Impairment of locomotor activity induced by the novel N-acylhydrazone derivatives LASSBio-785 and LASSBio-786 in mice

The N-acylhydrazone (NAH) analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785) and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786) were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294). The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30 mg/kg, ip) reduced locomotor activity from 209 ± 26 (control) to 140 ± 18 (P < 0.05) or 146 ± 15 crossings/min (P < 0.05), respectively. LASSBio-785 (15 or 30 mg/kg, iv) also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05) or 60 ± 16 crossings/min (P < 0.01), respectively. Likewise, LASSBio-786 (15 or 30 mg/kg, iv) reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01) or 96 ± 14 crossings/min (P < 0.01), respectively. Pretreatment with flumazenil (20 mg/kg, ip) prevented the locomotor impairment induced by NAH analogues (15 mg/kg, iv), providing evidence that the benzodiazepine (BDZ) receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30 mg/kg, ip, n = 10) increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO) to 66 ± 6 (P < 0.05) or 75 ± 4 min (P < 0.05), respectively. The dose required to achieve 50% hypnosis (HD50) following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5 mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia.

Use of the caffeine-halothane contracture test for the diagnosis of malignant hyperthermia in Brazil

Malignant hyperthermia (MH) is a pharmacogenetic disease triggered by volatile anesthetics and succinylcholine. Deaths due to MH have been reported in Brazil. The first Malignant Hyperthermia Diagnostic and Research Center in Latin America was inaugurated in 1993 at the Federal University of Rio de Janeiro, Brazil. The center followed the diagnostic protocols of the North America MH Group, in which the contractures of biopsies from the vastus lateralis muscle are analyzed after exposure to caffeine and halothane (CHCT). CHCT was performed in individuals who survived, their relatives and those with signs/symptoms somewhat related to MH susceptibility (MHS). Here, we report data from 194 patients collected over 16 years. The Southeast (N = 110) and South (N = 71) represented the majority of patients. Median age was 25 (4-70) years, with similar numbers of males (104) and females (90). MHS was found in 90 patients and 104 patients were normal. Abnormal responses to both caffeine and halothane were observed in 59 patients and to caffeine or halothane in 20 and 11 patients, respectively. The contracture of biopsies from MHS exposed to caffeine and halothane was 1.027 ± 0.075 g (N = 285) and 4.021 ± 0.255 g (N = 226), respectively. MHS was found in patients with either low or high blood creatine kinase and also, with a low score on the clinical grading scale. Thus, these parameters cannot be used with certainty to predict MHS. We conclude that the CHCT protocol described by the North America MH Group contributed to identification of MHS in suspected individuals at an MH center in Brazil with 100 percent sensitivity and 65.7 percent specificity.

Multigenerational Brazilian family with malignant hyperthermia and a novel mutation in the RYR1 gene

Malignant hyperthermia (MH) is a pharmacogenetic disease triggered in susceptible individuals by the administration of volatile halogenated anesthetics and/or succinylcholine, leading to the development of a hypermetabolic crisis, which is caused by abnormal release of Ca2+ from the sarcoplasmic reticulum, through the Ca2+ release channel ryanodine receptor 1 (RyR1). Mutations in the RYR1 gene are associated with MH in the majority of susceptible families. Genetic screening of a 5-generation Brazilian family with a history of MH-related deaths and a previous MH diagnosis by the caffeine halothane contracture test (CHCT) in some individuals was performed using restriction and sequencing analysis. A novel missense mutation, Gly4935Ser, was found in an important functional and conserved locus of this gene, the transmembrane region of RyR1. In this family, 2 MH-susceptible individuals previously diagnosed with CHCT carry this novel mutation and another 24 not previously diagnosed members also carry it. However, this same mutation was not found in another MH-susceptible individual whose CHCT was positive to the test with caffeine but not to the test with halothane. None of the 5 MH normal individuals of the family, previously diagnosed by CHCT, carry this mutation, nor do 100 controls from control Brazilian and USA populations. The Gly4932Ser variant is a candidate mutation for MH, based on its co-segregation with disease phenotype, absence among controls and its location within the protein.

