Biomedical subjects

Patrick J McNamara

Publications and source records attributed to Patrick J McNamara.

31 records · Page 2Linked to original sources

PubMed2004

Evolution of ciprofloxacin-resistant Staphylococcus aureus in in vitro pharmacokinetic environments.

The development of novel antibacterial agents is decreasing despite increasing resistance to presently available agents among common pathogens. Insights into relationships between pharmacodynamics and resistance may provide ways to optimize the use of existing agents. The evolution of resistance was examined in two ciprofloxacin-susceptible Staphylococcus aureus strains exposed to in vitro-simulated clinical and experimental ciprofloxacin pharmacokinetic profiles for 96 h. As the average steady-state concentration (C(avg ss)) increased, the rate of killing approached a maximum, and the rate of regrowth decreased. The enrichment of subpopulations with mutations in grlA and low-level ciprofloxacin resistance also varied depending on the pharmacokinetic environment. A regimen producing values for C(avg ss) slightly above the MIC selected resistant variants with grlA mutations that did not evolve to higher levels of resistance. Clinical regimens which provided values for C(avg ss) intermediate to the MIC and mutant prevention concentration (MPC) resulted in the emergence of subpopulations with gyrA mutations and higher levels of resistance. A regimen producing values for C(avg ss) close to the MPC selected grlA mutants, but the appearance of subpopulations with higher levels of resistance was diminished. A regimen designed to maintain ciprofloxacin concentrations entirely above the MPC appeared to eradicate low-level resistant variants in the inoculum and prevent the emergence of higher levels of resistance. There was no relationship between the time that ciprofloxacin concentrations remained between the MIC and the MPC and the degree of resistance or the presence or type of ciprofloxacin-resistance mutations that appeared in grlA or gyrA. Regimens designed to eradicate low-level resistant variants in S. aureus populations may prevent the emergence of higher levels of fluoroquinolone resistance.

Anti-Bacterial Agents↗

PubMed2004

Effect of fluticasone propionate nasal spray on bioavailability of intranasal hydromorphone hydrochloride in patients with allergic rhinitis.

STUDY OBJECTIVE: To investigate the effect of the nasal corticosteroid fluticasone propionate on the bioavailability and pharmacokinetics of single-dose intranasal hydromorphone hydrochloride in patients with allergic rhinitis. DESIGN: Randomized, three-way, crossover pharmacokinetic study. SETTING: University clinical research unit. PATIENTS: Twelve patients with allergic rhinitis. INTERVENTION: Hydromorphone hydrochloride 2.0 mg was administered by intravenous infusion (treatment A), intranasal spray without allergic rhinitis treatment (treatment B), and intranasal spray after 6 days of fluticasone propionate (treatment C). Blood samples were collected serially from 0-16 hours. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic parameters were determined by noncompartmental methods. An analysis of variance (ANOVA) model was used for statistical analysis. Mean (% coefficient of variation) absolute bioavailability of intranasal hydromorphone was 51.9% (28.2) and 46.9% (30.3) in patients with allergic rhinitis with and without treatment with fluticasone propionate, respectively. Mean maximum concentration (Cmax) values were 3.02 and 3.56 ng/ml, respectively. No statistical differences in Cmax and area under the concentration versus time curve were detected between intranasal treatments. Bioavailability values for both intranasal treatments were lower than those in healthy volunteers (57%). Median time to Cmax (Tmax) values were significantly different (p=0.02) for treatments B and C (15 and 30 min, respectively) using rank-transformed Tmax for ANOVA. Adverse effects were consistent with known effects of hydromorphone administered by other routes, with the exception of bad taste after intranasal administration. CONCLUSION: Hydromorphone was rapidly absorbed after nasal administration, with maximum concentrations occurring for most subjects within 30 minutes. Allergic rhinitis may affect pain management strategies for intranasal hydromorphone, with a delay in onset of action for patients treated with fluticasone propionate.

Administration, Intranasal↗

PubMed2003

Pharmacokinetics in the newborn.

