Ivermectin shows clinical benefits in mild to moderate COVID19: a randomized controlled double-blind, dose-response study in Lagos.

INTRODUCTION: In vitro studies have shown the efficacy of Ivermectin (IV) to inhibit the SARS-CoV-2 viral replication, but questions remained as to in-vivo applications. We set out to explore the efficacy and safety of Ivermectin in persons infected with COVID19. METHODS: We conducted a translational proof of concept randomized, double blind placebo controlled, dose response and parallel group study of IV efficacy in RT-polymerase chain reaction proven COVID 19 positive patients. Sixty-two patients were randomized to three treatment groups. (A) IV 6 mg regime, (B) IV 12 mg regime (given Q84 h for 2 weeks) (C, control) Lopinavir/Ritonavir. All groups plus standard of Care. RESULTS: The Days to COVID negativity (DTN) was significantly and dose dependently reduced by IV (P = 0.0066). The DTN for Control were, = 9.1+/-5.2, for A 6.0 +/- 2.9 and for B 4.6 +/-3.2. Two way repeated measures ANOVA of ranked COVID 19 +/- scores at 0, 84, 168 and252h showed a significant IV treatment effect (P = 0.035) and time effect (P < 0.0001). IV also tended to increase SPO2% compared to controls, P = 0.073, 95% CI-0.39 to 2.59 and increased platelet count compared to C (P = 0.037) 95%CI 5.55-162.55 × 103/ml. The platelet count increase was inversely correlated to DTN (r = -0.52, P = 0.005). No SAE was reported. CONCLUSIONS: 12mg IV regime given twice a week may have superior efficacy over 6mg IV given twice a week, and certainly over the non IV arm of the study. IV should be considered for use in clinical management of SARS-COV2, and may find applications in prophylaxis in high risk areas.

Progress in the experimental and computational methods of work function evaluation of materials: A review.

The work function, which determines the behaviour of electrons in a material, remains a crucial factor in surface science to understand the corrosion rates and interfacial engineering in making photosensitive and electron-emitting devices. The present article reviews the various experimental methods and theoretical models employed for work function measurement along with their merits and demerits are discussed. Reports from the existing methods of work function measurements that Kelvin probe force microscopy (KPFM) is the most suitable measurement technique over other experimental methods. It has been observed from the literature that the computational methods that are capable of predicting the work functions of different metals have a higher computational cost. However, the stabilized Jellium model (SJM) has the potential to predict the work function of transition metals, simple metals, rare-earth metals and inner transition metals. The metallic plasma model (MPM) can predict polycrystalline metals, while the density functional theory (DFT) is a versatile tool for predicting the lowest and highest work function of the material with higher computational cost. The high-throughput density functional theory and machine learning (HTDFTML) tools are suitable for predicting the lowest and highest work functions of extreme material surfaces with cheaper computational cost. The combined Bayesian machine learning and first principle (CBMLFP) is suitable for predicting the lowest and highest work functions of the materials with a very low computational cost. Conclusively, HTDFTML and CBMLFP should be used to explore the work functions and surface energy in complex materials.

Genital ulcer diseases among HIV-infected female commercial sex workers in Ibadan, Nigeria.

We evaluated the prevalence and association of Genital Ulcer Diseases (GUDs) among HIV-1 infected female commercial sex workers (FCSWs) in Ibadan, Nigeria. A total of 250 FCSWs from brothels in Ibadan were tested for presence of antibodies to HIV and Syphilis. Pelvic examinations for signs of sexually transmitted infections (STIs) were carried out on the subjects. Endocervical and high vaginal swabs were collected from each of the subjects to establish laboratory diagnosis of STIs. Their age ranged from 15 to 55 years (Mean = 25.8 yrs; SD = 3.74). Majority (246/250) were Nigerians, while 1.6% were from neighboring West African countries. Sixty four (25.6%) of the subjects were positive for HIV-1 while seven (2.8%) had dual HIV-1/2 infection. Analysis of the STIs showed that 49 (19.6%) of the CSWs had GUDs. Herpes genitalis was the commonest GUDs as it occurred in 25 (10%) of the subjects. Other STIs identified were chancroid (5.6%), syphilis (4.0%) and lymphogranuloma venerum (LGV) (4%). Sixteen (64.0%) of the CSWs with herpes genitalis had HIV-1 infection. The risk ratio of herpes genitalis for HIV acquisition was 3.0 (95% CI: 2.0 - 4.4). Syphilis and chancroid were also found tobe significantly associated with increased risk of HIV infection (p < 0.0001). The adjusted odd ratios for Herpes genitalis, chancroid, and syphilis were 3.7 (1-13.0, p < 0.05), 19.8 (2.7-13.0, p < 0.05) and 19.1 (1-231.0, p < 0.05) respectively. There is need to educate FCSWs continually to adopt safer sexual behaviours, seek early diagnosis and treatment of GUDs to reduce their risk of transmitting HIV infection.

