Potential tuberculostatic agent: Micelle-forming pyrazinamide prodrug

Pyrazinamide was condensed with the poly(ethylene glycol)-poly(aspartic acid) copolymer (PEG-PASP), a micelle-forming derivative was obtained that was characterized in terms of its critical micelle concentration (CMC) and micelle diameter. The CMC was found by observing the solubility of Sudan III in Poly(ethylene glycol)-poly(pyrazinamidomethyl aspartate) copolymer (PEG-PASP-PZA) solutions. The mean diameter of PEG-PASP-PZA micelles, obtained by analyzing the dynamic light-scattering data, was 78.2 nm. The PEG-PASP-PZA derivative, when assayed for anti-Mycobacterium activity, exhibited stronger activity than the simple drug.

Synthesis, X-ray structure and antimycobacterial activity of silver complexes with alpha-hydroxycarboxylic acids

In this paper, synthesis, characterization and antimycobacterial properties of a new water-soluble complex identified as silver-mandelate are described. Elemental and thermal analyses are consistent with the formula [Ag(C6H5C(OH)COO)](n). The polymeric structure was determined by single X-ray diffraction and the two-dimensional structure is based on the bis(carboxylate-O,O') dimer [Ag-O, 2.237(3), 2.222(3) angstrom]. The structure is extended along both the b and c axes through two oxygen atoms of a bidentate alpha-hydroxyl-carboxylate residue [Ag-OH(hydroxyl), 2.477(3) angstrom; Ag-O(carboxylate), 2.502(3) angstrom; O-Ag-O, 63.94(9)degrees]. A strong d(10)-d(10) interaction was observed between two silver atoms. The Ag...Ag distance is 2.8307(15) angstrom. The NMR C-13 spectrum in D2O shows that coordination of the ligand to Ag(l) occurs through the carboxylate group in solution. Potentiometric titration shows that only species with a molar metaHigand ratio of 2:2 are formed in aqueous solution. The mandelate complex and the silver-glycolate, silver-malate and silver-hydrogen-tartarate complexes were tested against three types of mycobacteria, Mycobacterium avium, Mycobacterium tuberculosis and Mycobacterium kansasii, and their minimal inhibitory concentration (MIC) values were determined. The results show that the four complexes are potential candidates for antiseptic or disinfectant drugs for discharged secretions of patients affected with tuberculosis. (c) 2006 Published by Elsevier B.V.

Synthesis, characterization and antimycobacterial activity of Ag(I)-aspartame, Ag(I)-saccharin and Ag(I)-cyclamate complexes

The present work describes the synthesis and antimycobacterial activity of three Ag(I)-complexes with the sweeteners aspartame, saccharin, and cyclamate as ligands, with the aim of finding new candidate substances for fighting tuberculosis and other mycobacterial infections. The minimal inhibitory concentration of these three complexes was investigated in order to determine their in-vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium malmoense, and Mycobacterium kansasii. The MIC values were determined using the Microplate Alamar Blue Assay. The best MIC values found for the complexes were 9.75 mu M for Ag(l)-aspartame against M. kansasii and 15.7 mu M for Ag(I)-cyclamate against M. tuberculosis.

Preparation of polymeric micelles for use as carriers of tuberculostatic drugs

Purpose: This paper focuses on the characterization of polymeric micelle-forming tuberculostatic prodrugs and the antimycobacterial activity of these prodrugs.Method: By the condensation of hydroxymethylpyrazinamide, isoniazid and rifampin with free carboxyl groups on the copolymer poly(ethyleneglycol)-poly(aspartic acid), micelle-forming carrier-drug conjugates were obtained. These micelles were characterized by dynamic light scattering, to measure the micelle diameter; by acid-base titration, to determine the percentage of carboxylic groups occupied by the tuberculostatic; by Sudan III solubility tests, to estimate the critical micelle concentration (CMC); and visual control and spectrophotometric measurement, to determine the stability of micelles. These micelles were tested in vitro against several Mycobacterium strains.Results: As expected, the size and distribution of the micelle-forming tuberculostatic prodrugs found to be small (78.2nm, 84.2nm and 98.9 nm) while the level of the drug conjugated was high (65.02-85.7%). Furthermore, the micelles were stable in vitro, exhibiting a low level of CMC and stronger antimycobacterial activity than the original drugs.Conclusion: the results demonstrate that polymeric micelles can be used as efficient carriers for drugs, which alone, exhibit undesired pharmacokinetics, poor solubility, and low stability. The synthesized micelle-forming tuberculostatic prodrugs opens a perspective of alternative prodrugs that prolong action and decrease the toxicity of the tuberculostatic drugs of choice.

