Biomedical subjects

J T Callaghan

Publications and source records attributed to J T Callaghan.

At least 19 recordsLinked to original sources

PubMed2005

The physical properties and response of osteoblasts to solution cast films of PLGA doped polycaprolactone.

Polycaprolactone films doped with poly(lactide-co-glycolide) (65:35) in 0, 10, 20, and 30 (wt%) were prepared and evaluated in terms of morphology, dynamic contact angle analysis, and thermal properties. The unique surface morphology of the doped PCL film resulted, without introducing significant microstructure disruption of PCL aggregation. The doped PCL film registered a lower contact angle and increased hydrophilicity. Osteoblast cells attached to all doped materials, the 10% and 20% doped materials demonstrating the greatest cell growth.

Actins↗

PubMed2000

Confidence interval criteria for assessment of dose proportionality.

PURPOSE: The aim of this work was a pragmatic, statistically sound and clinically relevant approach to dose-proportionality analyses that is compatible with common study designs. METHODS: Statistical estimation is used to derive a (1-alpha)% confidence interval (CI) for the ratio of dose-normalized, geometric mean values (Rdnm) of a pharmacokinetic variable (PK). An acceptance interval for Rdnm defining the clinically relevant, dose-proportional region is established a priori. Proportionality is declared if the CI for Rdnm is completely contained within the critical region. The approach is illustrated with mixed-effects models based on a power function of the form PK = beta0 x Dose(beta1); however, the logic holds for other functional forms. RESULTS: It was observed that the dose-proportional region delineated by a power model depends only on the dose ratio. Furthermore, a dose ratio (rho1) can be calculated such that the CI lies entirely within the pre-specified critical region. A larger ratio (rho2) may exist such that the CI lies completely outside that region. The approach supports inferences about the PK response that are not constrained to the exact dose levels studied. CONCLUSION: The proposed method enhances the information from a clinical dose-proportionality study and helps to standardize decision rules.

Analysis of Variance↗

PubMed1999

Olanzapine. Pharmacokinetic and pharmacodynamic profile.

Multicentre trials in patients with schizophrenia confirm that olanzapine is a novel antipsychotic agent with broad efficacy, eliciting a response in both the positive and negative symptoms of schizophrenia. Compared with traditional antipsychotic agents, olanzapine causes a lower incidence of extrapyramidal symptoms and minimal perturbation of prolactin levels. Generally, olanzapine is well tolerated. The pharmacokinetics of olanzapine are linear and dose-proportional within the approved dosage range. Its mean half-life in healthy individuals was 33 hours, ranging from 21 to 54 hours. The mean apparent plasma clearance was 26 L/h, ranging from 12 to 47 L/h. Smokers and men have a higher clearance of olanzapine than women and nonsmokers. After administering [14C]olanzapine, approximately 60% of the radioactivity was excreted in urine and 30% in faeces. Olanzapine is predominantly bound to albumin (90%) and alpha 1-acid glycoprotein (77%). Olanzapine is metabolised to its 10- and 4'-N-glucuronides, 4'-N-desmethylolanzapine [cytochrome P450 (CYP) 1A2] and olanzapine N-oxide (flavin mono-oxygenase 3). Metabolism to 2-hydroxymethylolanzapine via CYP2D6 is a minor pathway. The 10-N-glucuronide is the most abundant metabolite, but formation of 4'-N-desmethylolanzapine is correlated with the clearance of olanzapine. Olanzapine does not inhibit CYP isozymes. No clinically significant metabolic interactions were found between olanzapine and diazepam, alcohol (ethanol), imipramine, R/S-warfarin, aminophylline, biperiden, lithium or fluoxetine. Fluvoxamine, an inhibitor of CYP1A2, increases plasma concentrations of olanzapine; inducers of CYP1A2, including tobacco smoke and carbamazepine, decrease olanzapine concentrations. Orthostatic changes were observed when olanzapine and diazepam or alcohol were coadministered. Pharmacodynamic interactions occurred between olanzapine and alcohol, and olanzapine and imipramine, implying that patients should avoid operating hazardous equipment or driving an automobile while experiencing the short term effects of the combinations. Individual factors with the largest impact on olanzapine pharmacokinetics are gender and smoking status. The plasma clearance of olanzapine generally varies over a 4-fold range, but the variability in the clearance and concentration of olanzapine does not appear to be associated with the severity or duration of adverse effects or the degree of efficacy. Thus, dosage adjustments appear unnecessary for these individual factors. However, dosage modification should be considered for patients characterised by a combination of factors associated with decreased oxidative metabolism, for example, debilitated or elderly women who are nonsmokers.

