Pharmacokinetics of Benznidazole in Healthy Volunteers and Implications in Future Clinical Trials.

Despite its toxicity and low efficacy in the chronic phase, benznidazole is the drug of choice in Chagas disease. Scarce information about pharmacokinetics and pharmacodynamics of benznidazole has been published. We performed a phase I, open-label, nonrandomized pharmacokinetic study of benznidazole (Abarax) conducted with 8 healthy adult volunteers at the Infectious Diseases Department of the Vall d'Hebron University Hospital (Barcelona, Spain). The separation and detection of benznidazole were performed on a Waters Acquity ultraperformance liquid chromatography system (UPLC) coupled with a Waters Xevo TQ MS triple quadrupole mass spectrometer. The pharmacokinetic parameters were calculated based on a noncompartmental body model using Phoenix WinNonlin version 6.3 software. Furthermore, computational simulations were calculated for the multiple-dose administration at two dose regimens: 100 mg of benznidazole administered every 8 h and 150 mg of benznidazole administered every 12 h. After benznidazole administration, the median area under the concentration-time curve from time zero to time t (AUC0-t ) and extrapolated to infinity (AUC0-∞) were about 46.4 µg · h/ml and 48.4 µg · h/ml, respectively. Plasma benznidazole concentrations peaked at 3.5 h, with maximal concentrations of 2.2 µg/ml, and benznidazole exhibited a terminal half-life of 12.1 h. The median maximum concentration (Cmax) of benznidazole was lower in men than in women (1.6 versus 2.9 µg/ml), and median volume of distribution (V) as a function of bioavailability (F) was higher in men than in women (125.9 versus 88.6 liters). In conclusion, dose regimens (150 mg/12 h or 100 mg/8 h) reached a steady-state range concentration above of the minimum experimental therapeutic dose. Sex differences in the benznidazole pharmacokinetics were observed; mainly, men had lower Cmax and higher V/F than women.

Evaluation of cytokine profile and HLA association in benznidazole related cutaneous reactions in patients with Chagas disease.

BACKGROUND: Benznidazole is the drug of choice for Chagas disease. The major drawback of this drug is the high adverse events rate, being cutaneous reactions the most frequent one, leading to definitive withdrawal of treatment in 15%-30% of patients. METHODS: Prospective observational study where adult Chagas disease patients accepting to receive benznidazole (100 mg/8 hours for 60 days) were included. The objective was to characterize the skin toxicity of benznidazole in patients with Chagas disease, determine the serum cytokine profile, and evaluate the potential association with specific HLA alleles and benznidazole concentration. Serum cytokine levels were measured at day 0, 15, and 60 of treatment. Class I and II HLA alleles were determined. When cutaneous reaction was detected, a skin biopsy was performed. Serum benznidazole concentration was determined at the time of cutaneous reaction, or at day 15 of treatment. RESULTS: Fifty-two patients were included, 20(38.5%) had cutaneous reaction, and median time of appearance was 9 days. Skin biopsies showed histopathological findings consistent with drug eruption. Patients with cutaneous drug-reaction had higher proportion of eosinophilia during treatment, and higher interleukin (IL)-5 and IL-10 serum concentrations at day 15 of treatment than those without cutaneous reaction. Treatment interruption (that included moderate-severe cutaneous reactions) was more frequent in patients carrying HLA-B*3505 allele (45.5% vs 15.4%, P = .033). No differences in benznidazole serum concentration were found. CONCLUSIONS: Benznidazole related cutaneous reaction rate is high, and it was produced by a delayed hypersensitivity reaction with a Th2 response. Carrying HLA-B*3505 allele could be associated with moderate-severe cutaneous reaction.

Bioavailability of two metamizole (dipyrone) solutions as single doses of 2 g versus metamizole capsules.

