Pharmacokinetic/pharmacodynamic modeling of psychomotor impairment induced by oral clonazepam in healthy volunteers.

This study was undertaken to model the relationship between clonazepam plasma concentrations and a central nervous system adverse effect (impairment of the psychomotor performance) following the oral administration of immediate-release tablets of clonazepam in healthy volunteers. Such a (P)pharmacokinetic/(P)pharmacodynamic (PK/PD) study is important to interpret properly the consequences of determined levels of plasma concentrations of psychoactive therapeutic drugs reported to be involved in road-traffic accidents. Twenty-three male subjects received a single oral dose of 4 mg clonazepam. Plasma concentration, determined by on-line solid phase extraction coupled with high-performance liquid chromatography tandem mass spectrometry, and psychomotor performance, quantified through the Digit Symbol Substitution Test, were monitored for 72 hours. A 2-compartment open model with first order absorption and lag-time better fitted the plasma clonazepam concentrations. Clonazepam decreased the psychomotor performance by 72 +/- 3.7% (observed maximum effect), 1.5 to 4 hours (25th-75th percentile) after drug administration. A simultaneous population PK/PD model based on a sigmoid Emax model with time-dependent tolerance described well the time course of effect. Such acute tolerance could minimize the risk of accident as a result of impairment of motor skill after a single dose of clonazepam. However, an individual analysis of the data revealed a great interindividual variation in the relationship between clonazepam effect and plasma concentration, indicating that the phenomenon of acute tolerance can be predicted at a population, but not individual, level.

Validation of the determination of oxymetholone in human plasma analysis using gas chromatography-mass spectrometry. Application to pharmacokinetic studies.

A simple and rapid procedure for extraction of oxymetholone in human plasma using gas chromatography coupled with quadrupole mass spectrometric was evaluated. The method involves analyte extraction with tert.-butylmethylether after alkalinization of the plasma and derivatization with MSTFA-NH(4)I-2-mercaptoethanol before the high resolution gas chromatographic-mass spectrometry separation. Methyltestosterone was used as internal standard. The calibration curves were linear, with typical r(2) values >0.995 and F(table)>F(calculated) (alpha=0.05). Recovery from plasma proved to be more than 70%. The method was accurate and reproducible, and was successfully applied to determine the pharmacokinetic parameters of oxymetholone for healthy volunteers after oral administration of 50 mg of the compound. The (C(max)) and (T(max)) were 18.8 +/- 0.4 ng/ml and 210 +/- 42.4 min, respectively.

Glomeruloid hemangioma in POEMS syndrome: a report on two cases and a review of the literature.

Glomeruloid hemangioma is characterized by coiled capillary vessels contained within enlarged vascular spaces displaying an architecture that resembles renal glomeruli. The condition is strongly associated with POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes). The present paper reports on two cases of glomeruloid hemangiomas associated with POEMS syndrome, and includes a review of the literature. Case one refers to a 63-year old female patient admitted to hospital with ascites, hepatosplenomegaly, walking difficulties and cutaneous hemangiomas. Histopathology revealed a diagnosis of glomeruloid hemangioma and served to guide the clinical work-up, which revealed sensorimotor polyneuropathy, a plasmacytoma in the L4 vertebra with tumor cells positive for kappa chain, and diabetes mellitus. These findings permitted a diagnosis of POEMS syndrome to be reached. The second case consisted of a 39-year old woman admitted to hospital with edema, ascites, pleural effusion, glomeruloid hemangiomas and lymphadenopathy (Castleman's disease). Additional findings included monoclonal IgG-lambda paraproteinemia, blastic lesions in the right iliac bone and L4 vertebra, and demyelinating sensorimotor neuropathy affecting all four limbs. The final diagnosis in this case was POEMS syndrome associated with Castleman's disease.

Clinical and immunological insights on severe, adverse neurotropic and viscerotropic disease following 17D yellow fever vaccination.

Yellow fever (YF) vaccines (17D-204 and 17DD) are well tolerated and cause very low rates of severe adverse events (YEL-SAE), such as serious allergic reactions, neurotropic adverse diseases (YEL-AND), and viscerotropic diseases (YEL-AVD). Viral and host factors have been postulated to explain the basis of YEL-SAE. However, the mechanisms underlying the occurrence of YEL-SAE remain unknown. The present report provides a detailed immunological analysis of a 23-year-old female patient. The patient developed a suspected case of severe YEL-AVD with encephalitis, as well as with pancreatitis and myositis, following receipt of a 17D-204 YF vaccination. The patient exhibited a decreased level of expression of Fc-gammaR in monocytes (CD16, CD32, and CD64), along with increased levels of NK T cells (an increased CD3(+) CD16(+/-) CD56(+/-)/CD3(+) ratio), activated T cells (CD4(+) and CD8(+) cells), and B lymphocytes. Enhanced levels of plasmatic cytokines (interleukin-6 [IL-6], IL-17, IL-4, IL-5, and IL-10) as well as an exacerbated ex vivo intracytoplasmic cytokine pattern, mainly observed within NK cells (gamma interferon positive [IFN-gamma(+)], tumor necrosis factor alpha positive [TNF-alpha(+)], and IL-4 positive [IL-4(+)]), CD8(+) T cells (IL-4(+) and IL-5(+)), and B lymphocytes (TNF-alpha(+), IL-4(+), and IL-10(+)). The analysis of CD4(+) T cells revealed a complex profile that consisted of an increased frequency of IL-12(+) and IFN-gamma(+) cells and a decreased percentage of TNF-alpha(+), IL-4(+), and IL-5(+) cells. Depressed cytokine synthesis was observed in monocytes (TNF-alpha(+)) following the provision of antigenic stimuli in vitro. These results support the hypothesis that a strong adaptive response and abnormalities in the innate immune system may be involved in the establishment of YEL-AND and YEL-AVD.

