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J M Gallo

Publications and source records attributed to J M Gallo.

At least 91 records · Page 5Linked to original sources
PubMed1991

Pharmacokinetic evaluation of drug interactions with zidovudine. I: Probenecid and zidovudine in monkeys.

Pharmacokinetic evaluation of a drug interaction between zidovudine (AZT) and probenecid was conducted in monkeys. Six animals received 20 mg/kg of AZT as single intragastric (ig) and iv doses in the absence and presence of 50 mg/kg of probenecid administered ig. Plasma concentrations of AZT and its 5'-glucuronide metabolite (AZTG) were quantitated for 12 h by HPLC. Amounts of AZT and AZTG in urine were also measured, as were probenecid plasma concentrations. Non-compartmental methods were used to obtain pharmacokinetic parameters for AZT and AZTG. In the presence of probenecid, the total clearance of AZT decreased by 50%, renal clearance decreased, and elimination half-life increased. The volume of distribution at steady-state and systemic bioavailability of AZT were not significantly altered by probenecid. The areas under the plasma concentration-time curves and terminal half-lives of AZTG were increased, and renal clearances of AZTG were decreased. The alterations in AZT and AZTG pharmacokinetic parameters are consistent with inhibition of metabolism and renal tubular secretion by probenecid. Since AZT was administered by both oral and iv routes, clearance, volume of distribution, and bioavailability parameters were independently determined. Based on data reported for humans on the zidovudine-probenecid interaction, monkeys appear to be appropriate animal models for the evaluation of zidovudine drug interactions.

Animals↗
PubMed1991

Hybrid pharmacokinetic models to describe anti-HIV nucleoside brain disposition following parent and prodrug administration in mice.

Brain delivery of active anti-HIV compounds is important for successful treatment of the AIDS patient. As an initial step in predicting human brain drug concentrations, hybrid pharmacokinetic models were developed to characterize the disposition of anti-HIV nucleosides following parent and prodrug administrations in mice. Mouse data were obtained following intravenous administration of 3'-azido-2',3'-dideoxyuridine (AZddU or AZDU), 3'-azido-3'-deoxythymidine (AZT), and their dihydropyridine prodrugs (AZddU-DHP and AZT-DHP). Exponential equations were fitted to the serum concentration-time data for each species, including the pyridinium ion moieties, and subsequently used in differential mass balance equations describing the brain dynamics of each compound. Model parameters for the mass balance equations were estimated by various techniques, including the utilization of in vitro data. In general, model-predicted brain concentrations agreed with the observed data. Similar data in larger animals will permit scale-up of the current model to predict human brain drug concentrations.

Animals↗
PubMed1991

Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution, and specificity.

Antibodies to ubiquitin have been used to search for evidence of abnormal protein degradation in amyotrophic lateral sclerosis--motor neuron disease (ALS). Anterior horn cell ubiquitin-immunoreactive (IR) inclusions were present in all of 31 ALS cases but in none of 23 neurologically normal and in only 1 of 22 neurologically abnormal controls. These inclusions, which were present in familial and sporadic ALS cases, and in cases with dementia, took the form of dense rounded or irregular ubiquitin-IR cytoplasmic inclusions (dense bodies), or loosely arranged bundles ('skeins') of filamentous-appearing material. The presence of ubiquitin-IR inclusions corresponded to the pattern of selective neuronal vulnerability in ALS, although inclusions in pyramidal neurons of the motor cortex were infrequent and were noted in only a minority of cases. Ubiquitin-IR inclusions were more prevalent than Bunina bodies. The latter were present in 67% of ALS cases but were seldom labelled by antibodies to ubiquitin. Intraneuronal inclusions resembling Lewy bodies were present in 23% of ALS cases and were often identified by antibodies to ubiquitin. We conclude that the presence of ubiquitin-IR inclusions in lower motor neurons represents a characteristic pathological feature of ALS in its various clinical forms. Ubiquitin-IR inclusions in ALS differ from ubiquitinated inclusions in other neuronal degenerations in that they are not readily identified by antibodies to cytoskeletal proteins. They may represent accumulations of altered or abnormal neuronal proteins resistant to degradation via the ubiquitin proteolytic pathway.

Adult↗
PubMed1991

Pharmacokinetics of anti-HIV nucleosides in microswine.