OBJECTIVE: The aim of this study was to investigate the extent and the rate of absorption of metamizole, appearing in blood as methylaminoantipyrine (MAA), from a new oral solution and a parenteral solution administered by the oral route relative to capsules. METHODS: An open, randomized, 3 single-dose (2 g metamizole), crossover study with intervals of 7 days between periods was performed in 19 male and female healthy volunteers (age 22 - 45 years, body weight 49 - 88 kg, body height 156 - 189 cm). Metamizole metabolites were measured with an HPLC technique. The test formulations were considered bioequivalent with the reference formulation if the 90% confidence limits of the AUC0-->infinity and Cmax ratios and the tmax differences were within the range of 80 - 125%. RESULTS: The 90% confidence limits of the comparisons between capsules (reference) and oral solution, capsules (reference) and ampoules, and ampoules (reference) and oral solution were 98.5 - 117.8, 99.5 - 132.6 and 81.3 - 105.8 for AUC0-->infinity 98.7 - 119, 101.7 to 129.2, and 82.1 - 104.8 for Cmax, and 84.4 to 115.6, 100 - 105.6 and 70.3 - 100 for tmax, respectively. CONCLUSION: The oral solution was bioequivalent to capsules with regard both to the extent and the rate of MAA absorption. Metamizole as oral solution was bioequivalent to reference ampoules in the extent of MAA absorption, but absorption rate was faster. Ampoules showed a higher MAA bioavailability than capsules.

[Acute myocardial infarction in nocturnal paroxysmal hemoglobinuria]. / Infarto agudo de miocardio en el seno de hemoglobinuria paroxística nocturna.

The case of a 62-year-old diabetic and smoker male who was under study in another hospital due to anemia, thrombopenia and hematuria of several months of evolution is presented. The patient was admitted to the coronary unit for an acute extensive transmural myocardial infarction and treated with t-PA. A few hours later the patient presented hematuric urine, a decrease in hemoglobin and platelets and acute renal insufficiency. Hematologic study confirmed the diagnosis of paroxystic nocturnal hemoglobinuria. The evolution of the patient was poor despite intensive medical treatment requiring hemodialysis. The patient presented cardiac tamponade and died. The role of hematologic disease in acute myocardial infarction and the treatment and evolution of the coronary syndrome in the context of the disease are discussed.

Fatal pulmonary embolization of a right atrial mass during transesophageal echocardiography.

Transesophageal echocardiography is a semi-invasive diagnostic technique with a very low incidence of significant complications. Only two deaths related to the procedure have been reported in the literature. We present the case of a 46-year-old man with a right atrial mass, presumably a cardiac myxoma. During attempts at esophageal intubation for a transesophageal echocardiography procedure, the mass fragmented and dislodged, causing massive pulmonary embolism and death. We believe that to avoid this potential complication, great care must be taken in the evaluation of patients with a right intracardiac mass by means of transesophageal echocardiography.

[The absence of interference between GSM mobile telephones and implantable defibrillators: an in-vivo study. Groupe Systèmes Mobiles]. / Ausencia de interferencia entre teléfonos móviles GSM y desfibriladores implantables: estudio in vivo.

INTRODUCTION AND OBJECTIVES: The electromagnetic field created by mobile telephones can cause pacemaker dysfunction. Although implantable cardioverter defibrillators are also susceptible to electromagnetic interference, few studies have addressed this issue and compatibility with the GSM mode has not been tested. This study was developed to detect possible "in vivo" interference between GSM mobile telephones and implantable cardioverter defibrillators. MATERIAL AND METHODS: The study group is composed of 30 patients with 8 different models of defibrillators. Twenty six had endocardial leads and 4 epicardial. Three GSM mobile phones were used: Siemens S3 COM and Motorola 6200 in all cases and Ericsson GA 318 in one. The tests were performed under continuous electrocardiographic monitoring. All therapies were deactivated and sensitivities were set to maximal parameters. The telephones were positioned in close contact to the defibrillator can and precordium, in two different angles. Three situations were evaluated: calling, established contact for 15 seconds and ringing. The protocol was repeated during pacing to assess the possibility of pacemaker mode inhibition. RESULTS: No cases of electromagnetic interference were observed. One patient presented non-sustained ventricular tachycardia episodes during the tests that were detected by the defibrillator. CONCLUSIONS: These results suggest that electromagnetic interference by GSM mobile phones are not a probable cause of implantable defibrillators dysfunction.

Intravenous amiodarone in treatment of recent-onset atrial fibrillation: results of a randomized, controlled study.

