Anti-babesial activity of a series of 6,7-dimethoxyquinazoline-2,4-diamines (DMQDAs).

Diminazene aceturate (DA), imidocarb dipropionate (ID), atovaquone (ATO), azithromycin (AZI), clindamycin, and quinine have been used to treat animal and human babesiosis for many years, despite their negative effects and rising indications of resistance. Thus, finding anti-babesial compounds that can either treat the infection or lower the dose of drugs given has been a primary objective. Quinazolines are one of the most important nitrogen heterocycles, with a wide range of pharmacological activities including analgesic, anti-inflammatory, sedative-hypnotic, anti-histaminic, anti-cancer, and anti-protozoan properties. The present study investigated the anti-babesial activities of twenty 6,7-dimethoxyquinazoline-2,4-diamines on Babesia spp. One candidate, 6,7-dimethoxy-N4-ethylisopropyl-N2-ethyl(pyridin-4-yl)quinazoline-2,4-diamine (SHG02), showed potent inhibition on Babesia gibsoni in vitro, as well as on B. microti and B. rodhaini in mice. Our findings indicate that the candidate compound SHG02 is promising for further development of anti-babesial drugs and provides a new structure to be explored for developing anti-Babesia therapeutics.

Quest for a potent antimalarial drug lead: Synthesis and evaluation of 6,7-dimethoxyquinazoline-2,4-diamines.

Quinazolines have long been known to exert varied pharmacologic activities that make them suitable for use in treating hypertension, viral infections, tumors, and malaria. Since 2014, we have synthesized approximately 150 different 6,7-dimethoxyquinazoline-2,4-diamines and evaluated their antimalarial activity via structure-activity relationship studies. Here, we summarize the results and report the discovery of 6,7-dimethoxy-N4-(1-phenylethyl)-2-(pyrrolidin-1-yl)quinazolin-4-amine (20, SSJ-717), which exhibits high antimalarial activity as a promising antimalarial drug lead.

Kidney-protective effects of azelnidipine versus a diuretic in combination with olmesartan in hypertensive patients with diabetes and albuminuria: a randomized study.

BACKGROUND: A thiazide diuretic used in combination with benazepril is superior to amlodipine plus benazepril in reducing albuminuria in hypertensive patients with diabetes. However, calcium channel blockers have diverse characteristics. Thus, we investigated whether combining an angiotensin receptor blocker with either azelnidipine or a thiazide diuretic produced similar reductions in albuminuria in hypertensive diabetic patients for the same levels of blood pressure achieved. METHODS: Hypertensive patients with type 2 diabetes and albuminuria (30-600 mg/g creatinine) under antihypertensive treatment (mean age 67.0±7.6 years) were instructed to stop all antihypertensive treatment and take a combination of olmesartan (20 mg/day) and amlodipine (5 mg/day) for 3 months (run-in period). Then, patients were randomly assigned to receive either olmesartan plus azelnidipine (16 mg/day; n=71) or olmesartan plus trichlormethiazide (1 mg/day; n=72) for an additional 6 months. The primary end point was urinary excretion of albumin at 6 months after randomization. RESULTS: At the time of randomization, urinary albumin was 116.0 and 107.8 mg/g creatinine (geometric mean) in the azelnidipine and diuretic arms, respectively, and was reduced to a similar extent [79.8 (95% confidence interval 66.4-96.0) and 89.7 (74.6-107.7) mg/g creatinine, respectively, after adjustment for baseline values]. Blood pressure did not differ between the two groups throughout the study period. CONCLUSIONS: Azelnidipine is equally effective as a thiazide diuretic in reducing urinary albumin when used in combination with olmesartan.

Titration of telmisartan, but not addition of amlodipine, reduces urine albumin in diabetic patients treated with telmisartan-diuretic.

OBJECTIVES: Microalbuminuria is closely associated with an increased risk of renal and cardiovascular adverse outcomes. The present study tested the hypothesis that titration of telmisartan reduces urinary excretion of albumin more than does addition of amlodipine in patients treated with a standard dose of telmisartan combined with a low-dose diuretic for the same degree of blood pressure (BP) reduction. METHODS: Hypertensive patients with type 2 diabetes mellitus and microalbuminuria under treatment with a combination of a standard dose of telmisartan (40 mg/day) and trichlormethiazide (1 mg/day) were randomly assigned to receive either an increased dose of telmisartan (80 mg/day) combined with trichlormethiazide [increased dose angiotensin receptor blocker (ARB) group, n = 20] or a combination consisting of telmisartan (40 mg/day), trichlormethiazide, and amlodipine (5 mg/day) (triple combination group, n = 20) for 6 months. The primary endpoint was a reduction in urinary albumin levels. RESULTS: Although BP was reduced to a similar extent by the two regimens, patients receiving the increased dose ARB showed a higher reduction in urinary albumin (-37.4 ±â€Š16.9%) than those on the triple combination regimen (-8.9 ±â€Š23.7%; P < 0.0001). The reduction in urinary albumin was correlated with the drop in BP in the latter group, but not in the increased dose ARB group. CONCLUSION: Uptitration of telmisartan more effectively reduces urinary albumin than addition of amlodipine in hypertensive patients with diabetes treated with a combination of telmisartan and diuretic for the same degree of BP reduction.