Comparison of resazurin microtiter assay performance and BACTEC MGIT 960 in the susceptibility testing of Brazilian clinical isolates of Mycobacterium tuberculosis to four first-line drugs

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Rhodococcus equi isolation from sputum of patients with suspected tuberculosis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Evaluation of anti-Mycobacterium tuberculosis activity of Campomanesia adamantium (Myrtaceae)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Sidestream cigarette smoke effects on cardiovascular responses in conscious rats: involvement of oxidative stress in the fourth cerebral ventricle

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Evaluation of Hemodynamic, Metabolic, and Electrolytic Changes After Graft Reperfusion in a Porcine Model of Intestinal Transplantation

Background. We sought to establish an anesthetic protocol to evaluate the hemodynamic, metabolic, and electrolytic changes after graft reperfusion in pigs undergoing orthotopic intestinal transplant (ITX).Methods. Fifteen pigs were distributed into two groups: GI (n = 6), without immunosuppression, and GII (n = 9), immunosuppressed before surgery with tacrolimus (0.3 mg/kg). The animals were premedicated at 1 hour before surgery with IM acepromazine (0.1 mg/kg), morphine (0.4 mg/kg), ketamine (10 mg/kg), and atropine (0.044 mg/kg IM). Anesthesia induction used equal proportions of diazepam and ketamine (0.1-0.15 mL/kg/IV) and for maintenance in IV infusion of xylazine (1 mg/mL), ketamine (2 mg/mL), and guaiacol glyceryl ether 5% (50 mg/mL), diluted in 250 mL of 5% glucose solution. In addition, recipient pigs were treated with isofluorane inhalation. Heart rate (HR), systolic (SAP), mean (MAP), and diastolic (DAP) arterial pressure, pulse oximetry, respiratory frequency (f), capnography, body temperature (T), blood gas analysis (pH, PaCO(2), PaO(2), base excess, BE; HCO(3)(-), SatO(2)), serum potassium (K), calcium (Ca), sodium, hematocrit (Hct), and glucose (Glu) were measured at four times; MO: after incision (basal value); M1: 10 minutes before reperfusion; and M2 and M3: 10 and 20 minutes after graft reperfusion.Results. All groups behaved in a similar pattern. There was significant hypotension after graft reperfusion in GI and GII (M2 = 56.2 +/- 6.4 and M3 = 57.2 +/- 8.3 mm Hg and M2 = 65.7 +/- 10.2 and M3 = 67.8 +/- 16.8 mm Hg, respectively), accompanied by elevated HR. The ETCO(2) was elevated at M2 (42 mm Hg) and M3 (40 mm Hg). Metabolic acidosis was observed after reperfusion, with significant increase in K levels.Conclusion. The anesthetic protocol for donors and recipients was safe to perform the procedure, allowing control of hemodynamic and metabolic changes after reperfusion without differences regarding immunosuppression.

Effects of Compounds from Passiflora edulis Sims f. flavicarpa Juice on Blood Coagulation and on Proteolytic Enzymes

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Mutagenic and carcinogenic potential of a textile azo dye processing plant effluent that impacts a drinking water source

Recently a textile azo dye processing plant effluent was identified as one of the sources of mutagenic activity detected in the Cristais River, a drinking water source in Brazil [G.A. Umbuzeiro, D.A. Roubicek, C.M. Rech, M.I.Z. Sato, L.D. Claxton, Investigating the sources of the mutagenic activity found in a river using the Salmonella assay and different water extraction procedures, Chemosphere 54 (2004) 1589-1597]. Besides presenting high mutagenic activity in the Salmonella/microsome assay, the mutagenic nitro-aminoazobenzenes dyes CI Disperse Blue 373, Cl Disperse Violet 93, and CI Disperse Orange 37 [G.A. Umbuzeiro, H.S. Freeman, S.H. Warren, D.P Oliveira, Y. Terao, T. Watanabe, L.D. Claxton, the contribution of azo dyes in the mutagenic activity of the Cristais river, Chemosphere 60 (2005) 55-64] as well as benzidine, a known carcinogenic compound [T.M. Mazzo, A.A. Saczk, G.A. Umbuzeiro, M.V.B. Zanoni, Analysis of aromatic amines in surface waters receiving wastewater from textile industry by liquid chromatographic with eletrochemical detection, Anal. Lett., in press] were found in this effluent. After similar to 6 km from the discharge of this effluent, a drinking water treatment plant treats and distributes the water to a population of approximate 60,000. As shown previously, the mutagens in the DWTP intake water are not completely removed by the treatment. The water used for human consumption presented mutagenic activity related to nitro-aromatics and aromatic amines compounds probably derived from the cited textile processing plant effluent discharge [G.A. Umbuzeiro, D.A. Roubicek, C.M. Rech, M.I.Z.. Sato, L.D. Claxton, Investigating the sources of the mutagenic activity found in a river using the Salmonella assay and different water extraction procedures, Chemosphere 54 (2004) 1589-1597; G.A. Umbuzeiro, H.S. Freeman, S.H. Warren, D.P. Oliveira, Y. Terao, T. Watanabe, L.D. Claxton, the contribution of azo dyes in the multagenic activity of the Cristais river, Chemosphere 60 (2005) 55-64]. Therefore, it is important to evaluate the possible risks involved in the human consumption of this contaminated water. With that objective, one sample of the cited industrial effluent was tested for carcinogenicity in the aberrant crypt foci medium-term assay in colon of Wistar rats. The rats received the effluent in natura through drinking water at concentrations of 0.1%, 1%, and 10%. The effluent mutagenicity was also confirmed in the Salmonella/microsome assay with the strains TA98 and YG1041. There was an increased number of preneoplastic lesions in the colon of rats exposed to concentrations of 1% and 10% of the effluent, and a positive response for both Salmonella strains tested. These results indicate that the discharge of the effluent should be avoided in waters used for human consumption and show the sensitivity of the ACF crypt foci assay as an important tool to evaluate the carcinogenic potential of environmental complex mixtures. (c) 2006 Elsevier B.V. All rights reserved.

