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Biomedical subjects

J G Page

Publications and source records attributed to J G Page.

At least 19 recordsLinked to original sources
PubMed1992

The effects of lansoprazole, a new H+,K(+)-ATPase inhibitor, on gastric pH and serum gastrin.

This study examined the effects of dose and time of administration of lansoprazole on gastric pH and serum gastrin in healthy male volunteers. Three groups of six subjects received 10, 20 or 60 mg doses of lansoprazole or placebo. Doses were administered at 22.00 hours daily for 7 days. An additional 18 subjects received once daily 30 mg oral doses of lansoprazole or placebo; these subjects were dosed at either 08.00 hours or 22.00 hours in a randomized, crossover fashion with a 2-week washout period. Gastric pH was monitored for 24 h following the first and final dose, and 1 week following the completion of dosing. Lansoprazole, at all doses except 20 mg/day, significantly increased the median 24-hour gastric pH following 7 days of dosing (P less than 0.05). In addition, morning dosing in the 30-mg crossover group led to a higher 24-h median pH than evening dosing (P = 0.003). There was no difference in night-time median pH between morning and evening dosing. Morning dosing also led to a significant increase in gastric pH on study Day 1 (P less than 0.05). Plasma concentrations of lansoprazole were highly variable between subjects, but there was a significant correlation between AUC and the median 24-h gastric pH. Plasma concentrations and AUCs were higher on Day 7 than on Day 1 for subjects receiving 10 or 20 mg, but not for those receiving 30 or 60 mg doses. Lansoprazole bioavailability demonstrated a circadian effect manifested by higher plasma concentrations following morning dosing. Serum gastrin concentrations were elevated in all active medication groups.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1991

Pharmacokinetics of 2',3'-dideoxyadenosine in dogs.

The pharmacokinetics of 2',3'-dideoxyadenosine (ddAdo) and 2'-3'-dideoxyinosine (ddIno) were determined after intravenous bolus administration and long-term intravenous infusion of ddAdo in dogs. ddAdo was rapidly deaminated to ddIno and ddAdo plasma concentrations were only a fraction of ddIno concentrations. The total body clearance of ddAdo exceeded the literature value for the cardiac output of the dog, indicating an extremely rapid metabolism, and the existence of extrahepatic metabolism. Urinary excretion of unchanged ddAdo was a minor route of elimination (approximately 1%). The pharmacokinetics of ddIno was determined assuming complete conversions of ddAdo to ddIno. ddIno elimination was dose-dependent with total body clearance ranging from 4 to 55 ml/min/kg in individual animals. The plasma half-life was approximately 30 min after most routes of administration, but increased to approximately 60 min in two animals receiving a large intravenous dose of 500 mg/kg. ddIno penetrated into the cerebrospinal fluid to a limited extent, reaching concentrations of 3-11% of those in plasma. Urinary excretion of unchanged ddIno accounted for approximately 20% of the administered dose of ddAdo, while uric acid and hypoxanthine were minor urinary metabolites. Concentrations exceeding the in vitro minimal viral inhibitory concentration (2.4 micrograms/mL) could be safely maintained in plasma for a 10-day period. Infusions which gave cerebrospinal fluid concentrations of 12 to 17 micrograms/mL resulted in dose limiting myelosuppression and intestinal toxicity, after less than 10 days of infusion. Orally administered ddAdo was absorbed as ddIno, with bioavailabilities ranging from 28 to 93% in experiments where no emesis occurred. These studies indicate the rapid in vivo conversion of ddAdo to ddIno, and support the selection of ddIno over ddAdo for further drug development.

Administration, Oral↗
PubMed1991

The effect of the monoamine oxidase inhibitor isocarboxazid on the canine metabolism of the cell-differentiating agent hexamethylene bisacetamide.

The acute toxicities of the cellular differentiating agent hexamethylene bisacetamide (HMBA) in humans and animals include CNS toxicity (agitation, somnolence, seizures, hallucinations) and an anion-gap metabolic acidosis. N-Acetyl-1,6-diaminohexane (NADAH), the first metabolite of HMBA, is as active as the parent compound in causing differentiation of leukemic cells in vitro, whereas 6-acetamidohexanoic acid (6AcHA), which is formed by the oxidation of NADAH in the presence of monoamine oxidase (MAO) and aldehyde dehydrogenase, is inactive. To test whether the inhibition of MAO blocks the production of an inactive and possibly toxic HMBA metabolite (6AcHA) or increases the amount of active compounds (HMBA + NADAH) in vivo, we investigated the effect of the MAO inhibitor isocarboxazid on the metabolism and toxicity of HMBA in beagle dogs. Two groups of dogs, composed of one male and one female dog per group, were used in the study. One group received isocarboxazid (3.3 mg/kg p.o. q8h x 9) beginning at 24 h before the initiation of a 48-h i.v. infusion of HMBA (40 mg kg-1 h-1), whereas the other received placebo in an identical fashion prior to the start of an identical HMBA infusion. The mean plasma steady-state concentration (css) of HMBA was 0.91 mM in dogs given HMBA and isocarboxazid as opposed to 0.78 mM in those given HMBA and placebo. As measured spectrophotometrically, plasma MAO activity was inhibited by 86% +/- 3% in dogs receiving isocarboxazid. Gas chromatography/mass spectrometry detected 6AcHA in the plasma of animals that were given placebo but not in the plasma of dogs that received isocarboxazid. Gas chromatographic analysis of urine samples revealed that the total amount of 6AcHA and of NADAH excreted in urine was 8 times less and 3 times greater, respectively, in isocarboxazid-treated dogs than in animals that received HMBA and placebo. One dog was excitable after the initial two doses of isocarboxazid and developed seizures at the end of the HMBA infusion. Another dog was agitated during treatment with HMBA and isocarboxazid. No CNS toxicity occurred in animals that were treated with HMBA and placebo. We conclude that isocarboxazid inhibits the production of 6AcHA in vivo, thus supporting the involvement of MAO in HMBA metabolism. Because the combination of HMBA and isocarboxazid produces CNS toxicity, 6AcHA is probably not the neurotoxic agent in dogs.