Pathophysiologically based antihypertensive pharmacotherapeutics rationality, efficacy and safety in Sub Saharan African Nations - A review.

BACKGROUND: Hypertension (HT) prevalence, Uncontrolled Blood Pressure (UBP), morbidity and mortality are highest in Sub-Saharan Africa (SSA). Correlating pathophysiology of HT to pharmaco-therapy with antihypertensive drugs (AHD) may bring amelioration. Aims:To review peculiarities of HT in SSA, UBP causes, diagnostic modalities, AHD use, rationality and efficacy. METHODS AND RESULTS: 14 published therapeutic audits in 4 SSA nations on Google Scholar or PUBMED, (total n = 6496 patients) were evaluated. Calcium Channel blockers (CCB) amlodipine, and thiazide diuretics (TD), hydrochlorothiazide (HCTZ) were the commonest AHD. Thiazide Like Diuretics (TLD) were underutilized. The % of patients on AHD were: 1 drug 5.4-55%; 2 drugs 37-82%; >/ = 3 drugs 6-50.3%. 2-drug combinations were: ACEI/ARB + TD (42%); CCB + TD (36.8%); ACEI + CCB (15.8%) of studies. Triple/quadruple therapy included Methyldopa (MTD) with ACEI + CCB or TD. The (%) attaining BP < 140/< 90 mmHg, ranged from 29 to 53.6%, median, 44%. The co-morbidities, range and median were: Diabetes Mellitus (DM): 9.8-64%, 19.2%; Chronic Kidney Disease (CKD): 5.7-7.5%, 6.9%, and Coronary artery Disease (CAD): 0.9-2.6%, 2.3%. ACEI + CCB ± TD were the preferred AHD for comorbidities. CONCLUSIONS: Therapeutic inertia; Non-compliance; co-morbidities; refractory HT; ignorance; substandard AHD; contribute to UBP. Studies relating 24 hour ABPM to complications and mortality in SSA hypertensives; and impact of different AHD classes on ABPM, are needed. Study of ACEI + alpha-1 blockers + TLD on 24 hour ABPM and personalized care, are required.

Comparison of the effects of unfractionated heparin and the low-molecular-weight heparins dalteparin and enoxaparin on spontaneous platelet aggregation and adenosine diphosphate activity in platelets during the third trimester of pregnancy.

Low-molecular-weight heparins (LMWHs) have demonstrable pharmacokinetic, pharmacodynamic and safety advantages over unfractionated heparin (UH) in routine clinical use and are now the preferred agents in routine anticoagulant therapy. However, the utility and impact of the LMWH compared with that of UH has not been studied extensively in human pregnancy, wherein the prophylaxis against venous thromboembolism is imperative. Human pregnancy is a hypercoagulable state with an increase in spontaneous platelet aggregation (SPA) in vivo. We evaluated and compared the effects of UH and the LMWHs dalteparin and enoxaparin (10 U/ml) on SPA in citrated whole blood with an ultraflow platelet counter in pregnancy and also investigated the role of adenosine diphosphate (ADP) in heparin-induced platelet aggregation in the third trimester of pregnant women (aged 28 +/- 3 years, gestational age 34 +/- 5 weeks) and in healthy, age-matched nonpregnant women. Pregnant women showed a significantly increased SPA of 37% 6 5% compared with 16% 6 3% in nonpregnant women (p < 0.01). UH exerted a significantly greater proaggregatory effect on SPA compared with that of LMWHs or saline (p < 0.0002; ANOVA). The maximum values of SPA were as follows: UH, 69% +/- 5%; dalteparin, 46% +/- 5%; and enoxaparin, 54% +/- 3%. There was no difference between SPA induced by LMWHs and saline or between enoxaparin and dalteparin. At 480 s, there was no difference in SPA induced by LMWH between pregnant and nonpregnant women, but UH substantially and specifically increased SPA in pregnant women compared with that in nonpregnant women (p < 0.01). This heparin-induced platelet activation and thrombocytopenic response was reversed by apyrase grade II (ADP scavenger) that also inhibited SPA in pregnancy to a level similar to that of nonpregnant women (p < 0.0002; ANOVA). These results indicate that the LMWHs dalteparin and enoxaparin cause significantly less platelet aggregation in whole blood in pregnancy and in the nonpregnant state when compared with UH. The proaggregatory platelet effects of UH is substantially enhanced in pregnancy, a property not shared by LMWHs. The reversal of the heparin-induced platelet activation by apyrase grade II suggests that the mechanism is, at least in part, mediated by copious ADP release from platelets or red cells by heparin but not LMWHs.