Síndrome de ativação macrofágica em paciente com lúpus eritematoso sistêmico juvenil

A hemofagocitose reativa ou síndrome de ativação macrofágica (SAM) é uma complicação das doenças inflamatórias sistêmicas, causada por expansão de células T e macrófagos, com produção maciça de citocinas pró-inflamatórias, ocorrendo mais freqüentemente na artrite idiopática juvenil sistêmica e raramente no lúpus eritematoso sistêmico juvenil (LESJ). OBJETIVO: Relatar um caso de LESJ que evoluiu com SAM precipitada por infecção e infarto esplênico, com desfecho fatal. RELATO DE CASO: Uma menina de 7 anos, com diagnóstico de LESJ desde os 5 anos, evoluiu com artrite em atividade, alopecia intensa, citopenias, cefaléia, infecções respiratórias recorrentes e elevação intermitente de transaminases. Os anticorpos anti-DNA e anticardiolipina IgG e IgM foram identificados e a biópsia renal evidenciou glomerulonefrite lúpica de classe III. A paciente foi tratada com pulso de metilprednisolona, prednisona, azatioprina e hidroxicloroquina. Após dois anos, na vigência de pneumonia apresentou abdome agudo e convulsões, evoluindo para o choque hemorrágico fatal após esplenectomia, que evidenciou infarto esplênico e infiltração maciça por macrófagos hemofagocíticos CD163+. CONCLUSÃO: A revisão do desfecho sugere a SAM precipitada por infecção e sobreposta a atividade inflamatória do lúpus com febre persistente, citopenias, disfunção hepática, hepatomegalia e esplenomegalia, como efeitos do excesso de produção de citocinas. Os anticorpos anticardiolipina podem ter tido papel precipitante na coagulopatia, que resultou infarto esplênico e choque hemorrágico.

Clinical presentation and salivary gland histopathology of paediatric primary Sjogren's syndrome

ObjectiveExplore the presentation, diagnostic criteria and exocrine gland histopathology of paediatric primary Sjogren's syndrome (PPSjS).MethodsA case series of 8 children is reported and American-European Consensus Group (AECG-2002) criteria were examined, as well as minor labial salivary and lachrymal gland biopsies, which were scored by a pathologist blinded to outcome. For all cases, connective tissue diseases and parotid-related infectious disease were excluded.ResultsAge at onset varied from 5-13 years old; 6 were females, all followed from diagnosis up to the last visit (1-10 years). The main features at presentation were recurrent tender parotid swelling and sialectasis imaging, with decreased salivary function assessed by Tc-99 scintigraphy. Mild sicca symptoms were observed in 4/8 cases. Systemic features, including fatigue, myalgia, arthritis, tenosynovitis, joint contractures, transient Raynaud's and high ESR, were recorded at onset. Autoantibody profile was unremarkable for diagnosis, while lymphocytic infiltration of labial salivary glands and sialectasis were observed in all biopsies (8/8). In lachrymal glands, massive lymphocytic infiltration and lymphocytic gastritis were observed during complementary assessment. Flares were treated with low dose steroids and long-term use of hydroxychloroquine (5/8), although only 318 fulfilled AECG-2002 diagnostic criteria, throughout the disease course.ConclusionPPSjS is rare, slowly progressive and its early presentation is variable. Standardised diagnostic algorithms should include recurrent parotid swelling and early diagnosis should rely mostly on salivary and lachrymal gland histopathology in this age group.

Progression of articular and extraarticular damage in oligoarticular juvenile idiopathic arthritis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)