The objective of the study was to determine if the micropig (Sus scrofa) would serve as an animal model for the anti-HIV nucleosides 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (ddI), and 2',3'-dideoxycytidine (ddC). Four adult male micropigs were administered i.v. 20 mg kg-1 AZT, 20 mg kg-1 ddI, both as 10 min infusions, and 5 mg kg-1 ddC, as an i.v. bolus. At least 12 days separated each drug administration. Following each drug administration, blood samples were collected by venipuncture and urine was collected by placement of the animals in metabolism cages. Concentrations of parent drug and AZT's glucuronide metabolite were quantitated in plasma and urine by HPLC. Data were analysed by noncompartmental methods to obtain pharmacokinetic parameters for each drug. Total and renal clearances for AZT, 0.482 +/- 0.058 and 0.326 +/- 0.075 L h-1 kg-1, respectively, and for ddI, 0.500 +/- 0.057 and 0.337 +/- 0.100 L h-1 kg-1, showed that these drugs were eliminated primarily by renal excretion rather than by liver metabolism as in man. ddC's clearances were similar to rates in man. Volume of distribution at steady state values were 0.784 +/- 0.071, 1.192 +/- 0.288 and 0.886 +/- 0.199 L kg-1 for AZT, ddI and ddC, respectively. Half-life values for AZT, ddI and ddC were 1.39 +/- 0.127, 2.585 +/- 0.243 and 1.832 +/- 0.380 h, respectively. Based on these findings, the micropig could be an appropriate model for the study of ddC in man, but not for AZT of ddI.

Animals↗
PubMed1991

Pharmacokinetics of 2',3'-dideoxyinosine in monkeys.

Comparison of the pharmacokinetic parameters obtained for dideoxyinosine (ddI) in monkeys with those obtained for humans indicates that the monkey is an appropriate animal model for ddI pharmacokinetics in humans. Following intravenous administration of 20 mg of ddI per kg of body weight and measurement of ddI in plasma and urine by high-performance liquid chromatography, pharmacokinetic parameters were determined by noncompartmental analysis. Total systemic clearance was 0.74 liters/h/kg, volume of distribution was 0.92 liters/kg, and the elimination half-life of ddI was 1.22 h. The pharmacokinetics of ddI in five monkeys were determined following intravenous administration of 20 mg/kg and were found to be comparable to those obtained in patients with AIDS.

Animals↗
PubMed1991

Characterization of a monoclonal antibody to human proacrosin and its use in acrosomal status evaluation.

Among the monoclonal antibodies (MAb) selected after immunization of mice with a detergent-insoluble fraction from human spermatozoa, MAb 4D4 was found to stain in immunofluorescence the principal part of the acrosome of human spermatozoa. Acrosome reaction induced decreased and spotty 4D4 immunofluorescence staining. Immunoelectron microscopy before or after embedding revealed that the epitope defined by MAb 4D4 was sequestered in the anterior acrosomal matrix and, after the acrosome reaction, remained partly bound on matrix elements attached to the inner acrosomal membrane. Western blot analysis of sperm extracts showed that the epitope defined by MAb 4D4 was located on a 55 KD polypeptide in whole cells and on 55 and 50 KD polypeptides in non-ionic detergent fractions. Human proacrosin-enriched fraction obtained by FPLC purification exhibited several proteolytic activities against gelatin in gel enzymography: a 50 KD major band and two minor bands in the 20-30 KD area; the 50 KD polypeptide reacted with MAb 4D4 in Western blots. Furthermore, the 4D4-immunoprecipitated polypeptide from sperm extract showed that the 50 KD band exhibited proteolytic activity with an optimal pH at 8.0 that was strongly inhibited by soybean trypsin inhibitor and ZnCl2. MAb 4D4 also reacted with the acrosome of the monkey Macaca fascicularis but not with the acrosome of any of the other non-primate mammalian species examined so far. Various shape defects of the acrosomal principal region were revealed by 4D4 labeling of spermatozoa with head anomalies from infertile patients. MAb 4D4 also recognized proacrosin in paraffin-embedded human testis sections. These data make the monoclonal antiproacrosin antibody 4D4 an efficient tool for evaluation of the acrosomal status of human spermatozoa and spermatids.

Acrosin↗
PubMed1991

Human acrosome biogenesis: immunodetection of proacrosin in primary spermatocytes and of its partitioning pattern during meiosis.

