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The purpose of this study was to investigate the effect of varying drug load and concentration of a surfactant (sodium lauryl sulfate [SLS]) on the release characteristics of a model peptide (bovine serum albumin [BSA]), and study the net effects of the swelling properties of the hydrogel matrix [poly(vinyl alcohol) (PVA)]. The PVA hydrogel was prepared by a freeze-thaw process in the absence of a chemical crosslinking agent. The effect of protein loading on drug release was examined at three levels (0.65, 1.3, and 2%), whereas the effect of SLS was studied at four levels (0, 0.07, 0.13, and 0.26%). The baseline time for reaching equilibrium swelling was 48 hr for the hydrogel containing 0.65% BSA, and the equilibrium swelling time decreased significantly as the protein load was increased to 2%. The net effect of increased BSA concentrations resulted in faster BSA dissolution from the hydrogel matrix. The equilibrium-swelling ratio decreased from 21 to 10% when SLS was added to the PVA solution, which resulted in a reduction in the extent of equilibrium swelling; however, the time to reach equilibrium swelling was increased. The investigation provided a mechanistic basis toward the development of a hydrogel formulation by altering the concentration of two fundamental components, i.e., drug and surfactant, within the delivery system.

Opiate addiction is a serious problem that has now spread worldwide to all levels of society. Buprenorphine has been used for several years for the treatment of opiate addiction. The objective of this project was to develop sustained-release biodegradable microcapsules for the parenteral delivery of buprenorphine. Biodegradable microcapsules of buprenorphine/poly(lactide-co-glycolide) were prepared using two main procedures based on an in-water drying process in a complex emulsion system. These procedures differ in the way the organic solvent was eliminated: evaporation or extraction. The effect of drug loading and the effect of partial saturation of the aqueous phase with the core material during the in-water solvent evaporation were also studied. The efficiency of encapsulation increased from 11% to 34% when the drug loading was decreased from 20% to 5%. There was no significant change in the efficiency of encapsulation when the aqueous phase was partially saturated with buprenorphine. In changing the solvent removal process from evaporation to extraction, no significant change in the efficiency of encapsulation was observed. The microcapsules prepared by the solvent evaporation were smooth and spherical. However, the microcapsules prepared by the extraction of the organic solvent lost their surface smoothness and became slightly irregular and porous compared with the other batches. The average particle size of the microcapsules was between 14 and 49 microns. The cumulative drug release was between 2% and 4% within the first 24 hr. A sustained drug release continued over 45 days.

This scientific session was designed to provide participants with the most up-to-date information on cardiovascular (CV) research. The emphasis of this year's conference included: clinical trials involving growing blood vessels; vitamin E and fish oil; invasive versus non-invasive treatments; angioplasty versus stents; and, new oral antiplatelet drugs. Invited speakers, via podium and poster presentations, provided comprehensive overviews on these topics. The targeted audience for this symposium was scientists and physicians involved in CV research. Over 2300 abstracts were presented during this three-day conference.

Biodegradable microcapsules of pentamidine/poly(L-lactide-co-D,L-lactide) were prepared by solvent evaporation technique using a mixture of organic solvents. The control batch of microcapsules was prepared using dichloromethane. The effect of solvent on the characteristics of pentamidine loaded microcapsules was examined by substituting up to 30% of dichloromethane with acetone, methanol, DMSO, ethyl acetate, and ethanol, respectively. No significant change in the surface morphology was observed when dichloromethane was substituted with 20% or less amount of other solvents. These microcapsules were all porous and spherical. However, the use of 30% DMSO or ethanol, along with dichloromethane, resulted in a mixture of elongated and spherical microcapsules. The efficiency of encapsulation of these two batches was also significantly higher than the other batches of microcapsules. The average particle size of the microcapsules prepared with 30% DMSO (165 microm) was significantly higher than the other batches (< 80 microm). A substitution of 10-30% dichloromethane with other listed organic solvents also showed a significant difference in the initial drug release. The drug release within the first twenty-four hours varied from 4 to 16%. The use of a second organic solvent, except ethanol, resulted in a significantly higher drug release during the second half of the dissolution study. The drug release continued more than 60 days.

After treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), methyl methanesulfonate (MMS) and hydrogen peroxide, the level of alkali-labile sites and single-strand breaks (ssb) in DNA was investigated, using the comet assay. The ability of antioxidant pre-treatment to decrease DNA damage was assessed. Results showed the following. (a) All single-strand (ss) DNA breaks detected immediately after MNNG- and MMS-treatment in hamster V79 cells had the character of alkali-labile sites while true ssb of DNA were represented only as a minor statistically significant (p < 0.01) fraction at the highest MMS concentration. (b) Most ss DNA breaks detected immediately after H2O2-treatment had the character of true breaks in DNA and alkali-labile sites represented only a minor fraction. (c) Pre-treatment of hamster V79 and human CaCo2 cells with vitamin E significantly reduced the number of breaks induced by hydrogen peroxide, but has no effect on the level of breaks induced by MNNG or MMS. We suggest that MNNG and MMS do not induce significant oxidative damage of DNA. Most of breaks induced by hydrogen peroxide have the nature of oxidative lesions of DNA. (d) In contrast to the effect of vitamin E, stobadine (STB) decreased not only the breaks induced by hydrogen peroxide but also those induced by MNNG and MMS. The reduced level of DNA damage in STB pre-treated samples could be due to inactivation of these alkylating agents by STB.

Biodegradable microcapsules of four water-soluble drugs (pentamidine, captopril, diltiazem, and metoprolol) were prepared using a novel phase separation technique. The microcapsules prepared by this method were irregular in shape. Particle size of the microcapsules was between 60 and 500 microns. The efficiency of encapsulation for all four drugs was more than 40% at 20% drug loading. The encapsulation increased up to 75% or higher when the drug loading was reduced to 5%. The in vitro dissolution was drug dependent. The microcapsules prepared with 5% drug loading showed the minimum dissolution at the end of 24 hr. The initial drug release increased significantly when the drug loading was increased up to 20%. Although the formulations containing 5% drug maintained a sustained-release profile up to 45 days, the formulations containing 10 and 20% drug released more than 50% drug within the first 2 days.

Toxicokinetic behavior and recoveries of isoproturon from feces, urine, and different tissues of goat were determined after 4, 5, 6, and 7 days following single oral administration at 500 mg/kg. Isoproturon was rapidly absorbed and attained blood concentration within 15 min of administration. The kinetic behavior followed a two-compartment open model. The higher t(1/2)(beta) (9.78 +/- 0.33 h) and V(d)()area (4.49 +/- 0.41 L/kg) associated with lower Cl(B) (0.32 +/- 0.02 L/kg/h) suggested slow elimination from the blood. Approximately 56% of the total administered compound was recovered from feces. The rate of excretion of isoproturon through feces was maximum at 48 h and could not be detected beyond 120 h. The excretion pattern of isoproturon through urine resembled that of feces, and approximately 10-11% was eliminated in urine. A maximum quantity of residue was detected in all tissues of goats slaughtered after 4 days followed by a substantial decline after day 5, and nothing could be detected after day 7. Histopathological study revealed that isoproturon produced moderate cellular changes like fatty degeneration in the liver and kidney and emphysema in the lung after 7 days post administration.

