TargetHunter: an in silico target identification tool for predicting therapeutic potential of small organic molecules based on chemogenomic database.

Target identification of the known bioactive compounds and novel synthetic analogs is a very important research field in medicinal chemistry, biochemistry, and pharmacology. It is also a challenging and costly step towards chemical biology and phenotypic screening. In silico identification of potential biological targets for chemical compounds offers an alternative avenue for the exploration of ligand-target interactions and biochemical mechanisms, as well as for investigation of drug repurposing. Computational target fishing mines biologically annotated chemical databases and then maps compound structures into chemogenomical space in order to predict the biological targets. We summarize the recent advances and applications in computational target fishing, such as chemical similarity searching, data mining/machine learning, panel docking, and the bioactivity spectral analysis for target identification. We then described in detail a new web-based target prediction tool, TargetHunter (http://www.cbligand.org/TargetHunter). This web portal implements a novel in silico target prediction algorithm, the Targets Associated with its MOst SImilar Counterparts, by exploring the largest chemogenomical databases, ChEMBL. Prediction accuracy reached 91.1% from the top 3 guesses on a subset of high-potency compounds from the ChEMBL database, which outperformed a published algorithm, multiple-category models. TargetHunter also features an embedded geography tool, BioassayGeoMap, developed to allow the user easily to search for potential collaborators that can experimentally validate the predicted biological target(s) or off target(s). TargetHunter therefore provides a promising alternative to bridge the knowledge gap between biology and chemistry, and significantly boost the productivity of chemogenomics researchers for in silico drug design and discovery.

Epithelial Na channels and short-term renal response to salt deprivation.

To test the role of epithelial Na channels in the day-to-day regulation of renal Na excretion, rats were infused via osmotic minipumps with the Na channel blocker amiloride at rates that achieved drug concentrations of 2-5 microM in the lumen of the distal nephron. Daily Na excretion rates were unchanged, although amiloride-treated animals tended to excrete more Na in the afternoon and less in the late evening than controls. When the rats were given a low-Na diet, Na excretion rates were elevated in the amiloride-treated group within 4 h and remained higher than controls for at least 48 h. Adrenalectomized animals responded similarly to the low-Na diet. In contrast, rats infused with polythiazide at rates designed to inhibit NaCl transport in the distal tubule were able to conserve Na as well as did the controls. Injection of aldosterone (2 microg/100 g body wt) decreased Na excretion in control animals after a 1-h delay. This effect was largely abolished in amiloride-treated rats. On the basis of quantitative analysis of the results, we conclude that activation of amiloride-sensitive channels by mineralocorticoids accounts for 50-80% of the immediate natriuretic response of the kidney to a reduction in Na intake. Furthermore, the channels are necessary to achieve minimal rates of Na excretion during more chronic Na deprivation.

Familial hypomagnesemia--hypercalciuria and pseudotumor cerebri.

Approximately 30 patients with familial hypomagnesemia-hypercalciuria have been reported. We describe an 8-year-old girl with cardinal findings of familial hypomagnesemia-hypercalciuria (hypomagnesemia, hypermagnesiuria, hypercalciuria, renal insufficiency, hyperuricemia, elevated serum parathormone, hyposthenuria and nephrocalcinosis), who received combination therapy consisting of magnesium salts, thiazide diuretic and potassium supplementation. At the 4-year follow-up investigation under this treatment, the patient was found to have cerebral pseudotumor (increased intracranial pressure with normal or small ventricles on neuroimaging, no evidence of an intracranial mass and normal cerebrospinal fluid composition) with papilledema and visual field defects. Thiazide therapy was terminated and the cerebral pseudotumor disappeared. The authors hypothesize that cerebral pseudotumor in this patient was related to severe hypocalcemia, as a consequence of profound hypomagnesemia induced by protracted thiazide treatment. To our knowledge, this is the first report of a child with familial hypomagnesemia-hypercalciuria who developed pseudotumor cerebri after thiazide therapy.

Characterization of the thiazide-sensitive Na(+)-Cl(-) cotransporter: a new model for ions and diuretics interaction.