Characterization of α-Amylase from Soursop (Annona muricata Linn.) Fruits Degraded by Rhizopus stolonifer.

Rhizopus stolonifer is a fungus and one of the most common species of the genus Rhizopus. The organism has been a very important microbe used in the field of industrial microbiology. It has been used in the production of many hydrolytic and extracellular enzymes among which is the α-amylase. This enzyme has found various uses in the industry. Fruit juices are important sources of nutrients and they contain several important therapeutic properties that may reduce the risk of various diseases. An investigation on α-amylase extracted from soursop fruits deteriorated by R. stolonifer and the effect of the enzyme on soursop juice clarification was carried out in this study. The results obtained shows that the soursop juice with low concentration of extracted enzyme and less incubation time was more viscous and cloudy compared with the juice with high concentrations of amylase and higher incubation time which was clearer and less viscous. The results of this research will be very useful in soursop juice producing companies.

Castration reduces platelet thromboxane A2 receptor density and aggregability.

BACKGROUND: Exogenously administered testosterone upregulates platelet thromboxane A2 (TXA2) receptors and increases aggregation response to thromboxane mimetics in healthy male volunteers. However, the biological impact of endogenous testosterone on platelet TXA2 receptor expression, especially in older men at risk of coronary artery disease, is unclear. AIM: To investigate the impact of reduction in circulating testosterone on platelet TXA2 receptor expression in older men. DESIGN: Cross-sectional case-control study. METHODS: We studied surgically and/or medically castrated men with prostate cancer (group A, n = 8, aged 71 +/- 8 years) and age-matched, uncastrated urology patients (group B, n = 7, aged 67 +/- 9 years). Plasma testosterone was measured by radioimmunoassay. Platelet TXA2 receptor expression was assessed by radioligand binding studies using radioactive 125I-BOP. Platelet aggregation responses to TXA2-mimetic I-BOP, and to thrombin, were also studied. RESULTS: Group A had significantly lower plasma testosterone than group B (16 +/- 5 ng/dl vs. 308 +/- 47 ng/dl, p<0.001). Platelet TXA2 receptor density (B(max)) but not affinity (K(d)) was lower in group A (0.50 +/- 0.12 vs. 1.01 +/- 0.17 pmol/mg protein, p = 0.03). Maximum platelet aggregation response to I-BOP (E(max)), but not sensitivity (EC50) was lower in group A (53 +/- 2% vs. 63 +/- 2%, p = 0.003 ANOVA). In vitro, high concentrations of hydroxyflutamide (100 microM) competitively inhibited U46619-induced platelet aggregation in washed platelets, without affecting the binding of 125I-BOP to platelet TXA2 receptors. DISCUSSION: Endogenous testosterone regulates platelet TXA2 receptor B(max) and the E(max) aggregation response to thromboxane mimetic I-BOP. Blockade of androgen receptors or inhibition of testosterone production may reduce platelet aggregation responses. Preliminary evidence suggests the presence of functional androgen receptors on human platelets, which may regulate TXA2 receptor expression.

Clarification of Tomato Juice with Polygalacturonase Obtained from Tomato Fruits Infected by Aspergillus niger.

Two varieties of tomato fruits commonly available in Nigerian markets are the Roma VF and Ibadan local varieties of tomato fruits. The Roma VF fruits are oval in shape. It is a common type of cultivar in the Northern region of Nigeria and it is not susceptible to cracking. The Ibadan local variety of tomato fruits is a local variety commonly found on farmers fields in South-western region of Nigeria. They are highly susceptible to cracking. The Ibadan local variety was employed for this research. There are lots of benefits derived from the consumption of tomato fruits. The fruits can be made into tomato juice clarified with pectinases. Polygalacturonase is one of the pectinases used commercially in the clarification of fruit juice from different fruits. This study examined the production of polygalacturonase during the deterioration of tomato fruits by Aspergillus niger and the role of the purified polygalacturonase in the clarification of tomato juice. Tomato fruits of the Ibadan local variety were inoculated with mycelia discs containing spores of a 96-h-old culture of Aspergillus niger served as the inoculum. The organism from the stock culture was subcultured onto potato dextrose agar plates. The extraction of polygalacturonase after 10 days of incubation at 27 degrees C was carried out by homogenizing the fruits with liquid extractant using the MSE homogenizer after the deteriorated fruits had been chilled for 30 min inside a freezer. Control fruits were similarly treated except that sterile potato dextrose agar served as the inoculum. The effect of different temperature of incubation and different volume of enzyme on the tomato juice from the tomato fruits was investigated. Extracts from the inoculated fruits exhibited appreciable polygalacturonase activity. The juice with polygalacturonase was visually clearer and more voluminous than the juice treated with water for all parameters studied. The highest volume of juice was obtained after an incubation period of 30 min for the tomato fruits. The increase in juice yield can be attributed to the hydrolysis of pectin which releases the sap inside the cells of the pulp. The occurrence of polygalacturonase in tomato tissues infected by A. niger coupled with the trace amount in the non-infected tissues suggests that the enzyme is of fungal origin. The role of the polygalacturonase in the clarification process was established. This study will be very useful for industrial tomato juice production.

