Itching, chloroquine, and malaria: a review of recent molecular and neuroscience advances and their contribution to mechanistic understanding and therapeutics of chronic non-histaminergic pruritus.

Chloroquine (CQ) is an antimalarial drug that elicits severe pruritus in black Africans with malaria fever. This acute itching (2-7 days duration) exhibits age dependency and a racial and genetic predilection. CQ itch is non-histaminergic, which makes it both a good model and a tool to probe the mechanisms of chronic itch. This review focuses on recently discovered mechanisms, neuroscience, mediators, and receptors that are implicated in molecular studies of CQ pruritus. CQ pruritus mechanisms are also compared to that of itching following other systemic diseases, such as chronic kidney disease, chronic liver disease, skin disorders, and burns. There are striking similarities between CQ itching pathways and other chronic itch secondary to systemic disease with or without skin lesions, which have not been previously highlighted. Prominent among these are the shared roles of skin, neural and spinal µ opiate receptors, kappa opiate receptor, nitric oxide, serotonin via 5HT1B/D receptors, cytokines, especially interleukins, and tumor necrosis factor. There is elaborate "cross talk" among the diverse mediators and receptors involved in CQ-induced pruritus. CQ also binds to the mas-related G protein coupled receptors MrgprA3/MrgprX1 present in a small proportion (4-5%) of dorsal root ganglion neurons and skin. The mrgprA3 CQ receptors are coupled to PLC-ß3 and a chloride channel to initiate skin itch action potentials in C nerve fibers. Mrgpra3/X1 couples to TRPA1 for calcium influx into neuronal cells at noncutaneous sites. Central CQ itch occurs via gastrin-related peptide (GRP) and its receptor (GRPR) in the dorsal spinothalamic tracts, as well as glutamic mediated GRP projection to parabrachial nucleus. The possibility of chronic itch therapy based on personalized medicine, genetics, and transcriptomics or the use of itch "polypill/polycream" are discussed.

Influence of West African Ethnicity and Gender on Beta-Cell Function and Insulin Sensitivity in Essential Hypertensives Treated with Hydrochlorothiazide and Hydrochlorothiazide-lisinopril Combination.

OBJECTIVE: To assess the effects of hydrochlorothiazide (HCT) given alone and in combination with an angiotensin-converting enzyme inhibitor (ACEI) on beta-cell function in a negroid population to further explore possible ethnic differences in the effect of antihypertensive drugs on homeostasis model assessment - insulin resistance (HOMA-IR). MATERIALS AND METHODS: A total of 80 newly diagnosed Nigerian essential hypertensive patients were assigned to receive either HCT 25 mg daily or both HCT and lisinopril (Lis; 25/10 mg daily) in an open-label study for 12 weeks. The treatment groups were well matched in clinical and demographic baseline features. Changes in HOMA-IR from baseline to end of study (week 12), fasting plasma glucose (FPG), serum potassium, serum insulin, and blood pressure over the same period were also evaluated. RESULTS: After 12 weeks, mean delta HOMA-IR (and %) was higher in the HCT monotherapy group; although, this change did not reach statistical significance in both groups -0.1 ± 7.1, P = 0.538 (HCT) and 0.6 ± 4.2 P = 0.913 (HCT + Lis); an insignificant increase was observed in FPG and serum insulin in both groups, whereas serum potassium decreased in similar fashion. Blood pressure reduction was similar in both groups. Analysis of HOMA-IR change according to gender in response to HCT mono- or combination therapy with Lis showed no significant difference. CONCLUSIONS: HCT monotherapy in hypertensive indigenous Nigerians, was not associated with worse metabolic effects when compared with combination therapy using Lis, an ACEI after 12 weeks. Low-dose thiazide diuretic as first-line antihypertensive medication may be safe in the short-term, further larger and long-term studies are needed to corroborate this finding.

Valvular regurgitations may increase risk of arrhythmias in Nigerians with hypertensive heart failure.

