: Medical scheme data were obtained from a leading administrator for two health plans: one with comprehensive benefits covering 4593 beneficiaries (designated HI) and the other with lower benefits covering 54,374 beneficiaries (LO). Extracted data included beneficiary demographics, OTC medicines prescribed by doctors and/or dispensed by pharmacists, and monetary amounts claimed by individuals and paid by the medical schemes. Doctor consultations, costs and payments were also extracted, as were beneficiaries' records of their chronic disease(s) and any episode(s) requiring hospitalization. RESULTS: Some 60-70% of beneficiaries submitted claims for OTC medicines accessed directly or recommended by a pharmacist, and 80-90% claimed OTC medicines that were prescribed by a doctor during a consultation. Amounts claimed and percentages of original products prescribed were substantially higher when accessed directly by beneficiaries or recommended by pharmacists than when doctors prescribed the medicines. In multivariate analysis, there was no clear advantage of offering access to OTC medicines in order to reduce visits to general practitioners, although in the LO plan it appeared that beneficiaries with chronic diseases made less use of the OTC benefit and more use of medical specialists. CONCLUSION: Within these two plans, there were higher costs and greater use of original products when beneficiaries or pharmacies accessed OTC medicines than when these medicines were prescribed by doctors. A key question is whether access to these medicines and the costs thereof would be managed better if paid for directly by individuals and not as insured benefits through the medical scheme.

An update on the measurement and management of cholesterol with specific reference to secondary prevention of cardiovascular disease (CVD)

Cardiovascular disease remains the largest contributor to non-communicable adverse disease outcomes. Treatment and prevention of cardiovascular disease have evolved at a dramatic pace in the last 40 years. Serum-cholesterol has emerged as the dominant risk factor for coronary artery disease and events. The link between serum-cholesterol and arterial atherosclerosis is well documented. The attainment of cholesterol goals has historically concentrated on low-density lipoprotein cholesterol (LDL-C) levels. Current evidence and guidelines have shifted to the attainment of non-HDL-C target levels which represent a more thorough inclusion of small dense atherogenic particles. Methods to reduce serum-cholesterol mainly centre around the use of the HMG CoA-reductase inhibitors also known as the statins. High intensity statins like atorvastatin (80 mg) and rosuvastatin (40 mg) are now the preferred starting therapies to lower cholesterol by at least 40­50% in patients with established cardiovascular disease as secondary prevention. In the event of failure of these medications, evidence suggests that the addition of ezetimibe may enhance the total serum-lowering levels to 50­60%. New therapies aimed at inhibiting PCSK9 revealed exciting new targets for LDL-C lowering, but the high cost of these antibodies could preclude access to this therapeutic intervention. Aggressive pursuit of lower LDL-C or non-high-density lipoprotein cholesterol (non-HDL-C) levels may reduce the incidence of secondary myocardial infarctions, strokes and death from cardiovascular disease

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.

The evaluation of low-density lipoprotein cholesterol goals achieved in patients with established cardiovascular disease and/or hyperlipidaemia receiving lipid-lowering therapy: the South African Not at Goal study (SA-NAG).

AIM: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Dyslipidaemia is a major risk factor that leads to the clinical sequelae of CVD. As a result, it has become essential for South Africa to update its guidelines for the management of dyslipidaemia, and the South African scientific community has recently adopted the European guidelines on CVD prevention in clinical practice. The South African Not at Goal study (SA-NAG) was a survey done to determine the percentage of patients on lipid-lowering therapy who were not achieving guideline-specified low-density lipoprotein cholesterol (LDL-C) goals. METHODS: In this cross-sectional study, dyslipidaemic and/or CVD patients on lipid-lowering therapy for more than four months were enrolled. V olunteers had their demographic data and previous medical history documented. Blood samples from these patients were analysed (using standardised methods) to obtain fasting blood lipid and glucose levels. RESULTS: In total, 1,201 patients (age 58 +/- 11.4 years) were recruited by physicians and general practitioners from across South Africa. Under the new guidelines, 41% of patients were defined as low risk (LR) and 59% were high risk (HR). Sixty-three per cent of LR patients and 77% of HR patients (71% overall) did not achieve their LDL-C target goals of 2.5 and 3.0 mmol/l, respectively. The LR and HR patients who did not achieve their LDL-C goals were on average 19% (0.7 mmol/l +/- 0.5) and 31% (1.1 mmol/l +/- 1.1) above their LDL-C target levels, respectively. CONCLUSIONS: These results suggest that a considerable number of patients fall into the category 'not at goal' LDL-C. Patients who failed to achieve goal were also far above their LDL-C target levels. The adoption of the new guidelines will necessitate enhanced disease management to reduce the disease burden.