Antipsychotic Agents↗

PubMed1997

Olanzapine: interaction study with imipramine.

Olanzapine is an "atypical" antipsychotic agent with a high affinity for serotonin 5HT2A/C, 5HT3, 5HT6, and dopamine D1, D2, D3, D4 receptors. Depressed patients with psychotic disorders frequently require treatment with concomitant antipsychotic and antidepressant medications. Imipramine pharmacokinetics serve as a marker for hepatic CYP2D6, CYP1A2, CYP3A activity. An open-label, three-way randomized crossover study was done to determine the safety, pharmacokinetics, and potential for a drug interaction between olanzapine (5 mg) and imipramine (75 mg). Each drug was administered alone and in combination. Nine healthy men, ages 32 to 54 years, enrolled in the study. Psychomotor performance capacities, plasma olanzapine, imipramine, desipramine concentrations, and clinical laboratory tests were measured. Pharmacokinetic variables, vital signs, subjective tests for liveliness, and psychomotor outcomes were analyzed using a two-way ANOVA. Olanzapine was safe. Sedation, postural hypotension, and minor vital sign alterations occurred during all treatments. On the liveliness questionnaire, patients generally reported poorer (less lively) scores with olanzapine alone or coadministered with imipramine versus baseline scores. These effects disappeared within 24 hours after administration. Olanzapine alone and in combination decreased motor-speed tasks (finger tapping and visual-arm random reach) compared with baseline or imipramine treatment. Peak 6-hour changes were statistically significant but clinical importance was only marginal. Olanzapine concentrations were < 19% greater than with imipramine. But olanzapine did not affect the kinetics of imipramine or desipramine and, therefore, did not show a metabolic drug interaction involving CYP2D6.

Adrenergic Uptake Inhibitors↗

PubMed1997

Disposition and biotransformation of the antipsychotic agent olanzapine in humans.

Disposition and biotransformation of the new antipsychotic agent olanzapine (OLZ) were studied in six male healthy volunteers after a single oral dose of 12.5 mg containing 100 microCi of [14C]OLZ. Biological fluids were analyzed for total radioactivity, the parent compound (GC/MS), and metabolites (electrospray LC/MS and LC/MS/MS). Mean radiocarbon recovery was approximately 87%, with 30% appearing in the faces and 57% excreted in the urine. Approximately half of the radiocarbon was excreted within 3 days, whereas > 70% of the dose was recovered within 7 days of dosing. Circulating radio-activity was mostly restricted to the plasma compartment of blood. Mean peak plasma concentration of OLZ was 11 ng/ml, whereas that of radioactivity was 39 ng eq/ml. Mean plasma terminal elimination half-lives were 27 and 59 hr, respectively, for OLZ and total radioactivity. With the help of NMR and MS data, a major metabolite of OLZ in humans was characterized as a novel tertiary N-glucuronide in which the glucuronic acid moiety is attached to the nitrogen at position 10 of the benzodiazepine ring. Another N-glucuronide was detected in urine and identified as the quaternary N-linked 4'-N-glucuronide. Oxidative metabolism on the allylic methyl group resulted in 2-hydroxymethyl and 2-carboxylic acid derivatives of OLZ. The methyl piperazine moiety was also subject to oxidative attack, giving rise to the N-oxide and N-deemethyl metabolites. Other metabolites, including the N-deemethyl-2-carboxy derivative, resulted from metabolic reactions at both the 4' nitrogen and 2-methyl groups. The 10-N-glucuronide and OLZ were the two most abundant urinary components, accounting for approximately 13% and 7% of the dose, respectively. In fecal extracts, the only significant radioactive HPLC peaks were due to 10-N-glucuronide and OLZ representing, respectively, approximately 8% and 2% of the administered dose. Semiquantitative data obtained from plasma samples from subjects given [14C]OLZ suggest that the main circulating metabolite is 10-N-glucuronide. Thus, OLZ was extensively metabolized in humans via N-glucuronidation, allylic hydroxylation, N-oxidation, N-dealkylation and a combination thereof. The 10-N-glucuronidation pathway was the most important pathway both in terms of contribution to drug-related circulating species and as an excretory product in feces and urine.