Effect of fenvalerate on cell architecture, tissue biochemical parameters and its residual concentration was studied in broiler chicks following dermal application at 0.1 and 1% in ethanol once daily for 31 days. It did neither produce loss of body weight nor clinical signs of toxicity. Kidney contained maximal residue followed by heart, fat, liver and brain after 0.1%; and fat contained maximal residue followed by kidney, heart, liver and brain after 1% application. Fenvalerate (0.1%) increased the aspartate aminotransferase (AST) (except brain), alanine aminotransferase (ALT), alkaline phosphatase (AP), acid phosphatase (AcP) (only brain) activities, glycogen level (only liver) in liver, kidney, heart and brain tissues; and 1% increased the AST (except brain), ALT, AcP (except liver and kidney), AP (only heart), glycogen (only liver) and decreased AP (except heart), AcP (only kidney), cholesterol (except liver and heart), and acetylcholinesterase (AChE) (liver and brain) of liver, kidney, heart and brain tissue homogenates respectively. Histopathological examination in general showed aggregation of mononuclear cells in liver, around the kidney tubules and cardiac muscle fibre. In addition, fibrosis in the periportal area of liver, proliferation of ureter and tubular degeneration, and congestion of endocardial vessels were also observed. The intensity of cellular changes was more marked after 1% dermal application.

Susceptibility and/or immune response to tuberculosis may or may not be associated with particular histocompatibility leucocyte antigen (HLA) phenotype frequencies. The present study was undertaken to north eastern Indian population to verify any association between HLA phenotypes and immune response to mycobacterial antigen. HLA-typing was done in 60 well Tarasaki trays and T-cell subsets in each group were measured using Ficoll-hypaque nylon wool columns and dynabeads (M-450). No universal association with particular HLA-type and pulmonary tuberculosis has been confirmed.

Biodegradable microcapsules of zidovudine (AZT) were prepared using poly-(lactide/glycolide) by the solvent evaporation technique. The objective of this project was to focus on the effect of several formulation and processing factors on the efficiency of encapsulation, surface morphology, and drug release profiles. When the drug was incorporated as powder or as aqueous suspension containing a high amount of insoluble particles, to the organic phase the surface of the microcapsules was appeared to be wrinkled. The efficiency of encapsulation decreased when AZT powder was dispersed directly into the organic solvent instead of adding as an aqueous solution. When the relative volume of the aqueous phase containing 1% PVA was changed from 25 up to 125% of the volume of the organic phase, the efficiency of encapsulation, surface morphology, and release profiles did not change significantly. The efficiency of encapsulation decreased from 9 to 3.8% when the drug loading was increased from 10 to 50% of the weight of the polymer.

The objective of this study was to evaluate the effect of tablet integrity on the dissolution rate. The model drug used for this study was aspirin. A dissolution study was performed with three commercially-available aspirin tablets (ZORprin, Bayer 8-h aspirin and Bayer aspirin), two of which were sustained-release tablets. For ZORprin, the average dissolution data indicated that the in vitro release rate of aspirin was consistent with the intended design of the sustained-release wax matrix tablets only when the tablets were intact. The split tablets showed a consistently higher release profile over time, with a 50% higher release at 6 h. However, the Bayer 8-h aspirin and plain aspirin tablet data showed that tablet integrity had no significant impact on the dissolution rate, because the intact and split tablets showed similar drug release profiles over time. In conclusion, care should be taken to administer sustained-release tablets, avoiding any breaking or crushing of the tablets unless this is directed by the manufacturer.

Sustained release biodegradable microcapsules of AZT were prepared using different concentrations of copolymer of poly(lactic/glycolic) acid (PLGA 50:50 and PLGA 90:10). Solid microcapsules were collected following the complete evaporation of the solvent. The yield of microcapsules was increased two fold with a two-fold increase of the polymer concentration. The efficiency of encapsulation of AZT was also increased with the increase of the polymer concentration. These microcapsules were characterized using scanning electron microscopy. The dissolution of AZT from the microcapsules of PLGA (50: 50) was higher than the microcapsules of PLGA (90:10); the PLGA (50:50) microcapsules containing 1:10 drug/polymer ratio showed higher dissolution than the microcapsules containing 1:20 drug/polymer ratio. The PLGA (90:10) microcapsules containing 1:6 drug/polymer ratio showed higher dissolution than the microcapsules containing 1:10 drug/polymer ratio. In conclusion, the dissolution of AZT was dependent on the type of the copolymer used and the relative concentrations of the drug and the copolymer.

