Granule and tablet formulae study by principal component analysis

The authors wanted to demonstrate the interest of the use of Principal Component Analysis (PCA) for the interpretation of galenical results. To do this, they applied this method to the study of the effect on granules and tablets of diluent type, and concentration and viscosity of the wetting liquid.Following this work, it seems that PCA can be recommended when the number of formutae and parameters studied culminate in a large number of results. In fact, PCA enables better definition and limitation of the number of parameters involved. Where formula optimization is desired, a method such as Simplex can be used in a better clarified framework.     

Design of sterile muramyldipeptide-containing oligolamellar liposomes suitable for i.v. injection. Effect of liposome size and lipid composition on their ability to render peritoneal macrophages antitumoral

The water-soluble immunomodulator muramyldipeptide has been encapsulated in oligolamellar liposomes (mean diameter 200 nm) of various lipid compositions. These liposomes were sterilized by Millipore filtration without loss of entrapped solute and are therefore suitable for i.v. administration. The amount of encapsulated MDP increased when the volume of aqueous phase (containing a given MDP concentration) used for hydrating the phospholipid film increased and this did not vary for at least 15 days when the liposomes were kept at 4°C.The presence of cholesterol did not modify the encapsulation results but prevented the leakage of encapsulated water-soluble solute in serum-containing media.The internalization of various types of liposomes by murine peritoneal macrophages has been studied in order to define the best conditions for activating macrophages. For a given lipid composition, sterile oligolamellar vesicles (suitable for i.v. injection) were more efficient than multilamellar vesicles in rendering macrophages capable of inhibiting the growth of a syngeneic tumor, particularly when these vesicles contained muramyldipeptide in their aqueous space and cholesterol in their lipidic phase.     

Pharmacokinetics of cefotiam after i.v. administration to healthy volunteers

The inability to calculate a definitive value for apparent volume of distribution at steady state is discussed and a method presented whereby the possible minimum and maximum values for V_ss may be determined for a drug obeying linear kinetics whose disposition may be characterized by means of a tri-exponential equation.     

Accelerated stability studies on Rocephin by high-efficiency liquid chromatography

The stability of Rocephin in aqueous solutions was studied for different pH values in research into accelerated instability. The pH range studied was 2.5, 4.5, 5.5, 6.5, 7.4 and 8.0 adjusted to an ionic strength of μ = 0.5; each of these values was subjected to temperatures of 50, 60, 70 and 80 °C. From the experimental values found for the concentrations of undegraded Rocephin as a function of time it was seen that the degradation process of this cephalosporin follows first-order kinetics.The technique used for the determination of Rocephin was high-efficiency liquid chromatography, using a reverse phase (RP-18) as the stationary phase.Linear relationships were established for each pH studied, between the logarithms of the experimental degradation constants and the reciprocals of the absolute temperatures, obtaining correlation coefficients greater than 0.91.These values were used to calculate the values of the degradation constants, half-lives and expiry date for each pH at temperatures of 37, 20 and ?4°G Simultaneously, the activation energy and the logarithm of the frequency factor were determined, giving average values of 13.11 kcal/mol and 5.62, respectively.The values obtained for the expiry date at 20°C, greater than 7 h for all the pH values mean that in terms of pH-regulated degradation this antibiotic may be used in the normal perfusion liquids.     

Metabolism of aflatoxin B1 (AFB1), aflatoxin G1 (AFG1) and vitamin C intake by guinea pig liver preparation in vitro

Male and female guinea pigs weighing 150–200 g were divided into three groups, with equal number of males and females in each group. They were fed an experimental diet which varied as follows: group I, 0 mg vitamin C/g of diet; group II, 1.08 mg/g and group III, 5.4 mg/g, for 28 days. Twenty-four hours after the last feeding, liver slices and 9000 g supernatant were prepared from each group, according to sex, and used for enzyme assays. For the demethylation assay, enzyme activity expressed as amount of formaldehyde produced from AFB₁, or AFG₁/hr/g fresh liver was seen to increase with the two levels of ascorbic acid intake in females. Males showed an enhancement of activity only in group II and remained with the same production of formaldehyde as above in group III. Although in each dietary group, the activity was higher in males than in females the variation in the amount of formaldehyde produced from one group to another was higher with females than with male guinea pigs. However with both sexes, the production of formaldehyde from AFG₁, was greater than from AFB₁. For the hydroxylation assay, enzyme activity was expressed as amount of metabolites (a) and (b) produced. Compared to group II, which offered a control level of ascorbic acid, group I fed without vitamin C showed a decreased production of metabolite (a) and (b) with males and females. Moreover, high intake of ascorbic acid in group III decreased the production of metabolite (a) and (b) in males, while in female guinea pigs the reduction was observed only with (b).     

The lipophilicity of deuterium atoms. A comparison of shake-flask and HPLC methods

Isotopic effects are demonstrated in the lipophilicity, measured by shake-flask and HPLC methods, of a series of deuterated aromatic compounds. The results indicate that deuterated compounds are less lipophilic than their protium isomers by about ?0.006 per deuterium atom on the log P_oct scale. This isotopic effect is satisfactorily accounted for by differences in molar volumes of isotopomers. The partition coefficient of benzene and toluene is critically evaluated in view of the volatility of these compounds.     

