Ergosterone-coupled Triazol molecules trigger mitochondrial dysfunction, oxidative stress, and acidocalcisomal Ca2+ release in Leishmania mexicana promastigotes.

The protozoan parasite Leishmania causes a variety of sicknesses with different clinical manifestations known as leishmaniasis. The chemotherapy currently in use is not adequate because of their side effects, resistance occurrence, and recurrences. Investigations looking for new targets or new active molecules focus mainly on the disruption of parasite specific pathways. In this sense, ergosterol biosynthesis is one of the most attractive because it does not occur in mammals. Here, we report the synthesis of ergosterone coupled molecules and the characterization of their biological activity on Leishmania mexicana promastigotes. Molecule synthesis involved three steps: ergosterone formation using Jones oxidation, synthesis of Girard reagents, and coupling reaction. All compounds were obtained in good yield and high purity. Results show that ergosterone-triazol molecules (Erg-GTr and Erg-GTr2) exhibit an antiproliferative effect in low micromolar range with a selectivity index ~10 when compared to human dermic fibroblasts. Addition of Erg-GTr or Erg-GTr2 to parasites led to a rapid [Ca2+]cyt increase and acidocalcisomes alkalinization, indicating that Ca2+ was released from this organelle. Evaluation of cell death markers revealed some apoptosis-like indicators, as phosphatidylserine exposure, DNA damage, and cytosolic vacuolization and autophagy exacerbation. Furthermore, mitochondrion hyperpolarization and superoxide production increase were detected already 6 hours after drug addition, denoting that oxidative stress is implicated in triggering the observed phenotype. Taken together our results indicate that ergosterone-triazol coupled molecules induce a regulated cell death process in the parasite and may represent starting point molecules in the search of new chemotherapeutic agents to combat leishmaniasis.

[Nifedipine in the treatment of moderate and severe arterial hypertension. Long-term effect on arterial pressure and on the left ventricle]. / Tratamiento de la hipertensión arterial moderada y severa con nifedipino de liberación osmótica. Efectos a largo plazo sobre la presión arterial y la masa ventricular izquierda.

INTRODUCTION AND OBJECTIVES: Moderate-to-severe hypertension is less prevalent than mild hypertension, but it is responsible for more incidences of complications. Its complex treatment requires several drugs, and is often inadequate. This study assessed the efficacy and safety of nifedipine GITS (oral release osmotic system) as monotherapy, in addition to the effects on left ventricular hypertrophy, after a long term follow-up (one year). PATIENTS AND METHODS: Thirty patients with diastolic blood pressure above 105 mmHg were studied after a short placebo phase. They received nifedipine GITS as monotherapy in a single daily dose of 30 mg; dose titration was made the first three months according to response and until they reached figures equal to or below 95 mmHg. By M-Mode echocardiogram, left ventricular mass index and systolic function were calculated at the end of the placebo phase and at 3, 6, 9 and 12 months. Hematological parameters, lipid profile, electrolytes and liver enzymes were assessed at the same periods. RESULTS: In 70% of the patients the blood pressure reached values of 140-90 mmHg. In 16 patients with adequate M-mode recordings, a 12% reduction in left ventricular mass was observed without modification in systolic function. Five patients were retired: two due to adverse events and three due to different reasons (drop out, evidence for secondary hypertension). There were no changes of clinical significance in the hematological or biochemical parameters and no hypertensive crisis occurred. CONCLUSION: The monotherapy with nifedipine GITS was effective in reducing high blood pressure, induced regression in ventricular hypertrophy and showed good tolerance in one year follow-up.

[Increase of renal dopamine production induced by nifedipine in hypertensive patients. Double blind vs placebo study]. / Aumento de la producción de dopamina renal por nifedipina en pacientes hipertensos. Estudio a doble ciego vs. placebo.

Dopamine is synthetized and excreted by kidneys, this amine exerts its natriuretic and diuretic effects by inhibition of sodium reabsorption on kidney convoluted tubules. The objective of this study was to verify the changes of dopamine urinary excretion induced by nifedipine-LP treatment in hypertensive patients. Twenty four patients with essential hypertension (stages 1, 2) were included in this double-blind, placebo controlled study. Twelve patients received nifedipine (average daily dose, 21.5 mg/day) for 4 weeks, and 12 patients received placebo for the same time period. No significant changes were detected upon nifedipine treatment neither in plasma biochemical nor hematological parameters. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) was significantly reduced from pretreatment values 168.0 +/- 8.7 mmHg and 102.0 +/- 5.2 mmHg respectively, to end-treatment values 140.0 +/- 6.6 mmHg and 88.0 +/- 5.6 mmHg (p < 0.05). Placebo treatment did not modify SBP and DBP. Urinary dopamine excretion increased by 53% from 679.5 +/- 80.1 micrograms/24 h prior to treatment to 1040.0 +/- 110.1 micrograms/24 h after treatment (p < 0.009. 95% Confidence Interval of the Difference: -538.9 to -183.6). Urinary volume of nifedipine treated patients increased from 1613 +/- 85 mL/24 h to 1920 +/- 160 mL/24 h post-treatment (p < 0.05). No significant changes were observed in urinary noradrenaline and adrenaline excretion in nifedipine or placebo treated patients. Analysis of fluorescent light excitation and emission spectra (200 nm to 800 nm) of dopamine extracted from patient's urine submitted to nifedipine treatment did not reveal any interference when compared to chemically pure dopamine. If is concluded that nifedipine treatment of hypertensive patients increases kidney dopamine production which in turn can exert a natriuretic and diuretic effect besides its well known vasodilator properties.

Effects of nitrendipine on glucose tolerance and serum insulin and dehydroepiandrosterone sulfate levels in insulin-resistant obese and hypertensive men.