The disposition kinetics of fenvalerate were studied in goats after dermal application of 100 ml of 0.25% (w/v) solution. The insecticide persisted in the blood for 72 h. The mean (+/- SEM) Vd(area) and apparent t 1/2 (beta) were 9.92 +/- 1.44 L/kg and 17.51 +/- 2.65 h, while the AUC and ClB values were respectively 82.15 +/- 7.40 micrograms h/ml and 0.56 +/- 0.05 L/(kg h). Four days after the dermal application, the highest concentration of fenvalerate residues was found in the adrenal gland, followed by the biceps muscle, omental fat, liver, kidney, lung and cerebrum in that order. Fenvalerate caused hyperglycaemia but had no effect on serum protein and cholesterol levels. Serum acetylcholinesterase activities were increased after 24 h but were below the initial values from 48 to 120 h.

Fifty unrelated Indian Gurkha of Nepalese origin were studied to analyse the HLA antigen profile and their relation with other populations. Haplotype B35-Cw4 occurred with highest incidence and significant positive linkage disequilibrium in Gurkhas. Haplotype A10-B8 which occurs with the highest frequency in north Indians was also observed to occur with significant positive linkage in Gurkhas. HLA profile of Gurkhas thus may be the result of long-term isolation and genetic drift.

Subacute toxicity study of fenvalerate was carried out in broiler chicks after oral administration @ 525.6 mg/kg once daily for 28 days. The blood concentration of fenvalerate following 1 day post-administration (pd) was 39.65 +/- 2.67 micrograms/ml and maintained plateau thereafter up to day 21 pd, and then declined (18.46 +/- 1.47 micrograms/ml) on day 28 pd. Intestine contained maximum residue (7.46 +/- 1.96 micrograms/g) followed by fat (5.95 +/- 1.16 micrograms/g), brain (5.06 +/- 0.96 micrograms/g), liver (3.93 +/- 0.51 micrograms/g), kidney (3.79 +/- 0.72 micrograms/g) and heart (1.72 +/- 0.35 micrograms/g). Histopathological examinations showed focal areas of necrosis in liver, proliferation and fibrosis of bile duct, larger size of glomeruli, glomerular and tubular necrosis in treated birds. Fenvalerate significantly increased the cholesterol level in brain, GPT activity in liver and heart, GOT activity in heart, and alkaline phosphatase activity in heart and brain tissue. It significantly decreased the glycogen content in liver and heart, GOT activity in brain and acid phosphatase activity in all the tissues analyzed. It appears that comparatively fowl is resistant to fenvalerate toxicity.

A reversed-phase high-performance liquid chromatographic (HPLC) method for the analysis of perphenazine in rabbit plasma was developed. Amitriptyline HCl was used as the internal standard. The chromatography was performed using a Microsorb-CN column; the mobile phase consisted of 85:15 methanol/0.005 M ammonium acetate buffer; flow rate of 1.6 ml/min; and ultraviolet detection at 254 nm. Retention times were 10.8 and 18.1 min for perphenazine and amitriptyline HCl, respectively. The recovery of perphenazine added to plasma in the concentration range of 0.05-5 micrograms/ml was found to be greater than 80%. This procedure was used for the analysis of plasma samples collected over time following the oral administration of perphenazine tablets in rabbits.