Effect of naloxone on the actions of captopril.

Captopril inhibits the metabolism of endogenous opioids in vitro and potentiates their effects in vivo. We examined the hypothesis that endogenous opioids contribute to the actions of captopril in man. The acute cardiovascular and autonomic effects of oral captopril, intravenous naloxone, and their combination were examined in eight healthy men with normotension in a double-blind, placebo-controlled study of a Latin squares design. Naloxone altered neither blood pressure nor heart rate. There were significant falls in systolic blood pressure during captopril dosing alone, but there was no fall in blood pressure during combination therapy. Heart rates were higher during the combination than during captopril alone. The combination caused sedation, but neither captopril nor naloxone alone had any behavioral effects. Modification of the acute circulatory effects of captopril by naloxone suggests a role for endogenous opioids in the responses to converting enzyme inhibition. The sedation caused by the combination raises the possibility that captopril may exert central nervous actions in man.

Spectrum of hypertensive heart disease in Nigerians: cross-sectional study of echocardiographic indices and their correlation with treadmill exercise capacity.

OBJECTIVES: The aims of this study were to provide cross-sectional data on echocardiography in Nigerians with normotension, essential hypertension and hypertensive heart failure, and to correlate the echocardiographic indices with treadmill functional capacity. METHODS: M-mode and two-dimensional echocardiography and a Bruce protocol treadmill test were undertaken in Nigerians with essential hypertension (n = 22) and hypertensive heart failure (n = 12), and in matched healthy volunteers (n = 15). RESULTS: A striking echocardiographic feature was the tendency to eccentric or asymmetric left ventricular hypertrophy in Nigerians. The septum to posterior wall ratios were 1.4 +/- 0.1 in the normotensives, 1.6 +/- 0.1 in the hypertensives and 1.5 +/- 0.1 in the heart failure group. There was a progressive increase in left ventricular mass index and a reduction in fractional fibre shortening in the hypertensive spectrum. Treadmill exercise capacity also showed a progressive fall from normotensives through hypertensives to the heart failure group. A significant positive correlation was found between fractional fibre shortening and treadmill time in the heart failure group. CONCLUSION: In Nigerians with hypertensive heart disease, there was a striking tendency for eccentric (asymmetric) rather than concentric left ventricular hypertrophy. Systolic left ventricular contractility may be predictive of treadmill exercise capacity in hypertensives.

Acute and chronic effects of the converting enzyme inhibitors enalapril and lisinopril on reflex control of heart rate in normotensive man.

The effects of enalapril maleate and its lysine analogue, lisinopril, on reflex control of heart rate after acute and chronic administration were examined in 10 normotensive males. Both drugs reduced blood pressure without change in heart rate after acute dosing and after seven days. Both drugs impaired the vagally mediated early cardiac acceleration associated with lying down (standing to lying test). A similar effect was observed following edrophonium. After lisinopril bradycardia induced by facial immersion (diving reflex) was significantly attenuated. Edrophonium similarly attenuated the bradycardia. Both these reflexes are parasympathetically mediated. Neither drug altered heart rate or blood pressure changes following Valsalva's manoeuvre and the cold pressor test. Plasma noradrenaline was unchanged. Absence of reflex tachycardia with blood pressure reduction by converting enzyme inhibitors may be related to increased parasympathetic activity either centrally or peripherally without impairment of baroreflexes or sympathetic function.

The effects of enalapril-digoxin-diuretic combination therapy on nutritional and anthropometric indices in chronic congestive heart failure: preliminary findings in cardiac cachexia.