To determine whether the calcium channel blocker nitrendipine improves glucose tolerance, lowers circulating insulin, and raises serum dehydroepiandrosterone sulfate (DHEA-S) levels in insulin-resistant men, a total of 15 obese and hypertensive men were enrolled in a single blind, placebo-controlled study. A nitrendipine group (n = 8) and a placebo group (n = 7) were studied before and after treatment with either nitrendipine (10 mg) or a placebo capsule, twice daily for 7 days, by determining serum insulin, glucose, and DHEA-S levels in the fasting state and during an oral glucose tolerance test. Nitrendipine treatment 1) lowered fasting serum insulin from 265 +/- 24 to 194 +/- 22 pmol/L (P < 0.01) without changing fasting serum glucose, 2) reduced both the area under the curve for glucose (from 1246 +/- 31 to 1091 +/- 26 mmol/L.min; P < 0.005) and the area under the curve for insulin (from 123.6 +/- 9.4 to 82.9 +/- 10.0 nmol/L.min; P < 0.015) during the oral glucose tolerance test, and 3) increased fasting serum DHEA-S by 63% from 4.21 +/- 0.17 to 6.84 +/- 0.21 mumol/L (P = 0.0001). No change was noted in the placebo group. We conclude that nitrendipine treatment is associated with improved glucose tolerance, reduced fasting and glucose-stimulated serum insulin levels, and increased circulating DHEA-S levels.

[Arterial hypertension in the adolescent: its possible relation to the salt taste threshold]. / Hipertensión arterial del adolescente: relación posible con el umbral de sal al gusto.

The purpose of the study was to define the relationship between the salt intake and the levels of arterial blood pressure in adolescent people. Seventy-eight youngs between 12 and 18 years old with diastolic/systolic blood pressure above 95 percentile formed the hypertensive group; a similar population with the same characteristic (age, sex, race, weight and height) with normal blood pressure were selected as a control group. The salt taste threshold was carried out through tasting a saline solution in different concentrations, till it could be distinguished as salted. Moreover, 45 hypertensive adolescent were follow-up for 12 weeks under a hiposodic diet and consequently a new salt taste threshold was done. The results showed that the control group had a salt perception under 80 mg %, instead the hypertensive group showed a higher threshold (above 160 mg %). Those hypertensive adolescent which were followed for 12 weeks changed its pattern in this way: in 24, a lesser perception was observed with a reduction in their blood pressure in 11 of them. These findings suggest that hypertensive adolescent had an elevated threshold for salt, usually above 160 mg % and the test should be helpful for the identification of a subgroup "salt-sensible".

Successful pregnancy in a severe hypertensive patient treated with nitrendipine. Case report.

Nitrendipine (NIT), a new potent calcium channel blocking agent, was administered to a patient with essential severe (191/119 mm Hg), refractory, and resistant hypertension (HT) to conventional triple drug regime. Three previous pregnancies had been unsuccessful in the past 4 years because of uncontrollable HT and repeated hypertensive crises. NIT (20 mg tablets) was given PO as a single morning dose and 15 months after BP control, she became pregnant again. With a 20 mg/day dose of NIT throughout pregnancy, a healthy 2400 g, 47 cm male boy was delivered by a non-emergency cesarean section at 37 weeks' pregnancy. Both mother and son remain normal months after birth. The results suggest NIT may be considered as an alternative for this type of patients and should be studied in clinical trials.

Nitrendipine and atenolol in essential hypertension in young and middle-aged patients: effect on serum lipids and left ventricular mass.

This study was designed to compare the antihypertensive efficacy of nitrendipine and atenolol in young and middle-aged patients with mild or moderate essential hypertension and to assess treatment effects on plasma lipids and potential changes in left ventricular mass (LVM). After 2 weeks off medication and a 4-week placebo phase, patients who met the inclusion criteria [sitting diastolic blood pressure (DBP) 95 to 114 mm Hg, age below 50 years] entered a 12-week dose-adjustment and maintenance period with nitrendipine or atenolol. Serum lipids were determined before and after therapy. At the same time, LVM was evaluated echocardiographically (M mode). Twenty-two patients completed the double-blind, randomized study. After 12 weeks on nitrendipine, the systolic blood pressure (SBP) and DBP were reduced (p less than 0.005 and p less than 0.001, respectively). No significant changes in heart rate were observed. There were no changes in the lipid profile, and LVM was reduced from 93.7 to 23.4 to 82.4 +/- 22.6 g/m2 of body surface (p less than 0.05). On atenolol the SBP and DBP were reduced (p less than 0.001 and p less than 0.001, respectively). The expected reduction in heart rate was significant (p less than 0.05). Total cholesterol and LDL cholesterol increased by 11% (p less than 0.05) and 12.3% (p less than 0.01), respectively. HDL cholesterol showed a small reduction. Tryglycerides increased by 22% (n.s.). LVM did not change. In conclusion, nitrendipine and atenolol showed comparable antihypertensive efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term (3 years) sustained antihypertensive and metabolic actions of nitrendipine in severe, complicated, and resistant hypertension.

The antihypertensive efficacy of once-daily nitrendipine was studied in 18 patients with severe, resistant, refractory, and complicated hypertension. The dose range was 20-120 mg/day adjusted weekly for a total treatment period of 3 years. Nitrendipine produced a significant reduction in blood pressure compared to pretreatment baseline values with no significant effects on heart rate. Renal function was preserved and there was an increase in urine flow, urinary excretions of Na+, kallikrein, and prostaglandin E2, and plasma renin. Some patients experienced known calcium antagonist side effects but the drug was otherwise well tolerated.