Acetamides↗
PubMed1990

Pharmacological and toxicological evaluation of orally administered pyridostigmine in dogs.

Pyridostigmine bromide, a reversible cholinesterase inhibitor, was administered orally (capsule gavage) to beagle dogs (10-15 months of age) of both sexes once daily at 5, 10, or 20 mg/kg for 14 days; every 8 hr at 2 or 5 mg/kg for 28 days; or every 8 hr at 0.05, 0.5, or 2 mg/kg for 3 months as part of its preclinical safety assessment. A small portion of the dogs receiving pyridostigmine for 3 months were allowed an untreated recovery period of an additional 3 months. Daily doses of 10 or 20 mg/kg were lethal to some of the dogs when given for up to 14 days and caused severe intestinal distress, including diarrhea, emesis, and reddened feces in all animals. The cause of death was intestinal intussusception. Signs of systemic toxicity apparent at these doses included hypersalivation and tremors. Similar but less severe effects were produced by 5 mg/kg per day; plasma cholinesterase activities were inhibited by all three doses in a dose-related manner. Signs of toxicity in the 28-day and 3-month studies were generally limited to the gastrointestinal tract and included diarrhea or soft stools and reddened or mucoid-containing stools; these signs appeared to reverse upon discontinuation of the drug. A single dog at 2 mg/kg every 8 hr developed an apparent intussusception. There were no pathological changes in clinical chemistry, hematology, or urinalysis parameters associated with doses of 0.05, 0.5, or 2 mg/kg every 8 hr for up to 3 months, nor were any drug-related lesions observed upon gross necropsy and microscopic evaluation of the major tissues and organs. Red blood cell (RBC) acetylcholinesterase (AChE) activities in the 3-month study were inhibited by approximately 10, 50, and 70% in the 0.05, 0.5, and 2 mg/kg every 8-hr dose groups, respectively, and these degrees of inhibition were maintained throughout the period of treatment. These data suggest that prolonged oral administration of pyridostigmine at doses sufficient to cause profound and sustained inhibition of RBC AChE activity (i.e., as high as 70%) cause mainly local, gastrointestinal distress related to altered intestinal motility. At the extreme, this can be manifested as a life-threatening intestinal intussusception. Systemic anticholinesterase effects (other than enzyme inhibition) were observed only at doses of 2 mg/kg and greater, while local (gastrointestinal) effects and inhibition of RBC AChE were observed at doses as low as 0.05 mg/kg.

Administration, Oral↗
PubMed1989

Pharmacokinetics of buthionine sulfoximine (NSC 326231) and its effect on melphalan-induced toxicity in mice.

Intravenous doses of buthionine sulfoximine (BSO, NSC 326231), an inhibitor of glutathione synthesis, were eliminated rapidly from mouse plasma in a biexponential manner. The initial phase of the plasma concentration versus time curve had a half-life of 4.9 min and accounted for 94% of the total area under the curve. The half-life of the terminal phase of the curve was 36.7 min and the area accounted for only 6% of the total area under the curve. Plasma clearance of BSO was 28.1 ml/min/kg and the steady state volume of distribution was 280 ml/kg. The oral bioavailability of BSO, based on plasma BSO levels, was extremely low. However, comparable glutathione depletion was apparent after i.v. and p.o. doses of BSO, suggesting a rapid tissue uptake and/or metabolism of BSO. Therefore, due to the rapid elimination of BSO from mouse plasma, plasma drug levels do not directly correlate with BSO-induced tissue glutathione depletion. Administration of multiple i.v. doses of BSO to male and female mice resulted in a marked 88% depletion of liver glutathione at doses of 400-1600 mg/kg/dose. Toxicity of i.v. administered BSO was limited to a transient depression of peripheral WBC levels in female mice given six doses of 1600 mg/kg. Multiple i.v. doses of BSO of up to 800 mg/kg/dose (every 4 h for a total of six doses) did not alter the toxicity of i.v. administered melphalan. However, multiple doses of 1600 mg/kg/dose of BSO did potentiate histopathological evidence of melphalan-induced bone marrow toxicity in 30% of the mice and, additionally, the combination of BSO and melphalan produced renal tubular necrosis in 80% of the male mice. The potentiation of melphalan induced toxicity did not appear to be related to GSH depletion, since: quantitatively similar amount of GSH depletion occurred at lower dose of BSO without any increase in melphalan toxicity.

