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Biomedical subjects

G Torosian

Publications and source records attributed to G Torosian.

At least 19 recordsLinked to original sources
PubMed1994

Sustained-release oral delivery of theophylline by use of polyvinyl alcohol and polyvinyl alcohol-methyl acrylate polymers.

Crystalline polyvinyl alcohol (PVA) polymer and low-crystallinity polyvinyl alcohol-methyl acrylate copolymer (PVA-MA) were examined as sustained-release tablet excipients with theophylline as a model drug. By blending of different proportions of the crystalline polymer and the low-crystallinity copolymer, it was possible to affect the release characteristics of the tablets. Tablets made with crystalline PVA provided instant release of theophylline in vitro. Tablets made with a larger proportion of PVA-MA relative to PVA provided a very prolonged release profile in vitro. A formulation containing PVA-MA:PVA:theophylline in a ratio of 1:9:10 provided sustained-release profiles in vitro and in vivo in dogs. The dissolution release profile of this PVA-blend tablet formulation in vitro agreed extremely well with the percentage of bioavailable dose absorbed over time in vivo. The formulation provided a plateau of levels in plasma over 16 h. The oral bioavailability of theophylline from this formulation in dogs was approximately 80% and was equivalent to that obtained after administration of Theo-Dur, a marketed extended-release theophylline tablet from Key Pharmaceuticals.

Absorption↗
PubMed1994

Investigation of moricizine hydrochloride polymorphs.

The antiarrhythmic agent moricizine hydrochloride exhibits a single melting-decomposition endotherm peak at temperatures ranging from 209 to 214.5 degrees C (Form I) when recrystallized from polar solvents, as determined by differential scanning calorimetric analysis. However, a different polymorphic form (Form II), with a differential scanning calorimetric melting-decomposition peak temperature of 190 degrees C, was generated by recrystallizing moricizine hydrochloride from nonpolar solvents. These two polymorphic forms can be reversibly converted to one another by selecting recrystallization solvents. The existence of these polymorphs was confirmed by Fourier transform IR microscopy, X-ray powder diffractometry, and solution calorimetry. Polymorphic Form I exhibited a slightly slower initial dissolution rate than Form II, which correlated well with heats of solution data (less heat needed to dissolve Form II). A simulated wet granulation process did not change the polymorphic form, suggesting that wet granulation is feasible for tablet preparation.

Calorimetry, Differential Scanning↗
PubMed1992

Degradation kinetics and mechanisms of moricizine hydrochloride in acidic medium.

The degradation kinetics of moricizine hydrochloride (1) were examined over a pH range of 0.6 to 6.0 at an ionic strength of 0.3 and 60 degrees C. The disappearance of intact 1 was followed by a stability-indicating HPLC assay. The degradation products, which had approximate solubilities of less than 100 micrograms/mL, precipitated in aqueous solution. The precipitate was collected for HPLC analysis and identification of degradation products. Degradation of 1 was catalyzed by acetate and phosphate buffers and was pH dependent, with the pH of the minimum rate constant located between 2.8 and 3.2. At pH 0.6-2.0, 1 degraded via amide hydrolysis to yield first ethyl (10H-phenothiazin-2-yl) carbamate (2), an amide hydrolysis product, which further oxidized in parallel to give ethyl (3-oxo-3H-phenothiazin-2-yl) carbamate (3), ethyl (10H-phenothiazin-2-yl) carbamate S-oxide (4), and diethyl (3,10'-bi-10H-phenothiazine-2,2'-diyl)bis(carbamate) (5), the dimer of the amide hydrolysis product. At pH 2.2-6.0, 1 degraded via a reverse Mannich reaction, to form the reverse Mannich product ethyl [10-(1-oxo-2-propenyl)-10H-phenothiazin-2-yl] carbamate (6), and by parallel reaction via the described amide hydrolysis pathway. The dimer of the amide hydrolysis product was not detectable at pH greater than 2.8. At pH greater than 4.0, the reverse Mannich product was the predominant degradation product. Degradation of 1 was subject to positive and negative kinetic salt effects at pH 1.0 and 4.0, respectively. Arrhenius plots determined at pH 1.0 and 6.0 were linear between 37 and 70 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Buffers↗
PubMed1989

Self-association and solubility behaviors of a novel anticancer agent, brequinar sodium.