In addition to differences in the pharmacodynamic response in the infant, the dose and the pharmacokinetic processes acting upon that dose principally determine the efficacy and/or safety of a therapeutic or inadvertent exposure. At a given dose, significant differences in therapeutic efficacy and toxicant susceptibility exist between the newborn and adult. Immature pharmacokinetic processes in the newborn predominantly explain such differences. With infant development, the physiological and biochemical processes that govern absorption, distribution, metabolism, and excretion undergo significant growth and maturational changes. Therefore, any assessment of the safety associated with an exposure must consider the impact of these maturational changes on drug pharmacokinetics and response in the developing infant. This paper reviews the current data concerning the growth and maturation of the physiological and biochemical factors governing absorption, distribution, metabolism, and excretion. The review also provides some insight into how these developmental changes alter the efficiency of pharmacokinetics in the infant. Such information may help clarify why dynamic changes in therapeutic efficacy and toxicant susceptibility occur through infancy.

Gastric Mucosa↗

PubMed2003

Atelectasis causes vascular leak and lethal right ventricular failure in uninjured rat lungs.

During mechanical ventilation, lung recruitment attenuates injury caused by high VT, improves oxygenation, and may optimize pulmonary vascular resistance (PVR). We hypothesized that ventilation without recruitment would induce injury in otherwise healthy lungs. Anesthetized rats were ventilated with conventional mechanical ventilation (VT 8 ml/kg; respiratory frequency 40 per minute) and 21% inspired oxygen, with or without a recruitment strategy consisting of recruitment maneuvers plus positive end-expiratory pressure, in the presence or absence of a laparotomy. Additional experiments examined the impact of atelectasis on right ventricular function using echocardiography, as well as functional residual capacity and PVR. Lack of recruitment resulted in reduced overall survival (59% nonrecruited vs. 100% recruited, p < 0.05), increased microvascular leak, greater impairment of oxygenation and lung compliance, increased PVR, and elevated plasma lactate. Echocardiography demonstrated that right ventricular dysfunction occurred in the absence of recruitment. Finally, samples from nonrecruited lungs demonstrated ultrastructural evidence of microvascular endothelial disruption. Although such effects clearly do not occur with comparable magnitude in the clinical context, the current data suggest novel mechanisms (microvascular leak, right ventricular dysfunction) whereby derecruitment may contribute to development of lung injury and adverse systemic outcome.

Animals↗

PubMed2003

Basolateral active uptake of nitrofurantoin in the CIT3 cell culture model of lactation.

Nitrofurantoin and other agents are actively transported into human and rodent milk. The purpose of this study was to determine whether nitrofurantoin active transport across mammary epithelia occurs basolaterally or apically, using the CIT3 cell culture model of lactation. The CIT3 model actively transports nitrofurantoin in the basolateral to apical direction. Basolateral to apical permeability [92.9 +/- 6.6 (microl/h)/cm(2)] was differentially decreased by unlabeled nitrofurantoin (250 microM) on the basolateral, apical, or both sides [49.5 +/- 1.8, 57.9 +/- 1.4, or 48.5 +/- 1.6 (microl/h)/cm(2), respectively]. Apical to basolateral permeability [27.6 +/- 1.8 (microl/h)/cm(2)] was increased in the presence of unlabeled nitrofurantoin (250 microM) on the basolateral, apical, or both sides [36.4 +/- 1.5, 39.9 +/- 0.7, 42.4 +/- 1.1 (microl/h)/cm(2), respectively]. These data indicate a basolateral active uptake mechanism for nitrofurantoin, which remains to be identified. This mechanism may influence the exposure of suckling infants to xenobiotics, as well as having potentially toxic effects on the lactating mammary epithelium and possibly altering the nutritional quality of the milk.

Animals↗

PubMed2003

Hydromorphone transfer into breast milk after intranasal administration.