BACKGROUND: Body wasting is a clinical feature of a variety of chronic illnesses including congestive heart failure. The wasting associated with chronic congestive heart failure (cardiac cachexia) has recently been shown to portend a worse prognosis, and it is an independent predictor of mortality. The mechanisms underlying cardiac cachexia are multi-factorial, including metabolic, nutritional, neuroendocrine and immunological aberrations. There is, however, no direct evidence that current medical treatment reverses cachexia in chronic heart failure. METHODS: The effect of enalapril, digoxin and frusemide combination on clinical, biochemical and anthropometric indices were determined in eight cachectic Nigerians with chronic congestive heart failure [body mass index (BMI) 20.80+/-2.7 kg/m(2), left ventricular ejection fraction 29+/-4% and LV mass index 161+37 g/m(2)] at baseline, and again after 3 and 6 months of therapy. Ten age- and sex-matched healthy volunteers whose anthropometric data were concurrently measured served as controls. RESULTS: The anthropometric and clinical measurements were significantly (P<0.001) reduced in heart failure compared to the healthy controls. Congestive hepatomegaly significantly regressed from 161+/-20 mm to 123+/-13 mm after 6 months therapy (P<0.001 ANOVA). There was a significant increase in the sum of four skin fold thickness from 27.6+/-3.3 mm to 30.1+/-3.9 mm at 6 months (P<0.001 ANOVA) 95% confidence intervals for the difference being 1.42 to 3.4 mm. There was a significant increase in the mid-upper arm circumference (P<0.001 ANOVA) with a 95% confidence interval of 0.87-2.1 cm, and a similar trend for increased mid-thigh circumference (95% confidence limits 0.93-5.30 cm) was apparent. Plasma albumin and sodium increased significantly (P<0.05) from 30.1+/-3.8 g/l and 136+/-5.9 mmol/l to 32.9+/-2.5 g/l and 139+/-3.9 mmol/l, respectively. There was a positive and significant correlation between the treatment induced increases in plasma albumin and the increase in mid-upper arm circumference (y=0.25x+0.8, r=0.76, P=0.03 ANOVA) but not with the change in skin fold thickness. CONCLUSION: The preliminary results demonstrate increased subcutaneous fat (increased skin fold thickness), greater muscle bulk (increased mid-upper arm and thigh circumferences) together with a significant elevation in plasma albumin and the hematocrit, which reflect the anabolic state in patients treated with ACE inhibitor-digoxin-diuretic with congestive heart failure.

Shifting trends in the pharmacologic treatment of hypertension in a Nigerian tertiary hospital: a real-world evaluation of the efficacy, safety, rationality and pharmaco-economics of old and newer antihypertensive drugs.

The current prescription patterns for essential hypertension and the efficacy, safety, tolerability and cost-effectiveness of the newer antihypertensive drugs were evaluated in Nigerian patients. The findings were compared with that of a previous study conducted in the same tertiary hospital 10 years earlier. A cross-sectional evaluation of blood pressure (BP) control in a hypertension clinic was undertaken among 150 Nigerian patients aged 61 +/- 12 years (55% females), with a duration of treatment on a particular drug class or combination of 9 +/- 3 months. The initial blood pressure was 176 +/- 20/108 +/- 11 mmHg and 22% of the patient had concurrent diabetes mellitus. Thiazide diuretics (D) alone or in combination remained the most commonly prescribed drugs in 56% of all patients. There were significant increases in the prescriptions of calcium channel blockers (CCBs) (51%), P < 0.0001, and ACE-inhibitors (ACEIs) (24%), P < 0.0001, but a slight reduction in the use of methyldopa, and fixed drug combinations (P < 0.01) compared to the previous study. The fall in systolic blood pressure on D (r = 0.65, P < 0.001) or CCB (r = 0.48, P < 0.02) was significantly correlated with the initial systolic blood pressure, but not age. More patients achieved normotension BP < 140/90 mmHg on CCB monotherapy (71%), than D monotherapy (56%). Combination therapy with ACEIs + D or methyldopa+thiazides normalized BP in 63 and 68%, respectively. Pulse pressure, a surrogate marker for cardiovascular complications and mortality in essential hypertension, was significantly reduced (P < 0.01) equally by all treatments, with 95% confidence intervals ranging from -28 to -1 mmHg. However, hypertensive-diabetic (HT-DM) patients (n = 33) exhibited no significant change in pulse pressure in response to treatment. Adverse drug reactions that occurred in 11% were impotence or postural dizziness with D, headache and pitting oedema with CCB, and dry cough with ACEI. Pharmaco-economic comparison of the drug classes revealed that for every US dollar (dollar) spent per month, the percentage of treated patients attaining normotension was 18.6 for D, 4.73 for CCB, 3.5 for ACEI + D and 13.6 for methyldopa + thiazides. A combination of ACEI + CCB or D was the preferred treatment for hypertensive-diabetic Nigerians, but only 24% attained a BP < 130/85 mmHg. These results demonstrate a shift in trend to a more rational and efficacious treatment of hypertension over a 10 year period. This may be associated, at least in part, with the intensive and continuous education of the prescribers in rational drug use and the introduction of a hospital formulary. Methyldopa is still a highly efficacious and cost-effective drug in this population. Black HT-DM Africans still constitute a subgroup who not only require more and costlier antihypertensive drugs, but whose BP control is suboptimal, and exhibit a poor therapeutic response to other risk factors (pulse pressure) that constitute a continuing risk for cardiovascular mortality.