Antioxidative effects of thiazide diuretics in refractory hypertensive patients. A randomized crossover trial of chlortalidone and trichlormethiazide.

Some thiazide diuretics seem to exert antioxidant effects, which may be beneficial in the management of hypertension. Although many large-scale clinical trials on hypertension have proved that thiazide diuretics confer significant reductions in stroke and cardiovascular events, most of these trials preferentially used chlortalidone. Therefore, the difference in antioxidant effects between chlortalidone (CAS 77-36-1; 12.5 mg/day) and another thiazide diuretic, trichlormethiazide (CAS 133-67-5; 1 mg/day) was studied. Forty patients with refractory hypertension even after treatment with a combination of a calcium channel blocker and an angiotensin II receptor blocker were randomly assigned to additionally receive either chlortalidone or trichlormethiazide for 6 months. Then, diuretics were switched in each patient and they were treated for another 6 months. Ambulatory blood pressure was monitored for 24 h and markers of inflammation (C-reactive protein) and oxidative stress (8-isoprostane, malondialdehyde-modified low-density lipoproteins) were measured before and after each treatment. Addition of chlortalidone resulted in a greater reduction of blood pressure (mean of 24 h; from 146.8 +/- 18.0/83.8 +/- 12.2 mmHg to 122 +/- 18/72 +/- 11 mmHg) than that of trichlormethiazide (134 +/- 18/ 78 +/- 11 mmHg, p < 0.001). The levels of C-reactive protein, malondialdehyde-modified low-density lipoproteins, and 8-isoprostane were lower after chlortalidone therapy than after trichlormethiazide therapy. These results suggest that chlortalidone is superior to trichlormethiazide in patients with essential hypertension.

Crucial role of kidney function in resistance to antihypertensive therapy in patients with diabetes mellitus.

OBJECTIVES: Effective blood pressure (BP) control is difficult to achieve in diabetic patients. This study investigated factors that exacerbate resistance to antihypertensive medication in patients with diabetes. METHODS: Hypertensive patients with type 2 diabetes (n = 108, 67 ± 9 years) were subjected to a step-wise upward titration of medication (step 1, routine dose of angiotensin receptor blocker; step 2, routine doses of angiotensin receptor blocker and calcium channel blocker; step 3, step 1 + double dose of calcium channel blocker; step 4, double doses of angiotensin receptor blocker and calcium channel blocker; step 5, step 4 + routine dose of diuretic; step 6, step 5 + routine dose of ß-blocker; step 7, step 6 + routine dose of α-blocker; step 8, step 6 + double dose of α-blocker) implemented with a target home BP of below 130/80 mmHg. The step number at which target BP was achieved was considered the amount of antihypertensive medications needed for BP control. RESULTS: All patients reached the target BP at step 4.0 ± 1.5. Multivariate regression analysis identified estimated glomerular filtration rate, but not measures of glycemic control, as an independent predictor of the number of drugs needed for BP control (P < 0.0001). CONCLUSION: The number of antihypertensive medications needed for BP control in patients with diabetes mellitus is largely dependent on estimated glomerular filtration rate. Impaired kidney function could produce resistance to antihypertensive therapy in diabetic patients.

Carvedilol reduces elevated B-type natriuretic peptide in dialyzed patients without heart failure: cardioprotective effect of the beta-blocker.

Elevated plasma B-type natriuretic peptide (BNP) predicts future cardiovascular events in dialyzed patients without heart failure. We investigated whether carvedilol reduces the elevated BNP in these patients. Asymptomatic patients on chronic hemodialysis with elevated BNP but without clinical signs of heart failure were randomly assigned to receive either carvedilol (n = 10) or nothing (control group, n = 10). BNP and malondialdehyde-low density lipoprotein (MDA-LDL) were measured, and ultrasound cardiography was performed at baseline and at 3 months. Carvedilol reduced the concentrations of BNP (551 +/- 90 to 237 +/- 174 ng/L, P < 0.01) and MDA-LDL (174 +/- 63 to 85 +/- 23 U/L, P < 0.01) and increased the velocity ratio of E to A waves of the transmitral flow (E/A: 0.59 +/- 0.04 to 0.71 +/- 0.05, P < 0.05), while no such alterations were observed in the control group. The reduction in BNP concentration was correlated with that in MAD-LDL and the increase in the E/A. There was a significant correlation between the increase in the E/A and the reduction in MDA-LDL concentration. Thus, carvedilol reduces the elevated BNP by improving left ventricular diastolic function in dialyzed patients without heart failure, which may be attributable to the antioxidant property of the beta-blocker. Administering carvedilol may improve the prognosis in this population.