Comparative pharmacokinetics of different oral nifedipine preparations in healthy brazilian volunteers

The pharmacokinetics of different pharmaceutical preparations of oral nifedipine-Adalat (capsule), Oxcord and Cardalin (tablets)-was determined after administration of single oral doses of 10 mg to nine healthy young Brazilian volunteers (7 men). There no significant changes in heart rate or systolic and diastolic blood pressure measured in the sitting position within 8 h of nifedipine administration to these normotensive volunteers. No side effects were reported by the volunteers or observed by the attending physicians during the study. No significant differences were observed among the three preparations in relation to the following pharmacokinetic parameters obtained from the plasma concentration-time curves: area under the curve (AUC), slope (beta) and half-life (T½) of the elimination phase, volume of distribution (Vd/F) and total body clearance (CL/F), both expre4ssed as functions of the oral bioavailability (F) of nifedipine. The peak, plasma concentration of nifedipine (C max) and the time to reach C max (T max) were not different for the rwo tablet preparations. However, C max was significantly higher, and T max was significantly shorter for the capsule. These data indicate that the capsule and the tablet preparations are not bioequivalent

Pharmacokinetics of oral ciprofloxacin in healthy, young Brazilian subjects

1. The pharmacokinetics of ciprofloxacin were determined in 8 healthy young volunteers (5 men and 3 women) after administration of single oral doses of 25omg. 2. The peak plasma concentration of ciprofloxacin (Cmax = 1.26 ñ 0.21 mg/l), the time to reach Cmax (Tmax = 1.99 ñ 0.26 h), the area under the time-plasma concentration curve (AUC = 5.52 ñ 0.84 mg h 1**-1), the terminal phase half-life (T1/2 = 3.05 ñ 0.56 h), the volume of distribution (Vd/F = 195.4 ñ 14.01) and total body clearance (CL/F = 46.3 ñ 2.61/h), both expressed as functions of the oral bioavailability (F) of ciprofloxacin were within the corresponding values reported in the literature for other healthy population groups. 3. Multiple dose administration (250 mg, po, twice daily for 4 days) did not result in accumulation of ciprofloxacin in plasma. No adverse side effects occurred during the study. 4. The pharmacokinetic data are discussed in relation to the minimum inhibitory concentration (MIC) of ciprofloxacin for a number of common pathogens isolated from human infections in Rio de Janeiro

Efeito hemodinâmico da lidocaína em cäes / Hemodynamic effects of lidocaine in dogs

Em doze cäes anestesiados pela cloralose e submetidos a condiçöes controladas de ventilaçäo, estudou-se o efeito hemodinâmico produzido pela infusäo venosa de lidocaína (6 mg. kg-1 min-1, dose total 24 mg. kg-1). Durante o efeito máximo da lidocaína, verificou-se intensa depressäo da atividade mecânica e elétrica do coraçäo caracterizada por reduçäo da dp/dt máxima do ventrículo esquerdo (-67%), do débito cardíaco (-45%) e da freqüência cardíaca (-23%). A pressäo média do átrio direito elevou-se em 69%. Näo se evidenciou-se qualquer efeito vasodilatador direto da lidocaína. A resistência vascular periférica total näo variou de forma significativa. A pressäo arteiral média reduziu-se de 32% e o consumo de oxigênio miocárdio (variaçäo do duplo produto PS x FC) também se reduziu de 47%. A reduçäo da contratilidade e do débito cardíaco perdurou por mais de 10 minutos. A pressäo arterial, por outro lado, retornou aos valores de controle mais rapidamente, compensada por um aumento da resistência vascular periférica. Concluiu-se que doses tóxicas de lidocaína produzem depressäo hemodinâmica de origem cardíaca e näo vascular, em animais sob condiçöes normais de ventilaçäo