Gender difference in vascular and platelet reactivity to thromboxane A(2)-mimetic U46619 and to endothelial dependent vasodilation in Zucker fatty (hypertensive, hyperinsulinemic) diabetic rats.

We examined the hypothesis that gender differences exist in platelet and vascular reactivity in type-2 diabetes mellitus, using Zucker fatty diabetic rats of both sexes and their lean littermates. Type-2 diabetes is characterized by excessive platelet production of TXA(2), which is thrombogenic. Testosterone up-regulates platelet TXA(2) receptors and the aggregation response to thromboxane mimetics. Conversely, estrogen increases vascular nitric oxide (NO) production and inhibits platelet aggregation. Hemodynamic studies were undertaken with the determination of dose-response curve for MAP and renal cortical blood flow (RCF) in response to U46619, angiotensin-II, phenylephrine and endothelin-1, as well as the systemic hemodynamic response to acetylcholine and L-NG nitro-arginine methylester (L-NAME). Platelet aggregation response was evaluated using whole blood impedance aggregometry. There were significant gender differences in the systemic blood pressure and RCF response to TXA(2)-mimetic U46619 and angiotensin-II (P<0.02, ANOVA) but not to phenylephrine or endothelin-1. Male rats exhibited a paradoxical hypotensive response to U46619 (-18+/-11 mmHg) compared with a peak pressor response of +6+/-1 mmHg in female rats (P<0.01, ANOVA). The male rats exhibited an attenuated systemic vasodilator response (P<0.001, ANOVA) to acetylcholine (fall in MAP in male diabetic rats being -24+/-8 mmHg, compared with a fall of -50+/-8 mmHg in females), but a greater rise in the renal cortical resistance in response to NO inhibition by L-NAME (P<0.03) compared with the female rats. Both the slope (46+/-2) and the peak magnitude of the U46619-induced whole blood platelet aggregation (13+/-1) ohms were significantly higher (P<0.01, ANOVA) in male (n=10) compared with female diabetic rats (n=8) (29+/-0.8 slope, 10.0+/-0.8 ohms, respectively). Thus, the male diabetic Zucker rats exhibited an impaired response to vasoconstrictors (U46619 and angiotensin-II) and to endothelial (NO)-mediated vasodilation. The male gender may therefore be associated with the greater prothrombotic activity and a worse impairment of endothelial reactivity in the type-2 diabetic state.

Alteration in endothelin receptor sub-type responsiveness and in the endothelin-TXA(2) mimetic U46619 interaction, in type-2 hypertensive diabetic Zucker rats.

BACKGROUND: Type-2 diabetes is characterized by endotheliopathy, which increases target organ damage and mortality. There is excessive endothelin-1 and TXA(2) production, and abnormal vascular reactivity to endothelin-1, manifested as a paradoxical hypotensive action in Zucker diabetic, but not lean rats. We examined the hypothesis that there is an alteration in the ET-A/ET-B receptor subtype sensitivity, and/or the interaction or cross-talk between ET-1 and TXA(2) in type-2 diabetes, using Zucker diabetic rats and their lean littermates. MATERIALS AND METHODS: Hemodynamic studies were performed in lean and Zucker fatty diabetic rats of both sexes. Laser doppler flowmetry was used to measure renal cortical (RCF) and medullary blood flow (MBF) responses. Dose response curves for mean arterial blood pressure (MAP), MBF and RCF in response to ET-1, U46619, acetylcholine, and L-NAME (25mg/kg) were constructed after pre-treatment of the rats with either BQ610 1mg/kg i.v. or BQ788 0.5mg/kg i.v. The effects of BQ610 and BQ788 on whole blood impedance aggregation were also assessed. RESULTS: BQ788, but not BQ610 abolished both the paradoxical hypotensive action of ET-1 in Zucker diabetic rats (n=7 each, P<0.001 ANOVA) as well as the dose-dependent rise in MBF (P<0.001 ANOVA). BQ788, but not BQ610 abolished the difference in response to ET-1 between lean and diabetic Zucker rats. U46619 caused a hypotensive action in male Zucker rats which was abolished by L-NAME 25mg/kg or indomethacin 10mg/kg i.v. The U46619 interaction with BQ788 on both MAP and MBF was significantly (P<0.03 ANOVA) different between lean and diabetic Zucker rats. BQ788, but not BQ610 attenuated both the MAP and MBF responses to acetylcholine or L-NAME P<0.02 ANOVA). However, BQ610 dose-dependently attenuated the slope of platelet aggregation in both lean and Zucker diabetic rats (P<0.02 ANOVA). CONCLUSION: ET-B receptor antagonism abolished the abnormal vascular reactivity and MBF responses to ET-1, and also normalized the vasoactive responses to the level seen in healthy lean Zucker rats. ET-1 receptor blockade influences the responses to TXA(2) receptor activation. In the systemic and renal circulation, this interaction appears to be mostly ET-B receptor mediated, whilst in platelets, ET-A receptor role may be predominant. The interaction or cross-talk between ET-1 and TXA(2) is altered in the type-2 diabetic state. Collectively, these pathophysiological changes may contribute to the vicious circle of diabetic endotheliopathy.