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.

Citalopram enhances the activity of chloroquine in resistant plasmodium in vitro and in vivo.

Citalopram, is an extremely potent inhibitor of neuronal serotonin reuptake. It is structurally unrelated to other antidepressants, but it contains the chemical features associated with reversal of drug resistance and exhibits minimal cardiotoxic side effects and fewer of the anticholinergic and adrenolytic side effects associated with other psychotropic agents. Sensitivity tests to citalopram alone and in combination with chloroquine were performed against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum and Plasmodium chabaudi. Citalopram alone showed intrinsic activity against the chloroquine-resistant strains of P. falciparum (IC50 = 1.51 +/- .6 microM) but only limited activity against the chloroquine-sensitive strain (IC50 = 33.27 +/- 5.87 microM) and no activity in vivo. The interaction of chloroquine and citalopram in vitro resulted in a synergistic response in the chloroquine-resistant strain but there was no interaction between the drugs in the chloroquine-sensitive strain--a pattern found with other reversal agents. Citalopram enhanced chloroquine susceptibility in both strains of P. chabaudi, however, the potentiating effect was seen at lower doses in the chloroquine-resistant strain. The results of this study suggest that citalopram may have potential as a chemosensitizer in Plasmodium infections on the basis of the low toxicity of citalopram at concentrations potentiating chloroquine activity both in vitro and in vivo.

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 intracellular 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 microM (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.

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).

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 degrees 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.

The effect of external calcium concentration on the negative inotropic action of dantrolene in isolated hyperthyroid and euthyroid heart.

The effect of altering external calcium concentration [Ca2+]o on the negative inotropic action of dantrolene was tested in Langendorff-perfused hearts from euthyroid and hyperthyroid rats. Elevated contractility was demonstrated in the hyperthyroid hearts at all the [Ca2+]o tested. At a [Ca2+]o of 1.25 mM (physiological), dantrolene (5 x 10(-5) M) significantly reduced contractility (dP/dtmax) in hyperthyroid but not in euthyroid hearts (-42% and -4% of zero-time values at 12 min perfusion, respectively). When hearts from both groups were paced at 375 beats/min, dantrolene again exerted a greater negative inotropic action in the hyperthyroid preparations, showing that the effect was not heart rate related. Elevating the [Ca2+]o did not further affect the time course of dantrolene action in hyperthyroid hearts. In euthyroid hearts, however, raising the [Ca2+]o to 2.5 and 3.75 mM caused a progressive increase in the negative inotropic action of dantrolene (-15% and -56% of zero-time values at 12 min perfusion, respectively). Our results demonstrate that dantrolene exerts a negative inotropic action which at physiological [Ca2+]o is greater in the hyperthyroid than in the euthyroid heart thus indicating that calcium handling by the myocardium is altered in the hyperthyroid state. However, dantrolene action in the rat myocardium is more complex than was at first believed; as in euthyroid hearts, its negative inotropic action appears to be increased rather than reduced by increases in [Ca2+]o.

Effect of hypoxia and catecholamine stimulation on cardiac performance in the isolated working hyperthyroid rat heart.