Hemangioma glomeruloide e a síndrome POEMS: relato de dois casos e revisão da literatura / Glomeruloid hemangioma in POEMS syndrome: a report on two cases and a review of the literature

O hemangioma glomeruloide caracteriza-se por enovelados capilares contidos em espaços vasculares dilatados reminiscentes de glomérulos renais, sendo fortemente associado à síndrome POEMS (polineuropatia, organomegalia, endocrinopatia, gamopatia monoclonal e alterações cutâneas). Relatamse dois casos da síndrome associados a hemangiomas glomeruloides e faz-se uma revisão da literatura. O primeiro é uma paciente feminina, 63 anos, internada para investigação de ascite, hepatoesplenomegalia, dificuldade de deambulação e hemangiomas cutâneos. A histopatologia de uma dessas lesões estabeleceu o diagnóstico de hemangioma glomeruloide e direcionou a investigação, que revelou polineuropatia sensitivo-motora, plasmocitoma kappa-positivo em L4 e Diabetes mellitus, permitindo o diagnóstico da síndrome. O segundo caso é de uma paciente feminina, 39 anos, com edema, ascite, derrame pleural, hemangiomas glomeruloides e linfonodomegalias (doença de Castleman). Havia um componente monoclonal de IgG-lambda e lesões blásticas no ilíaco direito e em L4, assim como lesão desmielinizante sensitivo-motora nos quatro membros, compondo o diagnóstico de síndrome POEMS.

Glomeruloid hemangioma is characterized by coiled capillary vessels contained within enlarged vascular spaces displaying an architecture that resembles renal glomeruli. The condition is strongly associated with POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes). The present paper reports on two cases of glomeruloid hemangiomas associated with POEMS syndrome, and includes a review of the literature. Case one refers to a 63-year old female patient admitted to hospital with ascites, hepatosplenomegaly, walking difficulties and cutaneous hemangiomas. Histopathology revealed a diagnosis of glomeruloid hemangioma and served to guide the clinical work-up, which revealed sensorimotor polyneuropathy, a plasmacytoma in the L4 vertebra with tumor cells positive for kappa chain, and diabetes mellitus. These findings permitted a diagnosis of POEMS syndrome to be reached. The second case consisted of a 39-year old woman admitted to hospital with edema, ascites, pleural effusion, glomeruloid hemangiomas and lymphadenopathy (Castleman's disease). Additional findings included monoclonal IgG-lambda paraproteinemia, blastic lesions in the right iliac bone and L4 vertebra, and demyelinating sensorimotor neuropathy affecting all four limbs. The final diagnosis in this case was POEMS syndrome associated with Castleman's disease.

On-line solid-phase extraction coupled with high-performance liquid chromatography and tandem mass spectrometry (SPE-HPLC-MS-MS) for quantification of bromazepam in human plasma: an automated method for bioequivalence studies.

A validated method for on-line solid-phase extraction coupled with high-performance liquid chromatography tandem mass spectrometry (SPE-HPLC-MS-MS) is described for the quantification of bromazepam in human plasma. The method involves a dilution of 300 muL of plasma with 100 muL of carbamazepine (2.5 ng/mL), used as internal standard, vortex-mixing, centrifugation, and injection of 100 muL of the supernate. The analytes were ionized using positive electrospray mass spectrometry then detected by multiple reaction monitoring (MRM). The m/z transitions 316-->182 (bromazepam) and 237-->194 (carbamazepine) were used for quantification. The calibration curve was linear from 1 ng/mL (limit of quantification) to 200 ng/mL. The retention times of bromazepam and carbamazepine were 2.6 and 3.2 minutes, respectively. The intraday and interday precisions were 3.43%-15.45% and 5.2%-17%, respectively. The intraday and interday accuracy was 94.00%-103.94%. This new automated method has been successfully applied in a bioequivalence study of 2 tablet formulations of 6 mg bromazepam: Lexotan(R) from Produtos Roche Químicos e Farmacêuticos SA, Rio de Janeiro, Brazil (reference) and test formulation from Laboratórios Biosintética Ltda, São Paulo, Brazil. Because the 90% CI of geometric mean ratios between reference and test were completely included in the 80%-125% interval, the 2 formulations were considered bioequivalent. The comparison of different experimental conditions for establishing a dissolution profile in vitro along with our bioavailability data further allowed us to propose rationally based experimental conditions for a dissolution test of bromazepam tablets, actually lacking a pharmacopeial monograph.

Pseudoaneurisma da aorta abdominal / Pseudo-aneurysm of the abdominal aorta

Os autores relatam um caso de paciente feminina com massa pulsátil abdominal, anemia e velocidade de hemossendimentaçao elevada. Durante seis meses antes da internaçao referia dor lombar, febre e perda de peso importante. O diagnóstico de aneurisma inflamatório foi considerado no início, mas a cirurgia revelou dupla perfuraçao aórtica, resultando em pseudoaneurisma.