Prognostic indices for intra-hospital mortality in Nigerian diabetic NIDDM patients. Role of gender and hypertension.

Hypertension and diabetes mellitus are independently associated with a high rate of target organ complications, which is particularly accentuated in the Negroid race. The aims of this study were to evaluate the mortality associated with diabetes mellitus and concurrent hypertension and diabetes mellitus in indigenous Africans, and to identify and assess the factors that are predictive of intra-hospital mortality in Non-Insulin Dependent Diabetes Mellitus (NIDDM) diabetic Nigerians. The subsequent impact of the modification of these risk factors was also evaluated. A prospective study of 51 hypertensive-diabetic (Non-Insulin Dependent Diabetics, NIDDM) Nigerians (32 males, 19 females) over a 15-month period, from 1996 to 1997 was undertaken. The mean admission blood pressures were 170/102+/-35/22 mm Hg, with a body mass index (BMI) of 25.4+/-10.2 kg/m(2). A total of 54 normotensive (BP<130/85 mm Hg)-NIDDM diabetic Nigerians (30 men, 24 women), who were concurrently admitted in the hospital, were compared to the hypertensive-NIDDM. The total mortality of all the NIDDM diabetics, as well as the mortality rates in normotensives and hypertensive-diabetics, were computed. The causes of death and associated complications were noted. Predictive indices of intrahospital mortality were statistically evaluated by comparison of proportions, chi(2) test, Fischer's exact test, logistic regression, and analysis of variance (ANOVA).Over-all mortality rate among all the diabetics (both normotensive and hypertensive) was 26.6% (28/105), which was significantly higher than the crude death rate on the Internal Medicine service of 17.8% (P=0.006) or the non-obstetric crude death rate in the hospital of 10.96% (P=0.001) Among the hypertensive-NIDDM patients (n=51) the mortality rate was 31.4% (16 deaths/51 patients). This was slightly higher than the value of 22.2% (12 deaths/54 patients) seen in normotensive -NIDDM patients. The mortality rate among the male diabetics (23/63 patients) 46.6% was significantly higher than female mortality rate of 11.6% (5/43). The 95% Confidence interval for the difference in mortality rates being 16.9% to 53.3% (P<0.0001, z=3.57). The impact of gender remained significant by the chi(2) test, chi(2)=7.17, P=0.007. 50% of the deaths in hypertensive-diabetics had associated stroke (8/16), while none of the 12 deaths among the normotensive-diabetics was stroke-related (P=0.008, Fisher's exact test). The case fatality rate for stroke in hypertensive-NIDDM men (7/7.9) was significantly greater than in hypertensive-NIDDM women (1.0/7) (P=0.04,by Fisher's exact test). Male gender, presence of Hyperosmolar Non-Ketotic Coma (HONK) (P<0. 05), associated stroke (P<0.01) and a Glasgow coma < or =10 (P<0.01) were found to be poor prognostic indices for mortality in hypertensive-NIDDM. Aggressive anti-platelet, (aspirin) anti-hypertensive, and strict glycemic control, instituted early and intensively, especially in male hypertensive-NIDDM Nigerians have resulted in reduction in the mortality rates from 26.6% in 1997 to 12.6% in 1999 [P=0.05, 95% CI -26.9% to -1.3%]. The prognosis in 1999 of hospitalized African diabetics is still dismal. Hypertensive-NIDDM represents a higher risk group for intra-hospital mortality in black Africans. Male patients appear to have significantly (P<0.001) enhanced risk, especially with thrombotic/stroke-related deaths (P<0.01). However, intervention measures can reduce the mortality rate considerably, even in developing countries. The mechanisms of the apparent male mortality excess require elucidation.