The thiazide-sensitive Na(+)-Cl(-) cotransporter (TSC) is the major pathway for salt reabsorption in the apical membrane of the mammalian distal convoluted tubule. When expressed in Xenopus laevis oocytes, rat TSC exhibits high affinity for both cotransported ions, with the Michaelis-Menten constant (K(m)) for Na(+) of 7.6 +/- 1.6 mM and for Cl(-) of 6.3 +/- 1.1 mM, and Hill coefficients for Na(+) and Cl(-) consistent with electroneutrality. The affinities of both Na(+) and Cl(-) were increased by increasing concentration of the counterion. The IC(50) values for thiazides were affected by both extracellular Na(+) and Cl(-). The higher the Na(+) or Cl(-) concentration, the lower the inhibitory effect of thiazides. Finally, rTSC function is affected by extracellular osmolarity. We propose a transport model featuring a random order of binding in which the binding of each ion facilitates the binding of the counterion. Both ion binding sites alter thiazide-mediated inhibition of transport, indicating that the thiazide-binding site is either shared or modified by both Na(+) and Cl(-).

Long-term diuretic therapy in patients with chronic renal failure.

Ten patients with chronic renal failure from different genesis (serum creatinine levels 150-200 mumol/l), were evaluated from the aspect of the effect of the diuretic therapy. The effects of furosemide (FUR) and polythiazide (POL) were assessed after 3-month application. The mean values of the estimated parameters before treatment, after 3-month administration of FUR as a monotherapy and after the next 3 months simultaneously used (FUR + POL), presented a stable increase of the diuresis, without statistically significant changes of the global renal function, and triglyceride disorders. On the contrary, the improvement of calciuria through combined using of furosemide and polythiazide is statistically and clinically significant.

Spectrophotometric study of polythiazide-palladium (II) complex.

A quantitative spectrophotometric method using Pd(II) chloride as analytical reagent for the determination of polythiazide in pharmaceutical preparations is described in this study. It has been found that polythiazide reacts with Pd(II) chloride in the pH range 3.6-5.8, forming a red, water-soluble (1:1) complex with maximum absorbance at 527 nm. At the optimum pH of 4.8 and an ionic strength mu = 0.1 M, the conditional stability constant of the complex is found to be log K' = 4.77. The molar absorptivity at 527 nm is 3.2 x 10(3) l mol-1 cm-1. Good agreement with Beer's law was found for polythiazide concentrations up to 2.2 mmol l-1. The nominal percent recovery of polythiazide was 99.5% (n = 20). The simplicity, selectivity and sensitivity of the method described is suitable for rapid and accurate determinations of polythiazide in tablets.

Prazosin versus captopril as initial therapy. Effect on hypertension and lipid levels.

A randomized, parallel group study evaluated the safety, efficacy, and effect of the alpha blocking agent prazosin and the angiotensin converting enzyme inhibitor captopril on serum lipid levels in patients with mild to moderate hypertension. Baseline evaluations were performed on 31 patients after a four-week placebo washout period. Patients were randomly assigned to receive either prazosin (n = 15) or captopril (n = 16). Daily doses were titrated as follows: for prazosin, 1 mg two times daily to maximum of 20 mg per day; for captopril, 25 mg three times daily to a maximum of 450 mg per day. If diastolic blood pressure was not adequately controlled (less than 85 mm Hg) after four weeks of monotherapy, 1 mg of polythiazide was added to the daily regimen. There were no statistically significant differences between the drug groups for the measured variables in either the parallel or crossover phase of the study. Five of 15 prazosin-treated patients and six of 16 captopril-treated patients required the addition of thiazide to achieve blood pressure control.

Thiazide induced hypotension: the role of plasma volume reduction and the urinary kallikrein system.

The hypotensive response the thiazide diuretics was studied in 15 males with moderate essential hypertension and correlated with serial changes in plasma volume, weight, plasma renin activity, urinary aldosterone, and urinary kallikrein, both total and activity. A greater than 10 mmHg fall in mean arterial pressure after four weeks of treatment defined the responders to therapy (n = 10) while all others were considered non-responders (n = 5). In responders, the fall in mean arterial pressure was accompanied by sustained reduction in plasma volume and weight. No sustained fall in plasma volume was noted in non-responders. Plasma renin activity and urinary aldosterone excretion increased in responders but not in non-responders. Urinary kallikrein, both total and active, increased in the responders but remained unchanged in the non-responders. The results are consistent with the hypothesis that a sustained reduction in plasma volume is necessary for the maintenance of a hypotensive response to thiazides. Stimulation of the renal kallikrein-kinin system may be necessary to balance the antinatriuretic and pressor effects of the renin-angiotensin-aldosterone system. If unopposed, this system would return plasma volume and blood pressure to pretreatment levels.

Depression after treatment with thiazide diuretics for hypertension.

The authors reports eight cases of depression induced by thiazide diuretics prescribed for hypertension and discusses possible mechanisms behind this action. The side effects of thiazide diuretics may be overlooked when they are used with other hypertensives known to cause depression.