STUDY OBJECTIVES: To determine the distribution of hydromorphone into breast milk and the potential exposure of the suckling infant, and whether the distribution of hydromorphone into milk can be predicted accurately by a passive diffusion model. DESIGN: Single-dose, pharmacokinetic study. SETTING: University clinical research unit. PATIENTS: Eight lactating, nonsmoking, healthy women aged 24-32 years. INTERVENTION: Hydromorphone HCl 2 mg was given intranasally to the women to characterize its pharmacokinetics and extent of its transfer into breast milk. MEASUREMENTS AND MAIN RESULTS: Plasma and milk samples were analyzed using liquid chromatography with tandem mass spectrometry detection. The milk:plasma ratio (M:P) was calculated as the total area under the concentration-time curve (AUC) of the milk divided by the total AUC of the plasma. Predicted in vitro M:P ratios were calculated using a diffusion model. Protein binding in milk and plasma, partitioning into milk fat (whole milk:skim milk ratios), as well as pH partitioning between plasma and milk were incorporated in the model. Protein binding was determined by equilibrium dialysis. Protein binding was minimal in both milk and plasma, with unbound fractions of 1 and 0.84, respectively There was little partitioning into milk fat, as demonstrated by the whole milk:skim milk ratio of 0.98. The observed and predicted M:P ratios +/- SD for hydromorphone were 2.57 +/- 0.47 and 1.11 +/- 0.28, respectively. The 95% confidence interval for the observed M:P ratio overlapped the confidence interval of the predicted M:P ratio, a finding that supports a role for both passive diffusion and active transport as mechanisms of hydromorphone transfer into milk. CONCLUSION: Hydromorphone distributes rapidly from plasma into breast milk; however, the drug does not partition into fat. The suckling infant would receive approximately 0.67% of the maternal dose of hydromorphone (adjusted for body weight). As this is a limited exposure, further studies are needed to determine any potential impact to an infant who is fed breast milk from a mother treated with hydromorphone.

Administration, Intranasal↗

PubMed2002

Sodium dependence of nitrofurantoin active transport across mammary epithelia and effects of dipyridamole, nucleosides, and nucleobases.

PURPOSE: The sodium dependence and effects of nucleoside and nucleobase transport inhibitors were determined to ascertain the role of sodium dependent nucleoside or nucleobase transporters in nitrofurantoin active transport across mammary epithelia. METHODS: Five lactating female rats received steady-state intravenous infusions of nitrofurantoin with and without the broad-based inhibitor dipyridamole. In the CIT3 murine model of lactation, 14C-nitrofurantoin basolateral to apical permeability was examined in the presence of varying sodium concentrations, purine and pyrimidine nucleosides and nucleobases, and dipyridamole. RESULTS: Dipyridamole effectively inhibited 14C-nitrofurantoin flux across CIT3 cells, with Ki = 0.78 microM (95% C.I. = 0.11 to 5.3 microM) and significantly decreased the milk-to-serum ratio of nitrofurantoin from 29.2 +/- 5.0 to 11.0 +/- 6.3 without changing systemic clearance. Nitrofurantoin active transport was significantly inhibited by complete sodium replacement. Adenosine and guanosine significantly inhibited nitrofurantoin permeability (54.5 +/- 2.6 (microl/hr)/cm2 and 50.7 +/- 0.6 (microl/hr)/cm2, respectively, vs. control 90.5 +/- 4.6 (microl/hr)/cm2) but uridine, thymidine, and the nucleobases had no effect. CONCLUSIONS: Nitrofurantoin active transport was sodium dependent and inhibited by dipyridamole, adenosine, and guanosine, but known sodium dependent nucleoside or nucleobase transporters were not involved.

Animals↗

PubMed2002

Effects of a P-glycoprotein inhibitor on brain and plasma concentrations of anti-human immunodeficiency virus drugs administered in combination in rats.

