A novel non-antibacterial, non-chelating hydroxypyrazoline derivative of minocycline inhibits nociception and oedema in mice.

BACKGROUND AND PURPOSE: Many in vitro and fewer in vivo studies have shown that tetracyclines present anti-inflammatory activity. We investigated if a novel non-antibacterial, non-chelating hydroxypyrazoline derivative of minocycline, 12S-hydroxy-1,12-pyrazolinominocycline (PMIN), also induced antinociceptive and anti-inflammatory effects. EXPERIMENTAL APPROACH: Antibacterial effects against a minocycline-sensitive Staphylococcus aureus strain were evaluated by applying a cylinder-plate agar diffusion technique. Antibacterial effects of diluted serum from mice pre-treated with minocycline or PMIN were also evaluated. Ca2+ binding activity was assessed by spectrophotometry. Formalin-induced nociceptive responses and carrageenan-induced paw oedema were evaluated in mice. The rota-rod apparatus was used to evaluate motor coordination. KEY RESULTS: Minocycline, but not PMIN, inhibited bacterial growth. Serum from mice treated with minocycline, but not with PMIN, also induced such an effect. The UV absorption spectrum of solutions of minocycline, but not those of PMIN, was markedly changed in the presence of Ca2+. Minocycline or PMIN inhibited both phases of formalin-induced nociception and carrageenan-induced paw oedema. It is unlikely that antinociception resulted from lack of motor coordination, as tetracycline did not impair the performance of mice on the rotating rod. CONCLUSIONS AND IMPLICATIONS: These results indicate that inhibition of nociception and oedema by tetracyclines is neither necessarily linked to antibacterial nor to Ca2+ chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the treatment of painful and inflammatory diseases, as its lack of antibacterial and Ca2+ chelating activities might confer greater safety over conventional tetracyclines.

The influence of formulation on the dissolution profile of diclofenac sodium tablets.

In attempts to design delayed-release tablets of diclofenac sodium, seven experimental batches were produced. The influence of super-disintegrant croscarmellose sodium (CCS), the granulation process, and the thickness of Eudragit L 100 coating film were evaluated. The values of dissolution efficiency and the similarity factor were used to compare the dissolution profiles of each experimental batch and the reference Voltaren. Both methods appear to be applicable and useful in comparing dissolution profiles. Based on such values four batches were considered similar when contrasted with the reference. The results suggest an optimal relationship between the amount of CCS and the thickness of the coating film, which provides appropriate dissolution rate of diclofenac sodium from the dosage forms.

Optimization and statistical evaluation of dissolution tests for indinavir sulfate capsules.

An optimization, statistically based on t-student test, to set up dissolution test conditions for indinavir sulfate capsules is presented. Three dissolution media, including that reported in United States Pharmacopeial Forum, and two apparatus, paddle and basket, were applied. Two different indinavir sulfate capsules, products A and B, were evaluated. For a reliable statistical analysis eighteen capsules were assayed in each condition based on the combination of dissolution medium and apparatus. All tested media were statistically equivalent (P > 0.05) for both drug products when paddle apparatus was employed at the stirring speed of 50 rpm. The use of basket apparatus at the stirring speed of 50 rpm caused significant decrease in the drug release percent for the product B (P < 0.05). The best dissolution conditions tested, for products A and B, were applied to evaluate capsules dissolution profiles. Twelve dosage units were assayed and dissolution efficiency concept was used, for each condition, to obtain results with statistical significance (P > 0.05). Optimal conditions to carry out the dissolution test were 900 ml of 0.1 M hydrochloric acid as dissolution medium, basket at 100 rpm stirring speed and 260 nm ultraviolet detection.

Age effects on the pharmacokinetics of tityustoxin from Tityus serrulatus scorpion venom in rats.

The pharmacokinetics of scorpion venom and its toxins has been investigated in experimental models using adult animals, although, severe scorpion accidents are associated more frequently with children. We compared the effect of age on the pharmacokinetics of tityustoxin, one of the most active principles of Tityus serrulatus venom, in young male/female rats (21-22 days old, N=5-8) and in adult male rats (150-160 days old, N=5-8). Tityustoxin (6 microg) labeled with 99mTechnetium was administered subcutaneously to young and adult rats. The plasma concentration vs time data were subjected to non-compartmental pharmacokinetic analysis to obtain estimates of various pharmacokinetic parameters such as total body clearance (CL/F), distribution volume (Vd/F), area under the curve (AUC), and mean residence time. The data were analyzed with and without considering body weight. The data without correction for body weight showed a higher Cmax (62.30 +/- 7.07 vs 12.71 +/- 2.11 ng/ml, P<0.05) and AUC (296.49 +/- 21.09 vs 55.96 +/- 5.41 ng h(-1) ml(-1), P<0.05) and lower Tmax (0.64 +/- 0.19 vs 2.44 +/- 0.49 h, P<0.05) in young rats. Furthermore, Vd/F (0.15 vs 0.42 l/kg) and CL/F (0.02 +/- 0.001 vs 0.11 +/- 0.01 l h(-1) kg(-1), P<0.05) were lower in young rats. However, when the data were reanalyzed taking body weight into consideration, the Cmax (40.43 +/- 3.25 vs 78.21 +/- 11.23 ng kg(-1) ml(-1), P<0.05) and AUC (182.27 +/- 11.74 vs 344.62 +/- 32.11 ng h(-1) ml(-1), P<0.05) were lower in young rats. The clearance (0.03 +/- 0.002 vs 0.02 +/- 0.002 l h(-1) kg(-1), P<0.05) and Vd/F (0.210 vs 0.067 l/kg) were higher in young rats. The raw data (not adjusted for body weight) strongly suggest that age plays a pivotal role in the disposition of tityustoxin. Furthermore, our results also indicate that the differences in the severity of symptoms observed in children and adults after scorpion envenomation can be explained in part by differences in the pharmacokinetics of the toxin.