Acute cardiovascular effects of the concurrent administration of enalapril, prazosin or amlodipine in healthy Nigerians.

The acute circulatory effects of the combination of prazosin 1 mg, enalapril 10 mg or amlodipine 5 mg were evaluated and compared in a placebo controlled, randomised, double blind, latin-square, cross-over study in 8 normotensive healthy Nigerians. Supine and erect blood pressure were reduced by the active treatment combinations (F = 8.8, P = 0.0006, analysis of variance). In all, the onset of blood pressure fall was within 2 h, with a peak reduction at 4-6 h and persisting for at least 12 h. The combination of converting enzyme inhibitor and alpha blocker, however, caused a significantly greater hypotensive action than the other combinations (P < 0.05, analysis of variance). There was a modest reflex tachycardia in the erect position on all treatments (P = 0.008). Cardiac autonomic reflexes or left ventricular echocardiographic indices were unaffected by the drug combinations. The haemodynamic effect of enalapril plus prazosin combination, which separately cause little hypotensive effect in Africans, may reflect an important pharmacodynamic interaction between alpha 1 and angiotensin II vascular receptors. All combinations lower blood pressure and warrant further study in Nigerian hypertensives. However, the enalapril plus prazosin combination caused the greatest blood pressure fall, and caution is indicated during their concurrent use, owing to enhanced first dose hypotension.

Sustained beneficial effects of enalapril in Africans with congestive heart failure.

A single blind, placebo controlled, dose-ranging 3 month study of the effects of enalapril on cardiovascular parameters, clinical status and self-paced exercise capacity was undertaken in 12 Nigerians with chronic heart failure. Enalapril exerted only a modest reduction in blood pressure and heart rate but significantly improved functional capacity (P less than 0.01), and prolonged self-paced exercise time (P less than 0.05) compared to the placebo baseline. The pressure rate product and the double product corrected for exercise time, an index of myocardial oxygen demand, exhibited a significant and sustained reduction on enalapril treatment (P less than 0.01). Concentration of sodium in the serum was significantly increased (P less than 0.05) but concentrations of potassium and creatinine were unaltered. These results demonstrate the sustained efficacy of enalapril in black Africans with heart failure and indicate no important racial difference in the response to inhibition of angiotensin converting enzyme in congestive heart failure.

Symptom-limited, self-paced walking in the assessment of cardiovascular disease in patients with and without heart failure: the predictive value of clinical, anthropometric, echocardiographic and ergonometric parameters.

The assessment of functional capacity in heart disease remains problematic, and it is unclear whether maximal exercise testing is physiologically reflective of the activities of daily living or the quality of life. We therefore employed a symptom-limited, self-paced walking protocol to assess the physical conditions of 41 Nigerian cardiac patients, with and without heart failure. The walking time, walking speed and distance as well as the energy expenditure (Kcal.min-1) were markedly reduced (P less than 0.001) in patients with heart failure (n = 26) compared to the cardiac patients not in failure (n = 15). The double product corrected for exercise time (an index of myocardial oxygen use) was, however, significantly higher (P less than 0.001) in the group with heart failure. Using multiple regression analysis, the parameters of self-paced walking capacity (distance, walking time, and speed) could reliably be predicted (r2 greater than 0.9) from age, body surface area, energy expenditure, and echocardiographic left ventricular dimension in the patients without heart failure. The presence of heart failure appeared to weaken the predictability of the regressions. A significant correlation was obtained between the self paced exercise time and the Bruce protocol treadmill time (r2 = 0.91, P = 0.004) in a subgroup of the patients with heart failure. Thus, the self-paced walking test is sensitive to changes in congestive heart failure and the exercise capacity can be predicted from age and biophysical parameters. The wider clinical usage of this modality, especially in frail patients, is hereby recommended.

Sudden unexpected death from cardiac causes in Nigerians: a review of 50 autopsied cases.

Fifty cases of sudden and unexpected death from cardiac causes in individuals between the ages of 28 and 80 years are reviewed; the causes and circumstances of the deaths of these individuals are defined. 70% were males and 44% of the deaths occurred in the 41-50 years age group. Death was due to hypertensive heart disease in 82% of the cases and only 18% were previously diagnosed. Acute left ventricular failure was the commonest (68%) cause of death. Only 4% of the total died of acute myocardial infarction from coronary artery disease. The causes of sudden cardiac death in a developing country such as Nigeria, appears to be different to the pattern in Western countries.