Adult↗

PubMed1990

Role of serum prolactin determination in evaluation of impotent patient.

Hyperprolactinemia is a recognized cause of impotence. The discovery of elevated prolactin levels in impotent men is very important since pharmacotherapy in this instance is highly successful. We review our experience with prolactin determinations in impotent men, and a population is defined that may benefit from routine prolactin determination. In our experience, the predominant symptom associated with hyperprolactinemia in men is loss of libido.

Adult↗

PubMed1990

Secretion of nizatidine into human breast milk after single and multiple doses.

Disposition of the H2-receptor antagonist nizatidine was studied in serum, urine, and breast milk. Five lactating women and five nonlactating women participated; the disposition of nizatidine was studied in three of the lactating women. Single and multiple doses of 150 mg nizatidine were administered orally. The disposition of nizatidine (half-life, 1 1/2 hours; apparent serum clearance, 40 L/hr; renal clearance, 27 L/hr; and apparent volume of distribution, 1.4 L/kg) was similar in lactating and nonlactating women. These pharmacokinetic results were analogous to observations for men in other studies. Nizatidine breast milk concentrations were directly proportional to corresponding serum concentrations. On average, 96 micrograms nizatidine, less than 0.1% of the maternal dose, was secreted into milk during a 12-hour interval after either single or multiple doses.

Adult↗

PubMed1990

Relationship between steady-state plasma nizatidine concentrations and inhibition of basal and stimulated gastric acid secretion.

Steady-state plasma nizatidine concentrations were related in a linear fashion to nizatidine infusion rate. Infusion rates of 2.5, 10, and 20 mg/hr resulted in mean plasma nizatidine concentrations of 69, 247, and 575 ng/ml. Basal acid secretion was inhibited by 50% and 90% at mean plasma nizatidine concentrations of 60 and 430 ng/ml. Protein-stimulated acid secretion was inhibited by 50% and 90% at mean plasma nizatidine concentrations of 75 and 490 ng/ml. The mean pH of basal gastric secretions was 1.6 during placebo infusion and 4.6 when the mean plasma nizatidine concentration was 575 ng/ml.

Adult↗

PubMed1989

Effect of a leukotriene antagonist, LY171883, on cold air-induced bronchoconstriction in asthmatics.

Isocapnic hyperpnea (ISH) of cold air induces bronchoconstriction in many asthmatic subjects. Although this response is well described, it is unclear whether this bronchoconstriction is related to the release of bronchoactive mediators. We examined whether pretreatment with LY171883, a competitive antagonist of leukotriene D4 activity via LTD4 receptors, reduced the bronchospastic response to cold air ISH in asthmatics using a randomized, double-blind, two-phase crossover design. In 20 subjects, 2 wk of treatment with either LY171883 600 mg twice a day or placebo did not result in a change in FEV1 (3.45 +/- 0.21 L placebo versus 3.59 +/- 0.20 L LY171883; p greater than 0.05). Nineteen subjects underwent cold-air ISH; LY171883 increased the geometric mean respiratory heat loss required to reduce the FEV1 by 20% (PD20RHE) from 1.00 kcal/min with placebo to 1.24 kcal/min with LY171883 (p less than 0.05). A similar difference was noted when responses were expressed as a function of minute ventilation. LY171883 produced greater shifts in the PD20RHE in more reactive subjects (r = 0.69, p less than 0.002). Among 11 different symptom scores recorded by 18 subjects, there was a significant decrease in daytime chest tightness with LY171883 (p less than 0.03). The increase in PD20RHE while the subjects received LY171883 is consistent with the hypothesis that LTD4 becomes available during cold-air ISH and may mediate bronchoconstriction. The small magnitude of the effect on the PD20RHE may be due to the role of other mediators in cold-air-induced bronchoconstriction or, alternatively, to an inadequate blockade of LTD4 effects.

Acetophenones↗

PubMed1988

Nizatidine disposition in subjects with normal and impaired renal function.