Age effects on the pharmacokinetics of tityustoxin from Tityus serrulatus scorpion venom in rats

The pharmacokinetics of scorpion venom and its toxins has been investigated in experimental models using adult animals, although, severe scorpion accidents are associated more frequently with children. We compared the effect of age on the pharmacokinetics of tityustoxin, one of the most active principles of Tityus serrulatus venom, in young male/female rats (21-22 days old, N = 5-8) and in adult male rats (150-160 days old, N = 5-8). Tityustoxin (6 µg) labeled with 99mTechnetium was administered subcutaneously to young and adult rats. The plasma concentration vs time data were subjected to non-compartmental pharmacokinetic analysis to obtain estimates of various pharmacokinetic parameters such as total body clearance (CL/F), distribution volume (Vd/F), area under the curve (AUC), and mean residence time. The data were analyzed with and without considering body weight. The data without correction for body weight showed a higher Cmax (62.30 ± 7.07 vs 12.71 ± 2.11 ng/ml, P < 0.05) and AUC (296.49 ± 21.09 vs 55.96 ± 5.41 ng h-1 ml-1, P < 0.05) and lower Tmax (0.64 ± 0.19 vs 2.44 ± 0.49 h, P < 0.05) in young rats. Furthermore, Vd/F (0.15 vs 0.42 l/kg) and CL/F (0.02 ± 0.001 vs 0.11 ± 0.01 l h-1 kg-1, P < 0.05) were lower in young rats. However, when the data were reanalyzed taking body weight into consideration, the Cmax (40.43 ± 3.25 vs 78.21 ± 11.23 ng kg-1 ml-1, P < 0.05) and AUC (182.27 ± 11.74 vs 344.62 ± 32.11 ng h-1 ml-1, P < 0.05) were lower in young rats. The clearance (0.03 ± 0.002 vs 0.02 ± 0.002 l h-1 kg-1, P < 0.05) and Vd/F (0.210 vs 0.067 l/kg) were higher in young rats. The raw data (not adjusted for body weight) strongly suggest that age plays a pivotal role in the disposition of tityustoxin. Furthermore, our results also indicate that the differences in the severity of symptoms observed in children and adults after scorpion envenomation can be explained in part by differences in the pharmacokinetics of the toxin.

Technetium-99m labeling of tityustoxin and venom from the scorpion Tityus serrulatus.

The tityustoxin, the most toxic fraction from scorpion Tityus serrulatus venom, has been used as a tool in several neurochemical and neuropharmacological studies. Biological activities of labeled and unlabeled tityustoxin and venom were compared. The samples were labeled in the presence of stannous chloride and sodium borohydride with a yield of 60-70% for the venom and 75-85% for tityustoxin and then chromatographed in Sephadex G-10. Biological activities of tityustoxin and venom were preserved after labeling.

99mTechnetium labelled Escherichia coli.

Samples of a culture of unlabeled Escherichia coli were incubated with different concentrations of stannous chloride for various time periods. 99mTc (26.0 MBq) was added to each preparation and the results showed a labelling yield of 98% for E. coli. Since the bacterial viability of 99mTc-E. coli and E. coli did not show any statistical differences, these results demonstrate that labelling of E. coli with 99mTc does not modify the bacterial viability, and the radiolabelled bacteria may be a good model to study bacterial translocation.

Evaluation of secondary prophylactic schemes, based on benzathine penicillin G, for rheumatic fever in children.

Serum concentrations of penicillin were measured in children with rheumatic fever. The adequacy of the values after administration of 1.2 million units of benzathine penicillin G every 2 or 3 weeks was confirmed; the adequacy of a 4-week regimen was questionable. The administration of 0.6 million units every 3 weeks was found to be inadequate to maintain serum levels high enough for the secondary prophylaxis of rheumatic fever.

Perfil hematologico e bioquimico de pacientes com tuberculose / Hematological and biochemical profile of patients carrying lung tuberculosis

Foram colhidas amostras de sangue de 30 pacientes com tuberculose pulmonar comprovada atraves do encontro do B.A.A.R. em esfregaços de escarro corados pelo Ziehl-Neelsen.. As amostras de sangue foram empregadas, atraves de metodologia adequada, para a determinaçao do perfil hematologico e bioquimico dos tuberculosos em busca de alteraçoes que pudessem ser distribuidas a infeccao. Os resultados observados revelaram uma tendencia a leucocitose (23//dos casos com global acima de 10.000/mm3) e um elevado aumento da velocidade de hemossedimentaçao (86//apresentaram elevaçao com media de 72 a 44 mm para mulheres ehomens, respectivamente). A monocitose, referida por varios autores na tuberculose ativa, nao foi observada. Quanto ao perfil bioquimico, os resultados da determinaçao de fosfatase alcalina e valores obtidos de globulinas se mostraram elevados em 46//dos casos. Esses resultados representaram dados preliminares obtidos atraves das avaliaçoes hematologicas e bioquimicas de pacientes com tuberculose,realizadas antes do emprego da terapeutica recomendada. Estes pacientes representam uma amostragem adequadamente selecionada para a primeira etapa do projeto depesquisa sobre a avaliaçao da conduta farmacoterapeutica no setor publico, com aparticipaçao integrada dos Departamentos de Farmacia Social, Produtos Farmaceuticos e Analises Clinicas e Toxicologicas da Faculdade de Farmacia da UFMG.