Subacute toxicity of technical fenitrothion in male rats

Male CD-strain rats (100–125 g) received fenitrothion by oral gavage (2.5, 5.0, 10.0 or 20.0 mg/kg/day) for 30 consecutive days. Control animals received equivalent volumes of taurocholate vehicle. Animals were killed at 8, 15, 22 and 30 days during treatment and at 8, 15, 29, 57 and 85 days after terminating treatment. The brain plasma and erythrocyte cholinesterases, hepatic and renal non-specific carboxylesterases were assayed. Serum biochemical markers of hepatic function were measured. Histologically stained sections of liver were examined by light microscopy.Fenitrothion, at doses between 2.5 and 10 mg/kg body wt, caused few observable deleterious effects to male rats except those effects on tissue esterases associated with organophosphorus esters. Only 8 of 36 animals receiving the 20.0 mg/kg dose died, all in the first week of treatment. A dose-dependent decrease in tissue esterase activity was observed which persisted throughout the entire treatment period. Periodic signs of overt toxicity were observed only in animals receiving 20 mg/kg/day. Tissue esterase activities returned to control levels within 1 or 2 weeks of stopping treatment. No significant treatment-related changes were observed by serum biochemistry or by light microscopy.     

Assessment of mercuric chloride-induced nephrotoxicity by p-aminohippuric acid uptake and the activity of four gluconeogenic enzymes in rat renal cortex.

p-Aminohippurate (PAH) uptake and the activities of four gluconeogenic enzymes were used in vitro as indicators of nephrotoxicity in rats. The purpose was to compare the relative sensitivities of the gluconeogenic enzymes (pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-diphosphatase, and glucose-6-phosphatase), measured in renal cortical homogenates, and PAH uptake, measured in renal cortical slices, following ip treatment with mercuric chloride (HgCl₂). The morphologic aspects of the nephrotoxicity produced by HgCl₂ were also evaluated. A time study (30 days) following administration of 2 mg/kg of HgCl₂ showed that PAH uptake was more sensitive to HgCl₂ than the activities of the four gluconeogenic enzymes. The greatest inhibitory effect was noted on Day 6 and an increase toward normal was seen from Day 7. A dose-response study undertaken 6 days after HgCl₂ showed that 1 mg/kg caused significant decreases in the activities of fructose-1,6-diphosphatase and pyruvate carboxylase. However, PAH uptake was significantly reduced at 0.5 mg/kg; with this dosage no morphologic renal alterations were observed. PAH uptake was found to be more sensitive for detecting HgCl₂-induced nephrotoxicity than were the activities of the four gluconeogenic enzymes, with fructose-1,6-diphosphatase being the most sensitive of the four enzymes.     

The effect of streptozotocin diabetes on endotoxicosis in mice

Repeated injections of streptozotocin (SZN), to a total of 5 mg, produced a state of diabetes in mice without alteration in various parameters of the reticuloendothelial system (RES). This was associated with hyperreactivity to endotoxin lethality which decreased with time and which could not be correlated with blood glucose levels in SZN injected animals. One single injection of SZN, too, sensitized animals to endotoxin death, albeit less effectively than after repeated administration of small doses, although the effect was dose dependent. Impairment of protection by cortisol against endotoxin lethality in mice was less severe after a single injection of SZN vs administration of an equivalent amount of SZN divided over a 5 day period. Blood glucose levels diminished very rapidly after endotoxin administration and were only partially reversed during cortisol protection against the lethal effects of endotoxin in SZN pretreated animals. Streptozotocin impaired the induction of tolerance to endotoxin but not the activation of the RES that accompanies tolerance. It is suggested that the influence of various pharmacological agents that reverse SZN diabetes may form a new model to elucidate the pathophysiology of endotoxicosis.     

The binding of aryl carboxylic acid derivatives to human serum albumin--a structure-activity study

The binding interactions of some aryl carboxylic acid derivatives have been examined by circular dichroism and fluorescence spectroscopy. With specific probes, we have shown that the seven ligands under study bind primarily to the benzodiazepine site on HSA. Their association constants are in the range of 10(5)-10(6) M-1 as found by spectropolarimetric titration, and appear to be closely related to some chemical features. It is concluded that the binding is enhanced by the lengthening of the carbon chain substituent with a terminating carboxyl moiety and by halogen substitution in the aromatic rings. It is further shown that hydrophilic substitutions such as hydroxyl or ketone groups in the carbon chain substituent will decrease the binding.     

Inhibition by mepacrine and p-bromophenacylbromide of phosphoinositide hydrolysis,glucose oxidation,calcium uptake and insulin release in rat pancreatic islets

Mepacrine and p-bromophenacylbromide were both found to impair ³H-inositol phosphate production in response to both nutrient and hormone-neurotransmitter stimuli in islets prelabelled with ³H-inositol. Both drugs also inhibited net ⁴⁵Ca uptake in response to glucose or glibenclamide and considerably modified the patterns of ⁴⁵Ca and ⁸⁶Rb efflux from perifused islets under both basal and glucose-stimulated conditions. In addition, the oxidation of [U-¹⁴C] glucose in islets was impaired by either mepacrine or p-bromophenacylbromide. These inhibitory effects were found to be concentration-related for both mepacrine (0.01–1.0 mM) and p-bromophenacylbromide (0.03–0.3 mM) and were accompanied, in general, by a similar degree of inhibition of insulin secretion. These results suggest that both mepacrine and p-bromophenacylbromide can inhibit phospholipase C activity in intact islets, but also impair ⁴⁵Ca and ⁸⁶Rb fluxes and oxidation of nutrients. The diversity of these drugs' inhibitory actions makes them unsuitable tools for examining the role of specific cellular processes in the regulation of islet function.