Proacrosin biosynthesis timing during human spermatogenesis has been studied using the monoclonal antibody 4D4 (mAb 4D4). Frozen and paraffin-embedded sections of testicular biopsies were labelled by standard indirect immunofluorescence and avidin-biotin immunoperoxidase procedures. The labelling specificity was checked by immunochemistry assays on unrelated tissues and by western blotting of testis extracts showing that only the 50-55 x 10(3) Mr proacrosin was recognized by mAb 4D4. Proacrosin was first observed in the Golgi region of midpachytene primary spermatocytes. In late pachytene primary spermatocytes, proacrosin was observed in two regions located at opposite nuclear poles. During the subsequent steps of the first meiotic division, the two bodies containing proacrosin were located: (i) on opposite sides of the equatorial plate during metaphase; (ii) along the microtubular spindle during anaphase; and (iii) close to each chromosomal aggregate during telophase. Two bodies containing proacrosin were still observed in interphasic secondary spermatocytes. The single labelled area observed in early spermatids was found to increase considerably in size during spermiogenesis. Anomalies of proacrosin scattering were observed in patients with Golgi complex partitioning failure. These data reveal proacrosin biosynthesis during diploid and haploid phases of human spermatogenesis and the proacrosin partitioning pattern during meiosis.

Acrosin↗
PubMed1990

Effect of dosing vehicles on the pharmacokinetics of orally administered carbon tetrachloride in rats.

The primary objectives of this investigation were to determine whether oil and aqueous dosage vehicles alter the pharmacokinetics of orally administered carbon tetrachloride (CCl4) in rats, and to relate vehicle effects on CCl4 absorption and bioavailability to alterations of the acute hepatotoxicity of CCl4 seen in a companion study (H.J. Kim, S. Odend'hal, and J. V. Bruckner, 1990, Toxicol. Appl. Pharmacol. 102, 34-49). Fasted 200- to 230-g male Sprague-Dawley rats with indwelling arterial cannulas received 25 mg CCl4/kg body wt by gavage: in corn oil; as an Emulphor aqueous emulsion; in water; and as pure undiluted chemical. The 25 mg/kg dose was also given iv in PEG 400 through an indwelling jugular cannula. Serial blood samples were taken from the iv and gavage animals and analyzed for CCl4 content to obtain blood concentration-versus-time profiles. CCl4 was absorbed very rapidly from the GI tract, as peak concentrations of CCl4 in the blood were reached within 3-6 min of dosing in the aqueous emulsion and water groups. These peak levels were higher than those in the undiluted CCl4 group and substantially higher than those in the corn oil group. Corn oil markedly delayed the absorption of CCl4 from the GI tract and produced secondary peaks in the blood concentration-versus-time profiles. Elimination of CCl4 from the bloodstream of the iv group followed a triexponential pattern. CCl4 was eliminated from the blood at approximately the same rate in the iv and po groups, as reflected by similar elimination rate constant and half-life values. There was a high degree of correlation of both Cmax and AUC0(120) with hepatotoxicity. CCl4 was apparently less acutely hepatotoxic in corn oil due to delay and prolongation of CCl4 absorption, resulting in a marked decrease in the concentration of the chemical in the arterial blood. These findings suggest that corn oil has sufficient effect on the pharmacokinetics of orally administered CCl4 to require an appraisal of its use in studies of the acute oral toxicity of CCl4 and other volatile organic chemicals (VOCs). The use of aqueous Emulphor emulsions appears appropriate in studies of VOC contaminants of drinking water, in that the emulsion did not substantially alter the pharmacokinetics or hepatotoxicity of CCl4 from that ingested in water.

Absorption↗
PubMed1990

Brain targeting of anti-HIV nucleosides: synthesis and in vitro and in vivo studies of dihydropyridine derivatives of 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine.