The hyperthyroid heart has a greater oxygen demand due to its enhanced contractile state and higher basal metabolic rate. Consequently, it may be more sensitive to conditions of decreased oxygen supply or increased oxygen use. We, therefore, investigated the effect of a restricted oxygen supply (hypoxia) and enhanced oxygen demand (catecholamine stimulation) on cardiac function in the isolated working hyperthyroid heart. Hypoxia was induced by substituting 20% of the oxygen in the perfusate with nitrogen, while catecholamine stimulation was with isoproterenol. Hypoxia caused a 37% drop in cardiac output in the hyperthyroid heart and a 10% decrease in euthyroid hearts. In response to isoproterenol, a dose-dependent increase in heart rate was found in both groups which was greatly augmented in the hyperthyroid hearts by hypoxia. With isoproterenol stimulation under normoxic conditions, euthyroid hearts showed a moderate increase in contractile performance (cardiac output and dP/dtmax), while in hyperthyroid hearts contractile performance declined. Hypoxia exacerbated the decrease in function of the hyperthyroid heart. In conclusion, our results indicate that the hyperthyroid heart is very sensitive to imbalances in the myocardial oxygen supply/demand ratio, especially when demand is increased in the presence of decreased supply.

The role of calcium in the enhanced myocardial contractility of the hyperthyroid rat heart.

The hyperthyroid rat myocardium exhibits enhanced contractility. There is evidence that altered calcium handling by the myocardium may be responsible for this enhanced state. To investigate this, isolated hyperthyroid and euthyroid hearts were perfused in the working mode and exposed to alterations in external calcium concentration. Heart rate was not significantly different in either group of hearts, nor was it altered by the change in calcium. The concentration of calcium needed to elicit half-maximal contractility (dP/dtmax) was lower in the hyperthyroid (0.81 +/- 0.07 mM) than in the euthyroid hearts (1.12 +/- 0.09 mM, p less than 0.05). This increase in calcium sensitivity was unlikely to be at the site of the sarcolemma as verapamil exerted equal negative inotropic effects on both groups of hearts. Dantrolene, which blocks calcium release from the sarcoplasmic reticulum, exerted a significantly greater (p less than 0.01) depression in dP/dtmax after 12 min in the hyperthyroid (50 +/- 7%) than in the euthyroid heart (15 +/- 2%). We conclude from our results that the enhanced contractile state of the hyperthyroid rat heart is likely to involve an altered mechanical response to calcium which is possibly at the level of enhanced calcium release from the sarcoplasmic reticulum.

The effect of propranolol, verapamil and dantrolene treatment on cardiac hypertrophy, enhanced myocardial contractility and tachycardia in the hyperthyroid rat.

Experimentally induced hyperthyroidism is associated with cardiac hypertrophy, tachycardia and elevated myocardial contractility. To investigate the possibility of ameliorating the cardiac changes pharmacologically, hyperthyroid rats were treated with propranolol, verapamil or dantrolene. Cardiac hypertrophy was assessed from the heart mass: body mass ratio and cardiac function was measured in vitro. Both verapamil and propranolol reversed the cardiac hypertrophy of the hyperthyroid animals from 0.92 +/- 0.02 mg.g-1 to 0.70 +/- 0.01 mg.g-1 (P less than 0.001) and 0.72 +/- 0.02 mg.g-1 (P less than 0.001) respectively. Verapamil was effective in reducing the spontaneous heart rate from 331 +/- 8 beats.min-1 to 273 +/- 7 beats.min-1 (P less than 0.001) while propranolol reduced the dP/dtmax of the hyperthyroid hearts from 4089 +/- 87 mmHg.s-1 to 3497 +/- 97 mmHg.s-1 (P less than 0.001). Dantrolene had no effect on any parameter. We conclude from our results that cardiac hypertrophy of the hyperthyroid heart can be reversed by treatment with propranolol and verapamil probably via their inotropic and chronotropic properties.

Enhanced myocardial contractility but not tachycardia persists in isolated working hyperthyroid rat hearts.