Increased oxidative stress impairs endothelial modulation of contractions in arteries from spontaneously hypertensive rats.

OBJECTIVES: The endothelium modulates vascular contractions. We investigated the effects of oxidative stress on endothelial modulation of contractions in hypertension. METHODS: Changes in isometric tension of femoral arterial rings from spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats were recorded. RESULTS: The contractile response to norepinephrine of arteries with endothelium was greater in SHR than in WKY rats (P < 0.0001). Endothelium removal augmented the norepinephrine-induced contraction (P < 0.05). The augmentation was more pronounced in WKY than in SHR, which resulted in comparable contraction of arteries without endothelium in both strains. Nomega-nitro-L-arginine methyl ester (100 micromol/l) mimicked the effect of endothelium removal. Production of nitric oxide (NO, assessed by measuring nitrite/nitrate concentrations) during the contraction was not different between SHR and WKY. Vitamin C suppressed the contraction of arteries with endothelium from SHR but not from WKY (P < 0.05). Diphenyleneiodonium and apocynin, inhibitors of nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase, attenuated the contraction of arteries with endothelium from SHR (P < 0.001) but not WKY, but did not affect contractions induced by serotonin. Superoxide generated by xanthine oxidase/hypoxanthine enhanced the norepinephrine-induced contraction of arteries with endothelium from WKY (P < 0.0001), and this effect was reversed by vitamin C. CONCLUSIONS: In rat femoral arteries, NO released from the endothelium modulates vascular contraction. In SHR, production of superoxide by NADH/NADPH oxidase, which may be activated by norepinephrine, is enhanced, resulting in the inactivation of NO and impairment of endothelial modulation of vascular contractions. Vascular oxidative stress may contribute to the altered circulation in hypertension by impairing endothelial modulation of vascular contractions.

Effects of ascorbic acid on ambulatory blood pressure in elderly patients with refractory hypertension.

The increased production of reactive oxygen species plays a role in the etiology of hypertension, but the effects of antioxidants on blood pressure are controversial. However, antioxidants possibly lower blood pressure in elderly patients with hypertension, because vascular aging is also closely related to oxidative stress. Effects of chronic treatment with ascorbic acid (CAS 50-81-7; 600 mg/day for 6 months) on blood pressure and levels of C-reactive protein, 8-isoprostane, and malondialdehyde-modified low-density lipoproteins were examined in elderly patients (n = 12, six males/six females, age 78.3 +/- 5.0 years, mean +/- SD [range, 67 to 84 years]; elderly group) and adult patients (n = 12, five males/seven females, age 54.6 +/- 6.7 years [range, 39 to 621; adult group) with refractory hypertension. Chronic treatment with ascorbic acid markedly reduced systolic blood pressure and pulse pressure in ambulatory blood pressure monitoring in the elderly group (from 154.9 +/- 21.6 to 134.8 +/- 19.7 mmHg, p < 0.001; and from 79.1 +/- 22.1 to 63.4 +/- 18.7, p < 0.05; respectively), which was accompanied by an increase in the serum levels of ascorbic acid and decreases in the levels of C-reactive protein, 8-isoprostane, and malondialdehyde-modified low-density lipoproteins. In contrast, ascorbic acid did not affect blood pressure in the adult group. These results suggest that ascorbic acid is useful for controlling blood pressure in elderly patients with refractory hypertension.

Antihypertensive effects of long-acting calcium channel blockers on hemodialysis days--a randomized crossover trial between benidipine and nifedipine CR.

BACKGROUND/AIMS: Since antihypertensive effects of most calcium channel blockers largely depend on their plasma concentrations, a rapid increase in blood pressure may occur as circulating levels of such blockers decrease after hemodialysis. Thus, the effects of benidipine and nifedipine CR (extended-release coated tablets, Adalat CR), which are long-acting calcium channel blockers, on post-hemodialytic blood pressures were investigated. METHODS: A randomized crossover trial was carried out with 10 hypertensive patients on chronic maintenance hemodialysis. Patients were assigned to receive benidipine (4-8 mg/day) or nifedipine CR (20-40 mg/day), and after 4 weeks, 24-hour ambulatory blood pressure monitoring was performed on the day of hemodialysis and blood samples were obtained before and after hemodialysis to measure plasma concentrations of the blockers. The calcium channel blockers were then exchanged in each patient and the same protocol was repeated. RESULTS: The pattern of fluctuation of blood pressure differed markedly between the treatment with benidipine and nifedipine CR. Under treatment with nifedipine CR, rapid increase in blood pressure was observed after hemodialysis, while blood pressure remained at favorable levels with benidipine. Plasma concentrations of the blockers were significantly decreased by hemodialysis. CONCLUSION: Benidipine exerts more sustained antihypertensive effects than expected from its disposition in plasma. The stable depressor effects of benidipine even after hemodialysis may contribute to favorable control of blood pressure in this population.