Metabolomics, lipidomics and proteomics profiling of myoblasts infected with Trypanosoma cruzi after treatment with different drugs against Chagas disease.

INTRODUCTION: Chagas disease, the most important parasitic infection in Latin America, is caused by the intracellular protozoan Trypanosoma cruzi. To treat this disease, only two nitroheterocyclic compounds with toxic side effects exist and frequent treatment failures are reported. Hence there is an urgent need to develop new drugs. Recently, metabolomics has become an efficient and cost-effective strategy for dissecting drug mode of action, which has been applied to bacteria as well as parasites, such as different Trypanosome species and forms. OBJECTIVES: We assessed if the metabolomics approach can be applied to study drug action of the intracellular amastigote form of T. cruzi in a parasite-host cell system. METHODS: We applied a metabolic fingerprinting approach (DI-MS and NMR) to evaluate metabolic changes induced by six different (candidate) drugs in a parasite-host cell system. In a second part of our study, we analyzed the impact of two drugs on polar metabolites, lipid and proteins to evaluate if affected pathways can be identified. RESULTS: Metabolic signatures, obtained by the fingerprinting approach, resulted in three different clusters. Two can be explained by already known of mode actions, whereas the three experimental drugs formed a separate cluster. Significant changes induced by drug action were observed in all the three metabolic fractions (polar metabolites, lipids and proteins). We identified a general impact on the TCA cycle, but no specific pathways could be attributed to drug action, which might be caused by a high percentage of common metabolome between a eukaryotic host cell and a eukaryotic parasite. Additionally, ion suppression effects due to differences in abundance between host cells and parasites may have occurred. CONCLUSION: We validated the metabolic fingerprinting approach to a complex host-cell parasite system. This technique can potentially be applied in the early stage of drug discovery and could help to prioritize early leads or reconfirmed hits for further development.

The effect of the fast of Ramadan on ambulatory blood pressure in treated hypertensives.

Every year, millions of Moslems throughout the world fast from sunrise till sunset daily during the month of Ramadan, that is, experience repeated cycles of fasting-refeeding. Studies in animal models have shown that repeated cycles of fasting-refeeding may cause or exacerbate hypertension. Changes in sleeping patterns as well as changes in medication timing may also influence ambulatory blood pressure. We undertook this study in order to examine the effect of the Ramadan fast on treated hypertensive subjects. Seventeen hypertensive subjects were examined, and 24-h blood pressure monitoring was carried out twice, before and during the last week of the Ramadan. All continued their medications, which were all once-daily preparations. Twenty-four hour mean blood pressure as well as average awake and average asleep blood pressure were compared. There was no difference between mean blood pressure before and during the Ramadan (138.5 +/- 18.5/77.2 +/- 8.1 mm Hg vs 136.4 +/- 20.4/75.7 +/- 5.9 mm Hg, P-nonsignificant). Blood pressure load also did not differ before and during Ramadan (systolic load 49% vs. 44%, diastolic load 21% vs. 18%, P-nonsignificant). Weight was reduced by 1.4 +/- 1.6 kg (P < 0.002). We conclude, that according to our findings, treated, hypertensive patients may be assured that, with continuation of previous medications, traditional fasting during the month of Ramadan can be safely undertaken.

Sepsis: estudio comparativo en el tratamiento de las alteraciones de coagulación con concentrados de Antitrombina III o Heparina / Sepsis: Antitrombin III or Heparine therapy in disseminated intravascular coagulation, comparative study

Se efectuó el estudio en 48 pacientes con diagnóstico de sepsis, el mismo se hizo en todos los casos por el cuadro clínico y la confirmación bacteriológica, con aislamiento del germen por hemocultivo o cultivo de otras localizaciones. Se dividieron los pacientes en dos grupos distribuidos al azar, 24 pacientes fueron tratados con concentrados de AT III a las dosis de 1000 unidades cada 12 hs en infusión endovenosa durante 30 minutos, durante las primeras 48 hs. 24 recibieron heparina, 150 unidades por Kg por día en perfusión contínua durante 2 días, en el grupo con heparina si el paciente no mejoraba se mantenía la terapéutica más tiempo y si aparecían manifestaciones trombóticas (trombosis venosa profunda o tromboembolismo de pulmón) se aumentó la dosis a 500 unidades por Kg por día. A los pacientes se les efectuaron los siguientes controles de coagulación a las 0, 12, 24 y 48 hs: Tiempo de Quick, KPTT, Tiempo de Trombina, prueba de sulfato de protamina, recuento de plaquetas, determinación del factor II, V, VII-X y VIII, Pdf, D-Dimero, fibrógeno y AT III. Durante 7 días se siguió la evolución de los pacientes observando las complicaciones trombóticas, hemorrágicas y la mortalidad. En los resultados se pudo observar una mejoría en el grupo tratado con AT III en todos los parámetros de coagulación estudiados (P < 0,01), reducción de las hemorragias, trombosis y mortalidad, en este último caso cabe destacar que en el grupo tratado con AT III hubo 3 muertos contra 6 del grupo tratado con heparina, a pesar de ser el doble no es estadísticamente significativo, pero de aumentar el número de casos y mantenerse igual la proporción si llegaría a serlo