Clinical Study on Antihypertensive Effect of Minizide (Prazosin Hydrochloride and Polythiazide)

The antihypertensive effect of Minizide(0.5mg prazosin hydrochloride and 0.25mg polythiazide per tablet)was evaluated in 30 patients with essential hypertension with a dosage of one tablet a day for four weeks. The results were as follows : 1) Of 30 patients treated with Minizide, 21 patients(70.0%) achieved normalization of blood pressure and 5 patients(16.7%) had good response. 2) Mean drop in systolic and diastolic pressure were 29.0mmHg and 15.9mmHg respectively in supine position(P<0.005). 3) Mean drop in systolic and diastolic pressure were 28.5mmHg and 16.2mmhg respectively in sitting position(P<0.005). 4) In 14 patients(46.7%) among 30 patients treated with Minizide adverse reactions developed. The most frequent one was postural dizziness(23.3%). 5) Most adverse reactions were transient and tolerable. However, in three patients(two patients with postural dizziness and one patient with dry mouth) the medication was stopped due to adverse reactions.

Comparative effects of propranolol and prazosin upon serum lipids in thiazide- treated hypertensive patients.

Earlier reported thiazide-induced changes in serum lipid concentrations were confirmed with increased triglyceride and total cholesterol levels. However, lipoprotein cholesterol ratios were unchanged. Propranolol caused further increases in triglyceride and very low-density lipoprotein cholesterol, and lowered high-density lipoprotein cholesterol and the high-density lipoprotein:total cholesterol ratio. With the addition of prazosin to the polythiazide regimen, there was a significant increase in serum high-density lipoprotein cholesterol when compared with the placebo.

Effects of prazosin and propranolol on serum lipids in patients with essential hypertension.

The effects of prazosin and propranolol on total serum cholesterol concentration, low-density lipoprotein and high-density lipoprotein cholesterol fractions, and serum triglyceride concentration were compared in a crossover study in 29 patients with mild to moderate essential hypertension. All patients received polythiazide at a constant dose throughout control and drug treatment periods. Comparable blood pressure reduction was achieved with prazosin (9.3 +/- 7.1 mg per day) and propranolol (183.6 +/- 154.5 mg per day). Prazosin administration was associated with a significant reduction in the concentrations of total serum cholesterol (-5.5 percent), triglyceride (-20.0 percent), and low-density lipoprotein cholesterol (-10.1 percent). High-density lipoprotein cholesterol concentration increased (+8.0 percent) as did the ratio high-density lipoprotein: total cholesterol (+14.1 percent). No significant changes in any of the serum lipid fractions were observed during propranolol administration.

Prazosin as initial antihypertensive therapy: correlates of sympathetic function.

Abnormal sympathetic function has been proposed as a factor in the development of essential hypertension. If this is the case, prazosin hydrochloride, which works by a selective, peripheral, antisympathetic effect--postsynaptic alpha blockade--may have an advantage over other antihypertensive agents. In this study, blood pressure response and measures of sympathetic and baroreflex function were followed in 13 hypertensive patients. Prazosin alone significantly reduced standing and sitting diastolic blood pressures without affecting pulse rates, plasma catecholamines or baroreflex slopes in all patients. The addition of a thiazide diuretic in persons who did not achieve goal blood pressure on prazosin alone was generally successful in reducing blood pressure to desired levels, and increased both plasma renin activity and aldosterone concentrations. No significant relation was apparent between specific characteristics of sympathetic function and response to prazosin as initial therapy, although patients responding tended to have initially higher plasma norepinephrine concentrations.

Comparison of blood pressure, plasma lipid and cardiac performance responses to prazosin versus propranolol in thiazide-treated hypertensive patients.

Twenty-seven patients with uncontrolled hypertension (diastolic blood pressure greater than or equal to 95 mm Hg) receiving thiazide diuretics were treated with the addition of either propranolol (n = 10) or prazosin (n = 17). Nine patients were successfully controlled with propranolol and 12 with prazosin. Six patients required both study drugs for optimal blood pressure control, 5 of whom had received prazosin as the initial study drug. Changes in serum lipid components and cardiac performances with the addition of the study drugs were monitored. A decrease in total cholesterol and an increase in high-density lipoprotein (HDL) cholesterol were seen when prazosin was added, and an increase in total cholesterol and a decrease in HDL cholesterol occurred after the addition of propranolol. Although in this small group of patients these changes did not reach statistical significance, they were similar to changes described in other studies in which these drugs were used as monotherapy for hypertension. The only lipid change of statistical significance was a small increase in the serum triglyceride concentration in patients receiving propranolol. The findings for total cholesterol and its fractions suggest that the effects of the study drugs may not be additive to those of thiazides and that thiazides had already effected a maximal lipid response. Both agents in combination with a thiazide diuretic were equally effective in decreasing diastolic blood pressure to the goal of less than or equal to 85 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of prazosin versus nadolol in combination with a diuretic.