To aid in the selection of appropriate excipients to formulate brequinar sodium [6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxyli c acid sodium salt; DuP 785], studies were initiated to characterize thoroughly its solubility behavior. The measured solubilities at RT (approximately 23 degrees C) agreed with the theoretical values in the pH range from 0.5 to 7.2, but became significantly greater than theoretical values at pH values above 7.2. This deviation was likely due to the vertical stacking-type self-association between brequinar molecules in water. The NMR and pH methods determined a critical association concentration of 15 mg/mL. Sodium salicylate, which has been proven to interfere with molecular self-association, reduced drug solubility from 116 to 10 mg/mL. But urea, another deaggregative agent, gave about a twofold increase rather than a decrease in solubility. Addition of sodium chloride caused a 226-fold decrease in solubility. The apparent solubility product did not remain constant but decreased as sodium chloride concentration increased, suggesting that the added salt decreased the degree of self-association between brequinar molecules. Among four surfactants examined (a bile salt with a rigid fused ring versus three ordinary surfactants with a flexible chain structure), only sodium cholate significantly increased the aqueous solubility of brequinar sodium.

Antineoplastic Agents↗
PubMed1989

Polyvinyl alcohol-methyl acrylate copolymers as a sustained-release oral delivery system.

Low crystalline and crystalline polyvinyl alcohol-methyl acrylate (PVA-MA) copolymers were examined, because of their excellent flow and compressibility properties, as matrices for sustained-release tablets using phenylpropanolamine hydrochloride (PPA.HCl) as a model drug. Crystallinity of the copolymer affected the release characteristics from the tablet. Tablets made with low-crystalline PVA-MA provided sustained release of PPA, both in vitro and in vivo in dogs. PPA absorption from the low-crystalline PVA-MA tablet formulation was biphasic. An initial rapid phase was followed by a second, slower absorption phase which continued over 16 hr. Plasma PPA concentrations then declined with a half-life roughly parallel to the oral immediate-release half-lives. Oral bioavailability from the low-crystalline PVA-MA tablet formulation was 78.8 +/- 3.9%.

Acrylates↗
PubMed1985

Effects of prenatal exposure to tricyclic antidepressants on adrenergic responses in progeny.

Studies were undertaken to examine the effects on cardiovascular function in progeny of rats treated maternally with the tricyclic antidepressants, doxepin and imipramine. Doxepin was administered once daily during the first trimester (days 1-7), second trimester (days 8-14) or third trimester (days 15-21) of pregnancy, while imipramine was administered during the third trimester only. Exposure to doxepin during the first or second trimester increased infant mortality rate, while third trimester exposure to imipramine, but not doxepin, enhanced infant mortality. Additionally, third trimester imipramine, but not doxepin, exposure reduced birth weight and growth rate of progeny. Tests of cardiac and aortic response to adrenergic stimulation revealed that third trimester exposure to either of these tricyclic antidepressants enhance the responsiveness of the beta-adrenergic system in the aorta, while doxepin exposure during the other trimesters was without effect on aortic beta-response. Prenatal exposure to these antidepressants did not alter blood pressure or the contractile response of aortic tissues to alpha-receptor stimulation. Collectively, these studies reveal that at doses of tricyclic antidepressants which do not cause dysmorphic effects on the fetus, subtle alterations occur in selective adrenergic functions which can persist into adulthood in the rat.

Animals↗
PubMed1982

Solubility and ionization characteristics of doxepin and desmethyldoxepin.

The theromdynamic pKa values for doxepin and its metabolite desmethyldoxepin were determined by the solubility method to be 8.96 and 9.75, respectively at 25 degrees. The intrinsic solubilities for doxepin and desmethyldoxepin were linearly dependent upon ionic strength. The intrinsic solubilities at zero ionic strength and 25 degrees were determined to be 1,13 x 10(-4) M for doxepin and 3.95 x 10(-4) M for desmethyldoxepin. The solubility experiment was repeated at different temperatures and a constant ionic strength of 0.167 M. The change in enthalpy (6.71 kcal/mole) and entropy (-4.16 cal/mole degrees K) of solution for doxepin was determined from a van't Hoff plot for this nonideal system. The apparent partition coefficient between hexane and water for the doxepin free base was determined to be 13,615 at an ionic strength of 0.067 M.

Doxepin↗
PubMed1981

Pharmacokinetics of sulfisoxazole compared in humans and two monogastric animal species.

The pharmacokinetic profile of sulfisoxazole was studied and compared in dogs, swine, and humans. The trial was conducted over a 72-hr period after intravenous administration and a 96-hr period after oral administration in dogs and swine. In humans, the trial was conducted over an 8-hr period after oral administration. A two-compartment model system was used to define the pharmacokinetic profile. The mean half-lives for the distribution phase were 4.08, 1.30, and 0.56 hr in dogs, swine, and humans, respectively. For the elimination phase, the mean half-lives were 33.74, 46.39, and 7.40 hr in dogs, swine, and humans, respectively. The mean volume of the central compartment was approximately the same in dogs and swine, 10.6 and 10.5 liters, respectively. Humans had a smaller volume of distribution, 7.7 liters. The steady-state volumes of distribution were 17.2, 30.3, and 16.2 liters in dogs, swine, and humans, respectively. Dogs and swine excreted 42.2 and 30.7%, respectively, of the intravenous dose and 29.4 and 18.3%, respectively, of the oral dose. The bioavailability was 69.8% in dogs and 100.0% in swine. The fraction of drug bound ranged from 30 to 50% in dogs, 40 to 60% in swine, and 25 to 40% in humans.