Sepsis: estudio comparativo en el tratamiento de las alteraciones de coagulación con concentrados de Antitrombina III o Heparina / Sepsis: Antitrombin III or Heparine therapy in disseminated intravascular coagulation, comparative study

Se efectuó el estudio en 48 pacientes con diagnóstico de sepsis, el mismo se hizo en todos los casos por el cuadro clínico y la confirmación bacteriológica, con aislamiento del germen por hemocultivo o cultivo de otras localizaciones. Se dividieron los pacientes en dos grupos distribuidos al azar, 24 pacientes fueron tratados con concentrados de AT III a las dosis de 1000 unidades cada 12 hs en infusión endovenosa durante 30 minutos, durante las primeras 48 hs. 24 recibieron heparina, 150 unidades por Kg por día en perfusión contínua durante 2 días, en el grupo con heparina si el paciente no mejoraba se mantenía la terapéutica más tiempo y si aparecían manifestaciones trombóticas (trombosis venosa profunda o tromboembolismo de pulmón) se aumentó la dosis a 500 unidades por Kg por día. A los pacientes se les efectuaron los siguientes controles de coagulación a las 0, 12, 24 y 48 hs: Tiempo de Quick, KPTT, Tiempo de Trombina, prueba de sulfato de protamina, recuento de plaquetas, determinación del factor II, V, VII-X y VIII, Pdf, D-Dimero, fibrógeno y AT III. Durante 7 días se siguió la evolución de los pacientes observando las complicaciones trombóticas, hemorrágicas y la mortalidad. En los resultados se pudo observar una mejoría en el grupo tratado con AT III en todos los parámetros de coagulación estudiados (P < 0,01), reducción de las hemorragias, trombosis y mortalidad, en este último caso cabe destacar que en el grupo tratado con AT III hubo 3 muertos contra 6 del grupo tratado con heparina, a pesar de ser el doble no es estadísticamente significativo, pero de aumentar el número de casos y mantenerse igual la proporción si llegaría a serlo (AU)

Comparison of verapamil and captopril in elderly hypertensive subjects: results of a randomized, double-blind, crossover study.

The effectiveness and tolerability of captopril and verapamil SR were compared in a double-blind, crossover study in 23 elderly hypertensives [15 males and 8 females, aged (mean +/- SEM) 68 +/- 1 years]. After 2 weeks of placebo run-in, patients were randomized to a starting dose of captopril, 12.5 mg b.i.d. or verapamil SR, 120 mg q.d. plus matched placebo of the opposite drug. Medication was titrated up over 6 weeks to a maximum dose of 75 mg of captopril or 360 mg of verapamil SR to achieve a sitting diastolic blood pressure of < 90 mm Hg. After 2 weeks of placebo washout, captopril and verapamil were crossed over. In the 20 patients who completed the study, the dose at the end of the respective treatment periods averaged 63 +/- 4 mg of captopril and 270 +/- 21 mg of verapamil SR. Blood pressure at the end of the run-in and washout placebo periods were comparable: 164 +/- 4/97 +/- 1 and 163 +/- 4/98 +/- 2 mm Hg, respectively. However, the blood pressure was significantly lower after verapamil, i.e., 147 +/- 4/86 +/- 2 mm Hg, than after captopril, i.e., 155 +/- 4/90 +/- 1 mm Hg (p < 0.05, ANOVA). There was no significant change in heart rate and laboratory parameters and no orthostatic hypotension. Captopril-treated patients reported a positive change in well being compared with placebo, although there was no overall difference between the drugs in any of the ten quality of life measurements. Three patients discontinued treatment, two because of constipation (verapamil) and one due to lack of efficacy (captopril).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertensive crisis from chronic intoxication with nasal decongestant and cough medications.