Most of the existing anti-human immunodeficiency virus agents enter the central nervous system (CNS) inefficiently and thus may allow slow viral replication in the brain. This may provide a sanctuary for the virus in the CNS and contribute to the development of acquired immunodeficiency syndrome dementia complex. This study evaluates a prodrug approach to improve the CNS delivery of the reverse transcriptase inhibitor 2',3'-dideoxyinosine (ddI) in combination with inhibition of P-glycoprotein-mediated efflux to increase the CNS delivery of the protease inhibitor nelfinavir and to determine whether any unanticipated drug interactions occur in this combination therapy. Three rats received either 6-chloro-2'3'-dideoxypurine (6-Cl-ddP), a prodrug of ddI activated by adenosine deaminase, nelfinavir, nelfinavir and 6-Cl-ddP, nelfinavir and N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) (a P-glycoprotein inhibitor), 6-Cl-ddP and GF120918, or 6-Cl-ddP, nelfinavir, and GF120918. Both 6-Cl-ddP and nelfinavir were administered as i.v. infusions, whereas GF120918 was given as an i.v. bolus 2 h before sampling. Plasma and brain tissue concentrations of 6-Cl-ddP, ddI, and nelfinavir were determined. Neither nelfinavir nor GF120918 was shown to alter the brain/plasma ratios of 6-Cl-ddP or ddI. GF120918, however, increased the plasma concentrations of 6-Cl-ddP and ddI, resulting in increased brain concentrations. GF120918 increased the brain/plasma ratio of nelfinavir significantly (approximately 100-fold). The brain/plasma ratios of nelfinavir were reduced nearly 2-fold in rats treated with nelfinavir, 6-Cl-ddP, and GF120918 compared with rats receiving only nelfinavir and GF120918, suggesting a modest inhibition of nelfinavir uptake by 6-Cl-ddP. Overall, combined 6-Cl-ddP, nelfinavir, and GF120918 administration enhances the brain/plasma ratios of both ddI and nelfinavir.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Acyclovir, ganciclovir, and zidovudine transfer into rat milk.

Treatment with antiviral agents that accumulate in breast milk may offer a novel approach to reduce the rates of vertical transmission of important viruses and the risk of clinical illness in suckling neonates. The present study evaluated the extent and mechanism of transfer of three antiviral nucleoside analogues into milk in a lactating rat model system. Acyclovir (0.26 mg/h), ganciclovir (0.13 mg/h), and zidovudine (0.5 mg/h) were each infused to steady-state concentrations in six rats 15 to 16 days postpartum. The observed ratios of the concentrations in milk to the concentrations in serum (observed milk-to-serum ratio), calculated from the ratio of the steady-state concentration in serum to the steady-state concentration in milk, determined the extent of drug transfer into milk. To identify the mechanism of transfer into milk, the observed milk-to-serum ratio was compared to a predicted milk-to-serum ratio estimated from an in vitro passive diffusion model of transfer of each drug into milk. High-pressure liquid chromatography methods determined milk and serum drug concentrations. Mean +/- standard deviation observed milk-to-serum ratios for acyclovir, ganciclovir, and zidovudine were 5.1 +/- 1.4, 1.6 +/- 0.33, and 1.0 +/- 0.29, respectively, compared with their corresponding predicted ratios of 1.1, 0.85, and 0.71. These results suggest that acyclovir accumulates in milk due to active transport mechanisms, while passive diffusion processes govern the transfer of both ganciclovir and zidovudine into milk. The presence of all three antiviral drugs in milk and the potential for active drug transfer into milk warrants further investigation of the accumulation of other antiviral drugs in milk and their therapeutic benefits in reducing the vertical transmission of viruses and clinical sequelae in the breast-feeding infant.

Acyclovir↗

PubMed2002

GF120918, a P-glycoprotein modulator, increases the concentration of unbound amprenavir in the central nervous system in rats.

The goal of this study was to determine the distribution of unbound amprenavir in the central nervous system (CNS) of rats. The concentration of unbound amprenavir in the extracellular fluid of the brain and the blood was examined in the presence and absence of the MDR modulator GF120918 by microdialysis. The brain-to-blood ratio of amprenavir in the absence and presence of GF120918 was found to be significantly different (P < 0.003; 0.076 and 0.617, respectively). The use of the MDR modulator GF120918 could potentially increase the penetration of human immunodeficiency virus protease inhibitors into the CNS.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Protein binding predictions in infants.

Plasma binding protein levels are lower in the newborn than in the adult and gradually increase with age. At birth, human serum albumin (HSA) concentrations are close to adult levels (75%-80%), while alpha 1-acid glycoprotein (AAG) is initially half the adult concentration. As a result, the extent of drug binding to HSA is closer to that of the adult than are those drugs bound largely to AAG. A model that incorporates the fraction unbound in adults and the ratio of the binding protein concentration between infants and adults successfully predicted the fraction unbound in infants and children.