It is generally believed that the increased contractility and tachycardia of the hyperthyroid heart are a result of thyroid hormone-induced alterations of the mechanical and electrical properties of the heart, respectively. We compared the contractility (dP/dtmax) and the spontaneous beating rate of hyperthyroid and euthyroid hearts perfused in vitro in either a non-working or a working mode. The dP/dtmax (4196 +/- 74 mm Hg s-1) and beating rate (322 +/- 8 beats/min) of the non-working hyperthyroid hearts were significantly higher (p less than 0.001) than those of the euthyroid hearts (3267 +/- 115 mm Hg s-1 and 260 +/- 6 beats/min at an external Ca2+ of 2.5 mM). At 2.5 mM Ca2+, the working hyperthyroid hearts again displayed enhanced contractility (5636 +/- 179 mm Hg s-1 vs 4508 +/- 172 mm Hg s-1; p less than 0.001) but the spontaneous beating rate (275 +/- 7 beats/min) was not significantly different from euthyroid (261 +/- 8 beats/min). When hearts were subjected to periods of alternate non-working and working perfusion, the beating rate of the hyperthyroid hearts was significantly higher than euthyroid during non-working (p less than 0.02) but not during working perfusion. Increasing the afterload on the non-working preparations in a stepwise fashion from 75 cm H2O to 120 cm H2O caused significant changes in left ventricular pressure and dP/dtmax in both heart types but the tachycardia in the hyperthyroid hearts persisted (at 120 cm H2O; hyperthyroid, 294 +/- 9 beats/min; euthyroid, 224 +/- 10 beats/min; p less than 0.001). Alteration of the preload (10 to 25 cm H2O) and afterload (75 to 105 cm H2O) on working hyperthyroid and euthyroid hearts caused changes in both left ventricular pressure and dP/dtmax but the beating rates of both heart types were never significantly different. We conclude from our results that (i) the increased contractility of the hyperthyroid rat heart is due to thyroid hormone-induced alteration of the mechanical properties of the heart; (ii) the tachycardia of hyperthyroidism is not due to thyroid hormone-induced changes in the electrical properties of the heart, but probably involves some as yet unidentified chronotropic agent.

Independent mechanisms for the chronotropic and inotropic responses in hyperthyroidism.

We established a hyperthyroid rat model and compared the hemodynamic responses of the hypertrophied rat heart in vivo and in vitro. Heart rate (557 +/- 26 beats/min), systolic blood pressure (162 +/- 5 mmHg) and dry heart mass (230 +/- 11 mg) in hyperthyroid rats were significantly greater than in control animals (408 +/- 12 beats/min, 140 +/- 5 mmHg and 193 +/- 4 mg respectively). In vitro studies were performed in order to eliminate neurohumoral and peripheral circulatory factors which are present in vivo. In the in vitro "working" heart preparation, there was no significant difference between the heart rates of L-thyroxine-treated (263 +/- 9 beats/min) and control (258 +/- 10 beats/min) animals, implying that the tachycardia of hyperthyroidism is partly mediated by in vivo factors. Consistent with this hypothesis was the observation that the hyperthyroid heart was more sensitive to the chronotropic effects of physiological concentrations of the synthetic catecholamine, isoproterenol (10(-8) M, 10(-7) M) than the control heart. The maximum rate of left ventricular pressure rise (dP/dtmax) was used as an index of myocardial contractility. In vitro values for dP/dtmax were significantly greater in hearts from hyperthyroid rats (5338 +/- 228 mmHg/s) than in control hearts (4583 +/- 158 mmHg/s), suggesting that the increased contractile response of hyperthyroidism is intrinsic to the heart itself. Although persistence of the inotropic response of the hyperthyroid heart in vitro was associated with an increase in heart mass, this factor alone did not account entirely for the enhanced contractility. It appears that intrinsic functional changes also contribute to the inotropic response of the hyperthyroid heart.