OBJECTIVES: This study was designed to determine the efficacy of intravenous amiodarone in the management of recent-onset atrial fibrillation. BACKGROUND: The optimal approach for acute atrial fibrillation has not been established. Amiodarone is a unique antiarrhythmic agent with activity in both supraventricular and ventricular tachyarrhythmias, but its value for the restoration of sinus rhythm in patients with recent-onset atrial fibrillation has not been demonstrated. METHODS: Sample size was calculated to detect a 25% increase in reversion rate with amiodarone with a statistical power of 80%. One hundred consecutive patients with recent-onset (<1 week) atrial fibrillation and not taking antiarrhythmic agents were randomized to receive either intravenous amiodarone, 5 mg/kg body weight in 30 min followed by 1,200 mg over 24 h, or an identical amount of saline. Both groups received intravenous digoxin, 0.5 mg initially, followed by 0.25 mg at 2 h and 0.25 mg every 6 h thereafter, to complete 24 h while the ventricular rate was >100 beats/min. Amiodarone and digoxin blood levels were determined. Both groups were homogeneous regarding underlying heart disease, time from onset to treatment, initial ventricular rate and left atrial size. RESULTS: By the end of the 24-h treatment period, 34 patients (68%, 95% confidence interval [CI] 53% to 80%) in the amiodarone group and 30 (60%, 95% CI 45% to 74%) in the control group had returned to sinus rhythm (p = 0.532). Mean times (+/-SD) of conversion were 328 +/- 335 and 332 +/- 359 min, respectively (p =0.957). Among patients who did not convert to sinus rhythm, treatment with amiodarone was associated with a slower ventricular rate (82 +/- 15 beats/min in the amiodarone group vs. 91 +/- 23 beats/min in the control group, p = 0.022). After restoration of sinus rhythm, atrial fibrillation recurred during a 15-day follow-up period in 4 (12%) of 34 patients (95% CI 3% to 27%) in the amiodarone group and in 3 (10%) of 30 (95% CI 2% to 26%) in the control group (p = 0.861). CONCLUSIONS: Intravenous amiodarone, at the doses used in this study, produces a modest but not significant benefit in converting acute atrial fibrillation to sinus rhythm.

[Right ventricular arrhythmogenic dysplasia. The role of heart transplantation in its management]. / Displasia arritmogénica ventricular derecha. El papel del trasplante cardíaco en su manejo.

Arrhythmogenic right ventricular dysplasia is a rare disease that usually presents with ventricular arrhythmias and sometimes with heart failure. Rarely symptoms become severe and refractory to conventional therapy. We present the case of a 36-year-old man with this disease who had sustained ventricular arrhythmias and severe right heart failure. Because these symptoms were poorly controlled with medical therapy, cardiac transplantation was finally chosen as definitive treatment. The patient had a favorable course and now leads near-normal life.

[A heart transplant in a patient with doxorubicin-induced myocardiopathy as a complication of the treatment of a lymphoma]. / Trasplante cardíaco en un paciente con miocardiopatía por doxorrubicina como complicación del tratamiento de un linfoma.

We present the case of a young man who developed severe cardiomyopathy eight years after receiving high-dose doxorubicin therapy as treatment for diffuse lymphoblastic lymphoma. He underwent cardiac transplantation and eighteen months later the tumor has not recurred and the patient has no cardiac symptoms.

Randomized trial comparing ceftriaxone with cefonicid for treatment of spontaneous bacterial peritonitis in cirrhotic patients.

We compared cefonicid (2 g every 12 h) and ceftriaxone (2 g every 24 h) for their efficacy and safety in treating spontaneous bacterial peritonitis in cirrhotic patients in an open randomized clinical trial (30 patients in each group). Clinical, laboratory, and bacteriologic characteristics were similar in both groups. Ceftriaxone-susceptible strains were isolated on 44 occasions (94%), and cefonicid-susceptible strains were isolated on 43 occasions (91.5%). The antibiotic concentration in ascitic fluid/MIC ratio for ceftriaxone was > 100 throughout the dose interval (24 h), while it was lower for cefonicid (between 1 and 18). A total of 100% of patients treated with ceftriaxone, and 94% of those treated with cefonicid were cured of their infections (P was not significant). Hospitalization mortality was 37% in the cefonicid group and 30% in the ceftriaxone group (P was not significant). The time that elapsed between the initiation of treatment and the patient's death was shorter in the cefonicid group patients (5.3 +/- 3.90 days) than in the ceftriaxone group patients (11.8 +/- 9.15 days) (P < 0.05). None of the patients presented with superinfections, and only two patients treated with cefonicid and three patients treated with ceftriaxone developed colonizations with Enterococcus faecalis or Candida albicans. Ceftriaxone and cefonicid are safe and useful agents for treating cirrhotic spontaneous bacterial peritonitis, although the pharmacokinetic characteristics of ceftriaxone seem to be more advantageous than those of cefonicid.