Cardiac hypertensive structural changes, catecholamine-related cardiomyopathy, and congestive heart failure (CHF) have been encountered in pheochromocytoma, as a result of prolonged exposure to high concentrations of endogenous catecholamines. A 34-year-old man presented with severe hypertension, cardiomegaly, and CHF, presumably as a result of continuous alpha-adrenergic intoxication with oxymetazoline hydrochloride, phenylephrine hydrochloride, and ephedrine hydrochloride, consumed in massive doses by an overuse of nasal decongestants and cough syrup (daily doses of 20, 100, and 300 mg, respectively). Coadministered chlorpromazine hydrochloride and trimeprazine tartrate may have also contributed to the clinical presentation through their anticholinergic and antihistaminic properties. The possibility of an overuse of these over-the-counter drugs should be considered in the differential diagnosis of hypertensive emergencies, especially with the simultaneous use of anticholinergic and antihistamine medications, beta-blocking agents, or monoamine oxidase inhibitors.

Effectiveness of combined nifedipine and propranolol treatment in hypertension.

The long-term antihypertensive effect of combined nifedipine and propranolol therapy was assessed in an open trial in 26 hypertensive patients (19 men, seven women, mean age 53 years). On propranolol alone (160 to 240 mg/day), the patients' average sitting blood pressure was 192 +/- 5/114 +/- 2 mm Hg. Propranolol was continued in a fixed dose and nifedipine was added in a dose that was gradually increased from 30 to 90 mg/day to achieve blood pressure (BP) values below 160/95 mm Hg. Twenty-two patients remained on the combined regimen for 14 to 30 weeks. Their BP decreased to 136 +/- 3/84 +/- 2 mm Hg on an average daily dose of 59.5 mg nifedipine. Seventeen of the 22 subjects were subsequently treated sequentially with propranolol alone, combined therapy, and nifedipine alone, to assess the relative efficacy of each mode of therapy. The combined regimen was found to be more effective than either drug alone. Side effects occurred in 13 of 26 patients. Four dropped out 4 to 11 weeks after starting nifedipine because of either intolerable flushing (2), allergic rash (1), or headache (1). Nine subjects experienced mild reactions that were well tolerated. It is concluded that the combined use of propranolol and nifedipine is effective in the long-term treatment of moderately severe hypertension and offers an alternative therapeutic approach that deserves further evaluation.

Veno-occlusive disease and primary hepatic vein thrombosis in Israeli Arabs.

In a survey of nine major Israeli hospitals, 29 patients diagnosed between 1955 and 1975 as suffering from hepatic vein thrombosis were identified. Fifteen of the patients were Jews and 14 were Arabs. In contrast to the Jewish patients, all of whom were adults, the majority of the Arab patients were children below 10 years of age. Primary hepatic vein occlusion was 2.4 times more common among Arab than among Jewish patients. Of the 11 Arab patients with primary hepatic vein occlusion, three had histological changes typical of veno-occlusive disease; whereas in five others, thrombotic occlusion of large hepatic veins or of the vena cava was documented. Although no plant alkaloids could be directly implicated in any of the Arab patients, circumstantial evidence strongly supports such an etiology. All of our Arab patients originated from small agricultural communities where ancient methods of winnowing, which expose the home-ground wheat to a high risk of contamination by grains containing pyrrolizidine alkaloids, are still in use. This report confirms the world-wide distribution of veno-occlusive disease, and under-lines the need for a systematic search for possible sources of poisoning by pyrrolizidine alkaloids.

Hematin and propranolol in acute intermittent porphyria. Full recovery from quadriplegic coma and respiratory failure.

The authors present a case of acute intermittent porphyria (AIP) in an almost fatal relapse with quadriplegia, bulbar paralysis and coma. Intravenous hematin produced an immediate arousal from coma and allowed a gradual resumption of bulbar and autonomic functions. Persistent tachycardia and hypertension necessitated huge doses of intravenous propranolol. Both hematin and propranolol administrations were followed by a remarkable decrease in urinary amino-levulinic acid and porphobilinogen excretion. Nevertheless, after the acute stage, the patient was left with a severe generalized muscle wasting. After 7 months of intensive physical therapy, complete recovery of all neuromuscular functions was achieved. The modern aspects of the management of AIP are presented; the efficacy and the limits of hematin and propranolol therapy are discussed.