Freeze-fracture electron microscopic studies revealed that the liposomal membrane morphology was intact before and after osmotic treatment. This finding suggested that water leakage from the liposomes was not due to fusion of two or more lipid vesicles, but rather to the osmotic salt effect. A stop-flow spectrophotometric study revealed that epidermal lipid liposomes derived from stratum corneum lipids of porcine skin underwent increases of the absorbances with decreases of volume of the vesicles. The initial rate at which the changes in optical density occurs is a measure of the water permeability through the liposomes. The reciprocal of the changes in the absorbance at the equilibrium at different salt osmotic shocks showed a linear dependence on the reciprocal of the osmotic pressure gradient, indicating that epidermal lipid liposomes are an ideal osmometer. The present investigation reports that lignoceric acid is a potent water barrier. Present findings suggest that the initial rate of water penetration decreased in the liposomes made from 30-45% (wt% ratio) of cholesterol and ceramides. Oleic acid as drug penetration enhancer facilitated the water diffusion of the stratum corneum lipid liposomes by a fluidizing effect on the liposomal membranes. Furthermore, ceramides are important in the water barrier properties of the skin. The permeability of water depends upon the amount (wt%) and the type of lipid of the membrane.

The concentration of oxytetracycline (OTC) in plasma, after single dose i.v. administration at 10 mg kg-1, was determined during pre and post induced-hypercalcemia in goats. The pharmacokinetic variables were then calculated. Hypercalcemia caused several changes in the determined variables. The CPmax and CPmin of OTC observed at 0.08 and 4 hr in normal goats were respectively 34.50 +/- 1.65 and 1.19 +/- 0.14 micrograms ml-1, while the CPmax and CPmin of OTC in presence of calcium at 0.08 and 8 hr were 20.81 +/- 2.18 and 1.04 +/- 0.05 micrograms ml-1 respectively. Hypercalcemic state in goats increased t1/2 (alpha) (0.19 +/- 0.02 hr), t1/2 (beta) (2.77 +/- 0.03 hr), AUC (37.67 +/- 0.83 micrograms x hr x ml vd (area) (1.07 +/- 0.03 L kg-1) and vd (ss) (0.95 +/- 0.04 L kg-1) values of OTC compared to normal goats. The semilogarithmic plot of plasma level-time profile of OTC administered i.v. showed biphasic decline suggestive of two compartment open model 'kinetics' in both normal and hypercalcemic animals.

Polymyxin B produces dose dependent changes in the surface topography of pathogenic Vibrio cholerae cells. The susceptibilities of various vibrio strains to PB are also studied through analytical techniques. Statistical analysis shows significant differences among the four vibrios with regard to their sensitivities to PB, the classical strains being the most sensitive. Treating the classical strain with subinhibitory concentration of PB, we observed with both SEM and TEM that the normal smooth surface of the cell envelope develops some protruded structures (blebs and crenations). Further the TEM study of the ultrathin sections reveal that the rod like projections are formed by protrusions of the outer-membrane of the cell wall.

Polymyxin B produced dose dependent changes in the surface topography of the goat erythrocyte cells. Transformation from the normal biconcave discs through crenated structures to the final rounded or spherical shape was recorded by scanning electron microscopy. A maximum of three to four crenations per cell was recorded corresponding to a polymyxin dose of 15.62 micrograms/ml. Transmission electron microscopy of the ultrathin sections of treated or untreated erythrocytes indicated that the crenations were formed by protrusions of the plasma membrane, occurring presumably because of the local increase of membrane fluidity after polymyxin treatment. Changes in the shape of the erythrocytes to the ultimate rounded forms were also indicated by the transmission electron microscopy.

The phospholipid composition of three different strains of Vibrio cholerae was determined by quantitative two-dimensional thin-layer chromatography. The polymyxin sensitivity of the whole organisms or of the liposomes derived from the total phospholipids of these organisms depended solely on the phosphatidyl ethanolamine content of the system concerned and could be quantitatively related by the equations Y1 = 1.074 X1 - 9.828 and Y2 = 1.22 X2 - 34.47 where Y represents the maximum lysis (%)/hr and X, the % phosphatidyl ethanolamine content of the system concerned, the suffix 1 and 2 corresponding to the liposomal and the whole organisms respectively. The analysis revealed the requirement of a threshold amount of phosphatidyl ethanolamine for the expression of polymyxin action on the system concerned.