A significant number of patients with AIDS and AIDS-related complex develop neurological complications. Therefore, it is critical that anti-HIV agents penetrate the blood-brain barrier and suppress viral replication in the brain. In an effort to increase the brain delivery of anti-HIV nucleosides, in vitro and in vivo pharmacokinetics of dihydropyridine derivatives of 3'-azido-2',3'-dideoxyuridine (AzddU, AZDU, or CS-87) and 3'-azido-3'-deoxythymidine (AZT, Zidovudine) have been studied. In vitro studies of the prodrugs (AzddU-DHP and AZT-DHP) in human serum, mouse serum, and mouse brain homogenate indicated that the rates of serum conversion from prodrugs to parent drugs are species dependent: mouse brain homogenate greater than mouse serum greater than human serum. Half-lives in human serum, mouse serum, and mouse brain homogenate are 4.33, 0.56, 0.17 h, respectively, for AzddU and 7.70, 1.40, and 0.18 h, respectively, for AZT. In vivo studies of AzddU-DHP and AZT-DHP showed that the prodrugs have areas under the serum concentration-time curves (AUC) similar to those of the parent drugs. The AUC in serum for AzddU following prodrug administration is 25.79 micrograms h/mL, which is similar to the value of 25.83 micrograms h/mL when AzddU was administered. Analogously, the serum AUCs for AZT when AZT-DHP and AZT were administered are 25.38 and 26.64 micrograms h/mL, respectively. However, the brain AUCs for both AzddU and AZT derived from prodrugs, being 11.43 and 11.28 micrograms h/mL, respectively, are greater than the brain AUCs for AzddU (2.09 micrograms h/mL) and AZT (1.21 micrograms h/mL) when the parent drugs were administered. Thus, the relative brain exposure (re) for AzddU (5.47) and AZT (9.32) indicate a significant increase in exposure to the anti-HIV nucleosides following prodrug administrations. The results of extended half-lives of the synthesized prodrugs in human serum along with the higher re values in vivo warrant studies in larger animals to determine the potential usefulness of the prodrugs in humans.

Animals↗
PubMed1990

A simple rheological method for the in vitro assessment of mucin-polymer bioadhesive bond strength.

A simple viscometric method was used to quantify mucin-polymer bioadhesive bond strength. Viscosities of 15% (w/v) porcine gastric mucin dispersions in 0.1 N HCl (pH 1) or 0.1 N acetate buffer (pH 5.5) were measured with a Brookfield viscometer in the absence (eta m) or presence (eta t) of selected neutral, anionic, and cationic polymers (0.1-2.5%, w/v). Viscosity components of bioadhesion (eta b) were calculated from the equation, eta t = eta m + eta p + eta b, where eta p is the viscosity of corresponding pure polymer solution as measured by an Ostwald viscometer. The forces of bioadhesion (F) were calculated from the equation, F = eta b sigma, where sigma is the rate of shear/sec. eta b's and F's for polyelectrolytes, e.g., polyacrylic acid, cationic gelatin, and chitosan were always higher in acetate buffer than in HCl. Validity of the technique and the effect of ionic charge, polymer conformation, and rate of shear on eta b and F are discussed, as is a comparison of this method to other methods for evaluating bioadhesive materials.

Acrylic Resins↗
PubMed1990

3'-Azido-2',3'-dideoxyuridine (AzddU): comparative pharmacokinetics with 3'-azido-3'-deoxythymidine (AZT) in monkeys.

The pharmacokinetics of the anti-human immunodeficiency virus type 1 nucleosides, 3'-azido-2',3'-dideoxyuridine (AzddU) and 3'-azido-3'-deoxythymidine (AZT) were characterized in rhesus monkeys. Half-life, total clearance, and steady-state volume of distribution were similar for both compounds. The observed pharmacokinetic parameters for AZT were comparable to those previously reported in humans. Oral absorption of AzddU and AZT was virtually complete after 60 mg/kg. However, bioavailability of both nucleosides was markedly lower (less than 50%) after 200 mg/kg, possibly indicating the involvement of a saturable absorption mechanism. The nucleosides were also well absorbed after subcutaneous administration. AzddU and AZT penetrated the cerebrospinal fluid (CSF) with concentration ratios in CSF:serum ranging from 0.05 to 0.25 one hour after drug administration. The glucuronides of AZT and AzddU were readily detected in urine. Hemogram and blood chemistry values for animals receiving short-term treatment (3 doses) with either AZT or AzddU did not exhibit any significant changes when compared with untreated control monkeys. The similar pharmacokinetic characteristics of AzddU compared with AZT suggest that clinical trials of AzddU are warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Comparative pharmacokinetics and interspecies scaling of 3'-azido-3'-deoxythymidine (AZT) in several mammalian species.

Interspecies variation in drug disposition can be considered to be a function of species body weight. Therefore, it is possible to establish allometric relationships between pharmacokinetic parameters and species body weight. Interspecies scaling of pharmacokinetic data yielded from laboratory animals can often provide reliable predictions of pharmacokinetic parameters and drug disposition in humans. Significant correlations between 3'-azido-3'-deoxythymidine (AZT) pharmacokinetic parameters (total clearance, renal clearance, nonrenal clearance and steady-state volume of distribution) from mice, rats, dogs, monkeys and humans and body weight were found. Plasma AZT concentration versus chronological time profiles were markedly different for each species. However, when chronological time was converted to pharmacokinetic (physiologic) time these profiles were superimposible. These results demonstrate that interspecies pharmacokinetic scaling can be used to estimate plasma AZT concentrations in humans and can be used to design initial dosage regimens.