The comparative efficacy and effects on total body potassium of prazosin and polythiazide vs nadolol and polythiazide in the treatment of patients with mild to moderate essential hypertension unresponsive to diuretic alone were compared in an open, crossover trial involving 20 male patients. Both prazosin and nadolol reduced blood pressure to goal values in both study phases. Side effects were minor, and only 1 patient dropped out of treatment for reasons unrelated to the study drugs. Neither prazosin nor nadolol in combination with thiazide had significant additional adverse effects on total body potassium. These findings confirm that the efficacy of prazosin is equivalent to that of nadolol in the long-term management of patients with essential hypertension.

A double-blind study of trimazosin and methyldopa in hypertensive patients receiving polythiazide.

Data are presented on 22 hypertensive patients in an 18-week, double-blind comparison of trimazosin and methyldopa during which treatment with polythiazide was continued. Maximum daily doses of trimazosin and methyldopa were 800 and 2000 mg, respectively. Eight of nine patients receiving trimazosin and 8 of 12 receiving methyldopa had excellent or good overall responses. (One trimazosin patient was not evaluated for overall response.) Quantitative criteria of blood pressure response indicated that trimazosin was as effective as methyldopa. There were no clinically significant changes in results of Holter monitor recordings, ECGs, chest x-ray films, cardiopulmonary tests, or ophthalmoscopy. There were no abnormalities in laboratory tests of trimazosin patients. One patient receiving methyldopa had a positive Coombs' test. Significant side effects developed in two methyldopa patients-syncope in one patient and postural hypotension in the other. No significant side effects occurred in the patients taking trimazosin.

Double-blind comparison of trimazosin and propranolol in essential hypertension.

This report describes a double-blind, parallel, comparative study of trimazosin (+/- polythiazide) and propranolol (+/- polythiazide) in 130 patients with essential hypertension. Both treatment regimens were shown to be effective in achieving statistically significant sustained reduction in blood pressure. Propranolol alone was somewhat more effective, at the doses selected, than trimazosin alone, but the hypertension of nonresponders in each treatment group was effectively controlled by the addition of low doses of polythiazide. Trimazosin had no effect on heart rate, whereas propranolol significantly lowered resting heart rates, which was occasionally troublesome. Side effects were less frequent in the trimazosin-treated group. Trimazosin lowered serum creatinine and blood urea nitrogen, an effect significantly different from that of propranolol. There was also a tendency for serum uric acid to rise in patients receiving propranolol and fall in those receiving trimazosin; polythiazide significantly raised uric acid levels. The effects of trimazosin and propranolol on the lipid profile were small, but the difference between the increase in the high-density lipoprotein-cholesterol fraction in trimazosin-treated patients and the decrease in propranolol-treated patients was significant and thought to be of interest.

Effect of trimazosin on serum lipid profiles in hypertensive patients.

Abnormalities in the serum lipid profile correlate strongly with the presence and severity of atherosclerosis. Increases in serum lipids and a reduction in high-density lipoprotein (HDL) cholesterol have been demonstrated following treatment with some beta blockers and diuretics, either alone or in combination. A new alpha-1-adrenoceptor antagonist, trimazosin, was studied to determine its effects on serum lipids. Ninety-six hypertensive patients were randomly assigned in double-blind fashion to trimazosin or placebo for 8 weeks. Trimazosin was associated with a significant reduction (p less than or equal to 0.01) in total cholesterol when compared with the placebo group. This effect was seen in all patients regardless of whether or not they were taking a diuretic concomitantly. In addition, a 9-month, double-blind parallel comparison was made of trimazosin and propranolol. Trimazosin was found to be superior to propranolol in its effect on HDL cholesterol and the HDL/total cholesterol ratio. These studies have demonstrated that, in contrast to placebo and propranolol, trimazosin lowers total serum cholesterol without undesirable effects on other serum lipid fractions. When polythiazide is given concomitantly, it diminishes the favorable effects of trimazosin and accentuates the opposite, adverse effects of propranolol.