[The use of digoxin in primary care]. / Estudio de utilización de la digoxina en atención primaria.

OBJECTIVE: A study aimed at a population attended at the Primary Health level was designed, in order to reach a greater understanding of the use of Digoxin by doctors and patients. DESIGN: A crossover observational study, carried out wholly at the Primary Care level. PATIENTS: 205 patients under long-term Digoxin treatment were studied. 94 (46%) were men and 111 (54%) women. The average age (SD) was 67 (13). MEASUREMENTS AND MAIN RESULTS: The indication was considered adequate in 62.9% of patients. The average dose (AD) of Digoxin was 0.163 mg a day (0.04): the age of the patients is not taken into account on working out the dose of Digoxin. 52 patients (25.4%) recognised they had not properly carried out the prescription. In this group the view that Digoxin was unnecessary was more common (X = 10.63; p = 0.001). The average Digoxinemia (AD) was 0.85 (0.46) ng/ml. 57% of patients had plasmatic levels below a therapeutic level. The variables related to plasmatic level were: daily dosage (r = 0.4, p = 0.001); age (r = 0.2, p = 0.001; plasmatic creatinine (r = 0.3, p = 0.001); clearing of creatinine (r = -0.4, p = 0.001) and compliance (t = 2.42, p = 0.01). The same independent variables were identified as significant in the multivariant analysis. The week-end break from dosage supposed a fall in the plasmatic levels of 67.7%. CONCLUSIONS: In spite of being a widely-used drug, the dosage of Digoxin is not adequately worked out and compliance is a long way from the optimum. Digoxinemia correlates to the dosage, renal function and compliance with the prescription.

[Pharmacokinetics of acetylsalicylic acid for the prophylaxis of cardiovascular pathology]. / Farmacocinética del ácido acetilsalicílico para la profilaxis de patología cardiovascular.

BACKGROUND: The metaanalysis of clinical trials on the secondary prevention of myocardial infarction and cerebrovascular disease with antiplatelet drugs suggests that low doses of acetylsalicylic acid (ASA) reduce cardiovascular mortality and morbidity. The ideal galenic formulation should contain a low dose of ASA, should be enteric-coated--to reduce gastrointestinal toxicity--and should be slowly absorbed--to facilitate selective inhibition of thromboxane synthesis by platelets. METHODS: The kinetics of a single dose of an enteric-coated sustained-release preparation containing 300 mg of ASA were studied in 6 healthy volunteers. Plasma concentrations of ASA and salicylic acid (SA) were measured during 12 hours after its administration. RESULTS: The time elapsed to achieve maximum plasma concentrations in the systemic circulation was 1 to 4 hours, as compared with 0.25 to 1.5 hours with other conventional preparations of ASA. The maximum plasma concentration recorded in one subject was 1.2 micrograms/ml, as compared with 4.8, 12, and 14 micrograms/ml with other preparations. CONCLUSIONS: The pharmacokinetic profile of this new preparation fits that proposed by others to produce a selective inhibition of thromboxane synthesis by platelets.

Intracoronary platelet activation in ischemic heart disease: effects of ticlopidine.

Plasma levels of platelet factor 4 have been measured in the aortic and coronary sinus blood of 35 patients: group I (n = 12) with normal coronary arteriograms; group II (n = 15) with angiographically proven coronary artery disease; and group III (n = 8) composed of patients with ischemic heart disease who were being treated with the antiaggregant agent ticlopidine at the time of cardiac catheterization. The mean increase in platelet factor 4 levels through the coronary circulation was 27.4 +/- 21.9 ng/ml (mean +/- standard deviation) in group II, compared with -1 +/- 4.5 ng/ml in group I (p less than 0.01). In group III plasma levels of platelet factor 4 in aortic and coronary sinus samples were all within the normal range. Thus, we conclude that platelet activation constantly occurs in the coronary circulation of patients with stable coronary artery disease, and can be prevented with ticlopidine.