BACKGROUND: Hypertensive heart disease (HHD) is the commonest cause of sudden cardiac death among Nigerians. A high frequency and early onset of valvular regurgitations (VHD) in hypertensives, and greater concentric hypertrophy are also common in that population. AIMS AND METHODS: To further investigate the relationship between VHD and cardiac arrhythmias and their correlates seen in the hypertensive spectrum and to test the hypothesis that VHD predisposes to cardiac arrhythmias in hypertensive heart failure (HHF). HHF patients (n = 14), HHD patients n = 23, and normotensive controls (n = 9) all underwent 24 h electrocardiogram Holter monitoring as well as two-dimensional and Doppler echocardiography. Participants in each patient category were classified according to the presence and severity of VHD or its absence (NVHD). RESULTS: There were statistically significant differences in the mean supraventricular tachycardia (SVT) (P < 0.001 analysis of variance; ANOVA), the mean and median frequency of ventricular tachycardia episodes (P < 0.02 ANOVA), and couplets (P = 0.0002 ANOVA) between groups. HHF-VHD always had more SVT (81/24 versus 4.4/24 h; P = 0.016) and ventricular arrhythmias 69/24 versus 34/24 h (P < 0.02) than HHF-NVHD. Multivalvular regurgitations (three or more valves), higher left ventricular mass index (g/m2) [274 (24) versus 191(19); P < 0.001 ANOVA], and lower ejection fraction (EF; %) [29(3) versus 53(14)] in HHF-VHD were arrhythmogenic. Mean ventricular tachycardia/triplet frequency/24 h were HHF-VHD 69, HHF-NVHD 39, HHD-VHD 0.3, HHD-NVHD 6, and controls 0.2 (P < 0.02 ANOVA). Compared with 35% (10/27) of all VHD, 15.7% (3/19) of all NVHD participants had nonsustained ventricular tachycardia. The number of regurgitant valves was positively correlated with the frequency of the Lown class of the arrhythmias 0-IVB (r = 0.42, P = 0.003) and to ventricular tachycardia (r = 0.3, P = 0.04) (both n = 46). CONCLUSION: Left ventricular hypertrophy (LVH) increased arrhythmias. But multivalvular regurgitations predisposes to greater SVT and complex ventricular arrhythmias, especially in HHF. Low EF and concentric LVH are correlates.

Left Ventricular Diastolic Function in Nigerian Patients with Essential Hypertension: A Retrospective Study to Compare Angiotensin Converting Enzyme Inhibitors, Calcium Channel Blockade or Their Combination.

BACKGROUND: Hypertension in blacks imposes a greater left ventricular hypertrophy, and accelerated heart failure onset. We evaluated and compared the echocardiographically determined systolic and left ventricular diastolic functional indices in Nigerian hypertensive patients, associated with the chronic use of ACE inhibitors, Calcium channel blockers (CCB) or their combinations. METHODS: Ejection fraction -EF, intraventricular relaxation time (IVRT), E/A peak velocity ratio, E wave deceleration time] as well as the left ventricular mass index (LVMI) was undertaken among 41 Nigerian patients with essential hypertension only, on treatment for 4-6 months prior. The 41 patients (aged 59 +/- 10 years, 40% females) were divided into three groups; those receiving (i) ACE inhibitors; or (ii) CCB or (iii) combination of ACEI and CCB. All the three groups had a background of diuretic treatment for optimal blood pressure control. RESULTS: There were no statistically significant differences in the mean LVMI or sitting blood pressure between treatment groups. E/A ratio for ACEI treatment was 1.06 +/- 0.44, CCB 0.74 +/- 0.19, and for ACEI + CCB 0.87 +/- 0.26 (F = 3.29, P = 0.048 anova). The 95% confidence interval for the E/A ratio on ACEI was 0.8 to 1.33. The A wave duration time integral (AVVTi) were all abnormally large, but showed a significant between treatment group difference (P = 0.037, anova). The values were 21.9 +/- 4.7 for ACEI, 25.3 +/- 6.3 for CCB, and least at 20.1 +/- 3.6 cm for the ACE + CCB combination. Similarly, the IVRT was lowest and <100 ms with ACEI + CCB being 93 +/- 18 ms, ACEI 115 +/- 23 ms, and CCB being 117 +/- 22 ms (F = 4.92, P = 0.01, anova). The 95% CI for IVRT on ACEI + CCB was 82 to 104 ms. There were no between treatment group differences in systolic contractility, (fractional shortening or EF). CONCLUSIONS: The results indicate that use of an antihypertensive drug regime inclusive of an ACE inhibitor (+/-CCB) may be associated with greater salutary effect on indices of diastolic function, (E/A > 1, lower AVVTi, IVRT < 100 ms) even in the presence of an equivalent effect on systolic function and blood pressure.