Animals↗
PubMed1989

Evaluation of drug delivery following the administration of magnetic albumin microspheres containing adriamycin to the rat.

The disposition of adriamycin following its intra-arterial administration in rats as a solution (control) or via magnetic albumin microspheres (treatment group) has been investigated. The rat tail was demarcated into three segments: T1, the pre-target site; T2, the target site; and T3, the post-target site. In both groups, 2.0 mg/kg of adriamycin HCl was injected into the ventral caudal artery in T1 through a T-piece cannula. A magnetic field of 8000 G was directed towards T2. The concentration of adriamycin was measured in the heart, kidney, liver, lung, serum, small intestine, spleen, T1, T2, and T3 as a function of time using an ion-pairing HPLC assay. Areas under the mean adriamycin concentration-time curves were used to determine two indices of drug delivery: the relative tissue exposure and targeting efficiency. It was demonstrated that the magnetically responsive albumin microspheres altered the tissue distribution of adriamycin in rats. Administration of drug via magnetic microspheres was shown to increase the relative drug exposure to both T2 and liver.

Albumins↗
PubMed1989

Physiological pharmacokinetic model of adriamycin delivered via magnetic albumin microspheres in the rat.

The influence of magnetic albumin microspheres on the disposition of adriamycin was evaluated. Adriamycin concentrations were monitored in multiple rat tissues for 48 hr after its intra-arterial administration (2 mg/kg) as a solution and associated with magnetic albumin microspheres. The magnetic dosage form was targeted to a predefined tail segment with a magnetic field strength of 8000 G applied for 30 min after dosing. A physiological pharmacokinetic model was used to describe the disposition of adriamycin following its administration from either dosage form. The model developed for the data resulting from administration of adriamycin as a solution served as a foundation for the model developed for adriamycin resulting from the administration of adriamycin associated with the magnetic dosage form. The model for adriamycin following administration of the magnetic microspheres required additional relationships to describe the transport of adriamycin associated with the microspheres. For both models, the predicted adriamycin concentrations were in adequate agreement with the observed values. The present investigation demonstrates the use of a physiological pharmacokinetic modeling method to represent drug kinetics following its administration via a targeted drug delivery system.

Albumins↗
PubMed1989

The uptake and elimination of 1,1,1-trichloroethane during and following inhalation exposures in rats.

The pharmacokinetics of 1,1,1-trichloroethane (TRI) was studied in male Sprague-Dawley rats in order to characterize and quantify TRI uptake and elimination oby direct measurements of the inhaled and exhaled compound. Fifty or 500 ppm TRI was inhaled for 2 hr through a one-way breathing valve by unanesthetized rats of 325-375 g. Repetitive samples of the separate inhaled and exhaled breath streams, as well as arterial blood, were collected concurrently both during and following TRI inhalation and analyzed for TRI by gas chromatography. Respiratory rates and volumes were continuously monitored during and following exposure and were used in conjunction with the pharmacokinetic data to characterize profiles of uptake and elimination. TRI was very rapidly absorbed from the lung, in that substantial levels were present in arterial blood at the first sampling time (i.e., 2 min). Blood and exhaled breath concentrations of TRI increased rapidly after the initiation of exposure, approaching but not reaching steady state during the 2-hr exposures. The blood and exhaled breath concentrations were directly proportional to the exposure concentration during the exposures. Percentage uptake of TRI decreased 30-35% during the first hour of inhalation, diminishing to approximately 45-50% by the end of the exposure. Total cumulative uptake in the 50 and 500 ppm groups over the 2-hr inhalation exposures was determined to be 6 and 48 mg/kg body wt, respectively. By the end of the exposure period, 2.1 and 20.8 mg, respectively, of inhaled TRI was eliminated from rats inhaling 50 and 500 ppm TRI. A physiological pharmacokinetic model for TRI inhalation was utilized to predict blood and exhaled breath concentrations for comparison with observed experimental values. Overall, values predicted by the physiological pharmacokinetic model for TRI levels in the blood and exhaled breath were in close agreement with measured values both during and following TRI inhalation.

Administration, Inhalation↗