To test the hypothesis that renal insufficiency alters nizatidine disposition, we determined the pharmacokinetics of nizatidine and its major metabolite after a single oral dose in normal volunteers and patients with various degrees of renal dysfunction, after a single intravenous dose in normal volunteers and patients with severe renal failure and during hemodialysis. After intravenous administration the elimination half-life increased from 1.5 +/- 0.2 hours in normal volunteers to 6.9 +/- 3.3 hours in patients with renal failure. The plasma clearance decreased from 0.59 +/- 0.07 L/kg/hr in normal volunteers to 0.14 +/- 0.02 L/kg/hr in patients with renal failure. Nizatidine bioavailability was nearly 100% in normal volunteers but decreased to 75% in patients with renal failure. The volume of distribution was 1.3 +/- 0.1 L/kg in normal volunteers and was not different in patients with renal failure. Nizatidine protein binding was about 30% in normal and uremic plasma. The drug was not substantially removed by hemodialysis. Patients with creatinine clearances less than 50 ml/min/1.73 m2 should receive 150 mg nizatidine once each evening. Patients with creatinine clearances less than 20 ml/min/1.73 m2 should receive 150 mg nizatidine every other night.

Adult↗

PubMed1988

Double-blind comparator trials with pinacidil, a potassium channel opener.

The antihypertensive effects of pinacidil, a potassium channel opener, were studied in 4, dose titration, double-blind trials. Patients had mild to severe hypertension, with supine diastolic arterial pressures between 91 and 150mm Hg during the qualification assessment. Efficacy was assessed using an 'intention-to-treat' analysis. In one study, pinacidil-treated patients had a response rate significantly greater than placebo-treated patients. In another study, the pinacidil group had a response rate significantly greater than the prazosin group (83% vs 75%, respectively). In a third study, the response rate in the pinacidil group was marginally greater than in the hydralazine group (77% vs 73%, respectively). In a 'step 2' trial, pinacidil was as effective as methyldopa and more effective than placebo. Adverse experiences with pinacidil were associated with vasodilatation. Electrocardiographic T wave changes occurred intermittently and may be related to its mechanism of action. These studies suggest that antihypertensive monotherapy with pinacidil was effective and generally well tolerated.

Antihypertensive Agents↗

PubMed1987

Nizatidine, and H2-receptor antagonist: disposition and safety in the elderly.

Nizatidine is an orally active H2-receptor blocker. Its disposition and safety in eight young and 12 elderly volunteers were investigated. Single oral doses of nizatidine were administered: from 100 mg to 300 mg in the elderly, and from 100 mg to 350 mg in the young. The nizatidine AUC was directly proportional to dose for both groups. Calculated pharmacokinetic variables in the elderly vs. the young were t1/2 = 1.9 vs. 1.6 hr; CLp/f = 32 vs. 40 L/hr, and Vd beta/f = 1.2 vs. 1.3 L/kg. The impaired renal function of some elderly volunteers prolonged nizatidine elimination and lowered its clearance. Renal impairment rather than advanced age per se was the predominant factor in decreasing the nizatidine elimination rate. Because Clcr correlated directly with nizatidine renal clearance, Clcr values may be used to estimate nizatidine dosage reductions in renal insufficiency. During the trial, no serious adverse effects occurred.

Aged↗

PubMed1987

Absorption studies of the H2-blocker nizatidine.

The absolute and relative bioavailability of nizatidine, an H2-blocker, was studied in healthy male volunteers. The absolute oral bioavailability, relative to that after intravenous administration, was 98% +/- 14%. The bioavailability of single and multiple oral doses of 150 mg nizatidine was unaffected by concurrent food ingestion; nizatidine may be administered either with or without food. The relative bioavailability of nizatidine was compared when given simultaneously with placebo or Gelusil, 30 minutes after propantheline, or 60 minutes before activated charcoal. Gelusil reduced the amount of nizatidine absorbed by about 10%, charcoal reduced it by about 30%, and propantheline did not affect it.

Absorption↗

PubMed1987

A pharmacokinetic profile of nizatidine in man.