Administration, Oral↗
PubMed1979

Dissolution behavior of commercial enteric-coated aspirin tablets.

Dissolution behavior was studied for four commercial batches of enteric-coated aspirin tablets from two companies. The USP XIX dissolution procedure was modified by including pretreatment in simulated gastric juice. The effects of five pretreatment times were studied. Pretreated tablets yielded higher dissolution profiles and fewer undissolved fractions than nonpretreated tablets. Among pretreatments, 15 min was adequate and 60 min produced the highest dissolution profiles. None of the pretreatments differed significantly from each other. An F test and conducted on the data indicated that Product X was significantly better than Product Y at the p=0.05 level. Batch C was ranked as the best batch irrespective of pretreatment time, followed by Batch D. Batches A and B were equal, although Batch A appeared to be better than B for the 60-min pretreatment, as indicated by the lower t80% value.

Aspirin↗
PubMed1978

Loss of color from Jiffy tubes.

Colored, disposable applicator tubes have been said to lose color to their contents during use. Since they are used to contol the placement of a variety of accessory materials important to clinical dentistry, a selection of restorative materials and solvents was evaluated to determine which had a color-leaching potential. Neither aqueous system nor alcohol, chloroform, eugenol, xylene, or ether caused a loss of color that was clinically significant. Acetone and amyl acetate caused a visibly apparent loss of color and softening of the tube matrix. Methyl methacrylate completely dissolved specimens of celluloid tubes. Unfilled resins containing methyl methacrylate in their liquid catalysts leached sufficient red color form the test specimens to stain the restorative noticeably pink; the composite resins and cements that were evaluated did not.

Color↗
PubMed1978

beta-Cyclodextrin as an aid to peritoneal dialysis. Renal toxicity of beta-cyclodextrin in the rat.

A peritoneal dialysate containing beta-cyclodextrin has been shown to accelerate the removal of intravenously administered phenobarbital in rats. It was found that high concentrations of beta-cyclodextrin were toxic to the animals in the single exchange technique employed. The renal toxicity was estimated by measuring blood urea nitrogen values in the rats following oral and intraperitoneal administration of the cyclic amylose.

Amylose↗
PubMed1976

Effect of orange juice consumption on urinary pH.

The effect of orange juice consumption on urinary pH was studied in seven adult male subjects, each of whom served as his own control. The diet of the subjects was standardized during the work-day. The effects of two regimens of orange juice were studied: 1500 ml divided into five 300-ml portions during the day, and 300 ml once in the morning. Urine was collected, its pH recorded, and titrated with HCl to determine the mEq of base excreted per unit time. The consumption of 300 ml of orange juice did not significantly alter urinary pH. The consumption of 1500 of orange juice changed the urinary pH by an average of one pH unit. A change of this magnitude could cause clinically significant variation in the overall excretion pattern of acidic or basic drugs.

Adult↗
PubMed1975

Evaluation of preparations of patent blue (Alphazurine 2G) dye for parenteral use.

The stability and the behavior of patent blue (Alphazurine 2G) dye in a vehicle such as lidocaine hydrochloride injection were studied with regard to medication orders which may be prepared by hospital pharmacists. The patent blue family of dyes are sulfonated diaminotriphenylmethane, vital, acid dyes which have been used as diagnostic aids in both lymphography and burn debridement. A literature review, including some toxicological information, is presented. The occurrence of the sodium salt form and the equilibrium solubility of the patent blue sample studied are reported. Some implications of patent blue injections include: Clinical literature reports of toxicities, the unapproved status of patent blue by the Food and Drug Administration, results of stability studies, and the formation of viscid, water-insoluble precipitates of patent blue in combination with lidocaine hydrochloride. The extemporaneous preparation and subsequent use of parenteral prescriptions of patent blue dye in vehicles containing lidocaine hydrochloride and methylparaben are not recommended.

Aniline Compounds↗
PubMed1975

Extemporaneous preparation of methyldopa in two syrup vehicles.

The stability of methyldopa in two extemporaneous syrup preparations was studied. Film-coated methyldopa tablets were triturated and incorporated into (1) unpreserved Syrup USP and (2) an equal mixture of simple syrup containing 0.5% citric acid and 0.2 N hydrochloric acid, in concentrations of 50 mg/ml. The preparations were stored in the dark, for 14 days at 5 C and 25 C. Samples were analyzed spectrophotometrically for methyldopa content at various intervals. Both preparations were stable under the conditions studied.

Biological Availability↗