Administration, Oral↗
PubMed1989

Effects of leuprolide in the treatment of central precocious puberty.

Leuprolide acetate (D-Leu6 des-Gly-NH2(10), Pro-ethylamide9), a synthetic non-apeptide analog of naturally occurring gonadotropin releasing hormone, was used to treat 62 children with central precocious puberty. Sex steroid levels (testosterone in boys and estradiol in girls) were suppressed during treatment lasting from 3.5 to 24.9 months. Basal follicle-stimulating hormone values and both luteinizing hormone and follicle-stimulating hormone peak responses to stimulation by luteinizing hormone releasing hormone were also suppressed, although basal luteinizing hormone values did not differ. Linear growth rate and the rate of bone age advancement decreased during leuprolide therapy. Side effects were minimal. The long-term safety of this treatment has not yet been established; however, leuprolide appears to be an effective long-term therapy for central precocious puberty.

Child↗
PubMed1987

Comparison of in vivo and in vitro percutaneous absorption of T-2 toxin in guinea pigs.

The fate and distribution of T-2 were examined in 6 guinea pigs. T-2 (1.2 micrograms/cm2), in methanol or DMSO, was painted onto the shaved backs of guinea pigs, a screen barrier was applied, urine and feces were collected daily and the guinea pigs were killed after 48 hr. Disks of skin (lateral to the in vivo site of application) were excised from the guinea pigs and used for in vitro penetration studies with static diffusion cells. Skin excised from 6 additional guinea pigs was used for penetration studies with flow-through diffusion cells. For in vitro studies, T-2 dissolved in methanol or DMSO was applied to the epidermal surfaces and the appearance of penetrant in receptor fluid bathing the dermal surfaces was monitored for 48 hr. Metabolism of T-2 was measured by using thin layer radiochromatography to identify metabolites. In the in vivo study, mean cutaneous absorption (n = 3) after 48 hr (expressed as per cent dose) was 22.5 and 51.9 for the methanol and DMSO groups, respectively. In vitro cutaneous penetration for static diffusion cells was 3.9 and 38.4 for the methanol and DMSO groups. For flow-through diffusion cells, mean penetration (n = 9) was 14.6 and 42.6 for the methanol and DMSO groups. Urinary metabolites of T-2 were T-2 triol, 3' OH-HT-2, T-2 tetraol, the glucuronide conjugate of HT-2 and several more polar metabolites. The main metabolite of T-2 in the receptor fluid bathing the dermal surfaces of excised skin was HT-2.

Animals↗
PubMed1976

Metabolism of 1,4-dihydro-6-trifluoromethylquinoxaline-2,3-dione (Lilly 72525) in rats and cats.

1. The metabolism of 1,4-dihydro-6-trifluoromethylquinoxaline-2,3-dione (Lilly 72525), a sedative hypnotic drug, was studied in rat and cat. 2. Plasma concentrations of Lilly 72525 were measured fluorometrically after oral and intravenous doses of the compound in rats. A comparison of the area under the two curves suggested that 84% of the oral dose was absorbed. 3. Studies with 14C-labelled material in both species confirmed that the drug was well absorbed after oral administration and revealed that the dione was mainly eliminated unchanged in the urine. Bile duct cannulation experiments suggested that biliary excretion accounted for most or all of the drug present in faeces of rats. 4. Metabolites isolated from urinary extracts by t.l.c. were identified by g.l.c.-mass spectrometry. The only metabolite detected in rat urine or bile extracts was a ring-hydroxylated compound. This metabolite plus two N-hydroxylated metabolites were identified in extracts of cat urine.

Administration, Oral↗
PubMed1975

Species differences in the metabolism of alpha-1-trans-4-dimethylaminotetrahydro-3-furyl-cyclohexanephenylglycolate, an experimental anticholinergic agent.

Metabolism studies in the rat, dog and cat have demonstrated a definite species difference in biotransformation and elimination of alpha-1-trans-4-dimethylaminotetrahydro-3-furylcyclohexanephenylglycolate (Lilly 82537), an experimental anticholinergic agent. Separation and identification of urinary and biliary metabolites by gas chromatographic mass spectrometric analysis has shown three mechanisms to be involved in the metabolism of Lilly 82537 in these species; N-demethylation, aliphatic hydroxylation ahd ester hydrolysis. A major portion of the drug administered was eliminated unaltered in the cat and dog, while only trace quantities of parent drug were observed in the urine and bile of rats. These metabolic differences may be responsible for observed species differences in the pharmacologic activity of Lilly 82537.

Animals↗