In this report, the pharmacokinetic, pharmacodynamic, and hormonal effects of nizatidine are reviewed in healthy volunteers and in patients with renal or hepatic impairment. The absolute oral bioavailability of nizatidine exceeded 90%; the half-life (t1/2), plasma clearance (Clp), and volume of distribution (Vd) of iv nizatidine were 1.3 h, 461/h, and 1.21/kg, respectively. Within 16 h of dosing volunteers with nizatidine, more than 90% of the administered dose was recovered in urine as parent drug and metabolites; unchanged nizatidine accounted for 65 and 75% of the recovered substances, after oral and intravenous administration, respectively. Renal impairment decreased the elimination of nizatidine and dosage reductions are recommended for patients with creatinine clearance (Clcr) less than 50 ml/min/m2. Nizatidine suppressed gastric acid secretion produced by sham meals, protein meals, or pentagastrin; its antisecretory activity was dose and concentration dependent. Nizatidine was three times more potent than cimetidine. Nizatidine, after oral or iv administration, did not alter hormone concentrations in plasma.

Adult↗

PubMed1985

Intravenous nizatidine kinetics and acid suppression.

The effectiveness of intravenous nizatidine in suppressing gastric acid secretion was evaluated by different methods of inducing secretion in two single-blind studies. In study 1, seven subjects were given single, 20-min intravenous infusions of nizatidine (6.25, 25, 75, 150, or 250 mg) before modified sham feeding (MSF). Gastric acid suppression after nizatidine was contrasted with that after placebo and MSF. All doses of nizatidine reduced secretion; the 150- and 250-mg doses of nizatidine suppressed secretion for at least 2.5 hr. In study 2, eight subjects received one 5-min intravenous infusion of placebo, cimetidine (300 mg), or nizatidine (25, 50, 100, or 250 mg) weekly for 6 wk. Secretion was induced by infusing pentagastrin (2 micrograms/kg/hr) 45 min before the study drug was dosed and for 3.5 hr thereafter. Again, all doses of nizatidine reduced gastric acid, chiefly by decreasing volume. Nizatidine induced a clear dose-response effect; nizatidine (100 mg) and cimetidine (300 mg) had approximately equal suppressive effects. Nizatidine (100 mg) and cimetidine (300 mg) reduced acid output by 62% and 63% and reduced volume of secretion by 48% and 51% over the 3.5-hr period. Gastric acid suppression and plasma nizatidine concentrations were directly related. Nizatidine kinetics were linear and proportional to dose. The t1/2 was 1.3 hr (range 0.7 to 2.1 hr), the volume of distribution was 1.2 +/- 0.5 l/kg, and clearance was 0.6 +/- 0.2 l/kg/hr. Laboratory abnormalities and side effects were minor in both studies.

Adult↗

PubMed1983

Effect of cholestyramine and colestipol on the absorption of phenytoin.

The hypocholesterolemic cation resins, cholestyramine and colestipol, have variable effects on the absorption parameters of a number of lipophillic, anion drugs. Because of the unpredictable nature of this interaction, we have assessed in human volunteers the effect of these resins on the rate and total absorption of phenytoin. Our results indicate that these resins do not affect the absorption parameters of phenytoin and that special care does not have to be exercised when these agents are co-administered.

Adolescent↗

PubMed1983

Suppression of mitogen-induced lymphocyte transformation in cigarette smokers.

Mitogen- and antigen-induced lymphocyte transformation was determined in peripheral blood lymphocytes from tobacco smokers and nonsmokers. Each group was evaluated by race, sex, and age subgroups. Male smokers as a group had depressed responses to phytohemagglutinin (PHA), concanavalin A, and pokeweed mitogen. The effect was most pronounced in all subjects on PHA stimulation. There was no apparent relationship to age or race. Antigenic stimulation of lymphocytes with mumps skin test antigen was not affected in any of the groups studied.

Adult↗

PubMed1983

Delayed hypersensitivity to mumps antigen in humans.

Sixty-one subjects, preselected for mumps sensitivity, were entered into a double-blind protocol to standardize Mumps Skin Test Antigen. Four lots of mumps antigen selected on the basis of in vitro potency tests were used. Four other antigens, Histoplasmin, Dermatophytin-O, Dermatophytin, and fluid tetanus toxoid were also tested; positive reactions for these four antigens occurred in 48, 68, 25, and 43% of individuals, respectively. The mumps lots exhibited delayed hypersensitivity with positivity ranging from 63 to 67% at 20 CFU/ml and 77 to 84% at 80 CFU/ml in the acceptable lots. Side effects were primarily local and minor in nature. Mumps Skin Test Antigen is a useful measure of the integrity of the immune system, but lacks complete specificity because of local dermal factors.

Adult↗