Adult↗

PubMed2002

Ontogeny of hepatic and renal systemic clearance pathways in infants: part I.

Dramatic developmental changes in the physiological and biochemical processes that govern drug pharmacokinetics and pharmacodynamics occur during the first year of life. These changes may have significant consequences for the way infants respond to and deal with drugs. The ontogenesis of systemic clearance mechanisms is probably the most critical determinant of a pharmacological response in the developing infant. In recent years, advances in molecular techniques and an increased availability of fetal and infant tissues have afforded enhanced insight into the ontogeny of clearance mechanisms. Information from these studies is reviewed to highlight the dynamic and complex nature of developmental changes in clearance mechanisms in infants during the first year of life. Hepatic and renal elimination mechanisms constitute the two principal clearance pathways of the developing infant. Drug metabolising enzyme activity is primarily responsible for the hepatic clearance of many drugs. In general, when compared with adult activity levels normalised to amount of hepatic microsomal protein, hepatic cytochrome P450-mediated metabolism and the phase II reactions of glucuronidation, glutathione conjugation and acetylation are deficient in the neonate, but sulfate conjugation is an efficient pathway at birth. Parturition triggers the dramatic development of drug metabolising enzymes, and each enzyme demonstrates an independent rate and pattern of maturation. Marked interindividual variability is associated with their developmental expression, making the ontogenesis of hepatic metabolism a highly variable process. By the first year of life, most enzymes have matured to adult activity levels. When compared with adult values, renal clearance mechanisms are compromised at birth. Dramatic increases in renal function occur in the ensuing postpartum period, and by 6 months of age glomerular filtration rate normalised to bodyweight has approached adult values. Maturation of renal tubular functions exhibits a more protracted time course of development, resulting in a glomerulotubular imbalance. This imbalance exists until adult renal tubule function values are approached by 1 year of age. The ontogeny of hepatic biliary and renal tubular transport processes and their impact on the elimination of drugs remain largely unknown. The summary of the current understanding of the ontogeny of individual pathways of hepatic and renal elimination presented in this review should serve as a basis for the continued accruement of age-specific information concerning the ontogeny of clearance mechanisms in infants. Such information can only help to improve the pharmacotherapeutic management of paediatric patients.

Humans↗

PubMed2002

Ontogeny of hepatic and renal systemic clearance pathways in infants: part II.

Maturation of drug systemic clearance mechanisms during the postnatal period produces dramatic and rapid changes in an infant's capacity to eliminate drugs. A tentative general mathematical model describing the ontogeny of hepatic cytochrome P450 (CYP) enzyme-mediated clearance and renal clearance due to glomerular filtration in the first 6 months of life was elaborated from age-specific in vitro hepatic microsomal activity data (normalised to amount of hepatic microsomal protein) for enzyme-specific probe substrates and in vivo probe substrate data for glomerular filtration (normalised to bodyweight), respectively. The model predicts an age- and clearance pathway-specific Infant Scaling Factor (ISF) for the first 6 months of life. The ISF reflects functional maturation of a specific clearance pathway (normalised to bodyweight) relative to adult values. Therefore, the ISF directly correlates adult clearance values with an infant's capacity to eliminate drugs. Substitution of appropriate model parameter estimates and the age of the infant into the model provides an estimated ISF value, which may then be used to predict the contribution of a particular clearance pathway to total systemic clearance in the infant when adult systemic clearance values are known. The model was tested for its ability to predict infant systemic clearance of drugs whose elimination is principally mediated by a single CYP enzyme or by glomerular filtration. The model performed reasonably well for CYP1A2 and CYP3A4, but poorer predictions were obtained for CYP2D6 and CYP2C because of lack of model complexity and/or inadequate hepatic microsomal activity data to fully describe the maturational process of functional enzyme. For renal clearance due to glomerular filtration, data normalised to bodyweight (kg) showed a limited maturational trend, suggesting that adult renal clearances normalised to bodyweight might reasonably predict infant renal clearances in the first 6 months of life. The model provided reasonable predictions of renal clearance due to glomerular filtration in the infant.

Cytochrome P-450 Enzyme System↗