bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of Human Immunodeficiency Virus Infection and Its Associated Complications in Children
Authors: Brady Michael T.
Published: March 2013

Providing care to human immunodeficiency virus (HIV)‐infected children requires a comprehensive, multidisciplinary approach. This review will address the current status of supportive care, treatment of HIV‐associated complications and specific antiretroviral therapy. HIV affects multiple locations in the body resulting in a myriad of possible complications. These include opportunistic infections and malignancies secondary to immunodeficiency and central nervous system or other specific organ‐related disease secondary to direct HIV involvement. Recent scientific advances have markedly enhanced the quantity and quality of life of HIV‐infected children. Prophylaxis of Pneumocystis carinii pneumonia is the single most important therapeutic advance for the HIV‐infected patient. Other advances for the treatment and prevention of HIV‐related infections should similarly improve survival and reduce hospital stays. Antiretroviral therapy is relatively new. The currently available nucleoside reverse transcriptase inhibitors have proven efficacy. The role of single agents or combinations is being established. However, this group of antivirals has limitations that make alternate approaches essential. Augmentation of the patient's immune response will likely be a key to any future successful treatment regimen.
A Comparison of 10% Pentastarch and 5% Albumin in Patients Undergoing Open‐Heart Surgery
Authors: Mastroianni Linda , Low Henry B. C. , Rollman James , Wagle Manisha , Bleske Barry , Chow Moses S. S.
Published: March 2013

Colloids are useful in cardiac surgery to increase preload and improve cardiac output without the risks associated with blood transfusions. Pentastarch is a new low‐molecular weight hydroxyethyl starch compound under investigation for this purpose. The authors compared, in a randomized fashion, 12 patients who received pentastarch and 17 patients who received albumin for volume expansion after open‐heart surgery. During the 24‐hour study period there was no significant difference between the two groups with respect to systemic blood pressure, mean arterial pressure, cardiac index, right atrial pressure, and pulmonary capillary wedge pressure, with the exception of a higher mean arterial pressure and systolic blood pressure at 4 hours in the albumin group and higher heart rate at 12 hours in the pentastarch group. In addition, postoperative prothrombin time, partial thromboplastin time, fibrinogen, platelets, and factor VIII levels were not significantly different between the two groups. There were no complications attributed to colloid administration. The hemodynamic parameters were further evaluated in a subset of 6 pentastarch and 9 albumin patients who received the first 500 mL of colloid in a similar time frame and under similar clinical conditions. The patients who received pentastarch showed a significantly greater increase in cardiac index than did the patients who received albumin. No significant change in other parameters were noted between the two groups. The authors conclude that pentastarch is as safe as albumin and may be a more effective volume expander than albumin when used in open‐heart surgery patients.
Pharmacokinetics of Orally and Intravenously Administered Cyclosporine in Pre—Kidney Transplant Patients
Authors: Aweeka Francesco T. , Tomlanovich Stephen J. , Prueksaritanont Thomayant , Gupta Suneel K. , Benet Leslie Z.
Published: March 2013

The pharmacokinetics of cyclosporine (CSA) and four metabolites were evaluated in eight hemodialysis subjects awaiting renal transplantation to compare metabolic patterns with those observed in post‐transplant patients and normal volunteers. Each subject received a single 4‐mg/kg intravenous and a single 10‐mg/kg oral dose separated by a 1‐week washout period. Blood samples were collected before and at .5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, and 24 hours after CSA dosing. Cyclosporine blood, plasma, and metabolite (M17, M1, M18, M21) levels were determined by high‐pressure liquid chromatography. Mean (±standard deviation) CSA blood clearance was .47 ± .15 L/hour/kg, steady‐state volume of distribution (Vss) was 1.9 ± .5 L/kg, and mean residence time (MRT) was 4.4 ± 1.8 hours after intravenous dosing. With plasma, mean clearance was .70 ± .31 L/hour/kg, Vss was 2.4 ±1.2 L/kg, and MRT was 3.7 ± 2.2 hours. Cyclosporine bioavailability (F) averaged 24 ± 11 and 24 ± 15%, using blood and plasma, respectively. Values for clearance and Vss were approximately 30 to 100% greater than comparable estimates in healthy volunteers, but F and MRT were not altered to this extent. These changes might be explained on the basis of decreased protein binding in uremic patients. The area under the curve ratio for M17 and M1 to CSA increased an average of 1.7‐ and 3.9‐fold, respectively, after oral dosing compared with intravenous administration, indicating increased conversion during first‐pass metabolism.
Hypoglycemia Caused by Selegiline, an Antiparkinsonian Drug: Can Such Side Effects Be Predicted?
Authors: Rowland Michael J. , Bransome Edwin D. , Hendry Lawrence B.
Published: March 2013

Treatment with selegiline produced profound hypoglycemia in a 70‐year‐old man with Parkinson's disease. The hypoglycemia was accompanied by hyperinsulinemia and persisted for 1 week after selegiline was discontinued. Although this side effect of antidepressant monoamine oxidase inhibitors was well documented in 1959–1968 publications, it was not known to the manufacturer of selegiline. Effects of drugs on glucose metabolism may be predictable through a novel molecular modeling technique developed in our laboratories, which shows that glucose exhibits stereochemical complementarity to a specific site in partially unwound DNA. Selegiline and other molecules affecting glucose metabolism fit into the same DNA base sequence. It therefore should be possible to employ this technique to identify pharmaceutical agents that possess hypoglycemic or hyperglycemic effects in vivo.
Absolute Bioavailability and Absorption Characteristics of Aerosolized Tobramycin in Adults with Cystic Fibrosis
Authors: Cooney G. F. , Lum B. L. , Tomaselli M. , Fiel S. B.
Published: March 2013

Administration of antibiotics by the inhalational route has become part of standard protocols for treatment of and prophylaxis for Pseudomonal pneumonias in patients with cystic fibrosis. For tobramycin, however, limited data are available on the aerosol absorption patterns, and no absolute bioavailability data for tobramycin exist. The purpose of this study was to measure the absolute bioavailability and systemic absorption characteristics of tobramycin when administered in high doses by a nebulizer. Multiple serum concentrations of tobramycin were measured after administration of an intravenous dose (mean, 2.9 mg/kg every 6 hours) and after an inhalational dose (5.6 mg/kg over 1 hour). Inhalational doses were superimposed over the “tail” of a steady‐state intravenous dose to improve the sensitivity of the assay procedure (Abbott‐TDX). Absolute bioavailability (F) was determined from AUC ratios normalized for dose. Model‐independent pharmacokinetic parameters (volume of distribution [Vss] and total clearance [CLt]) were determined for each subject. Absorption characteristics (absorption rate constant [Ka] and mean absorption time [MAT]) were assessed after calculation of the cumulative fraction of drug absorbed, amount of bioavailable drug, and percent remaining to be absorbed per unit time using the Loo‐Riegelman method. Three men and three women completed the study, and all received concurrent doses of ceftazidime. Mean absolute bioavailability (± standard deviation) was 9.13% (± 3.82), and the rate of absorption into the systemic circulation was consistent with a zero‐order model profile for all subjects. Mean absorption time values reflected a wide degree of subject variability and ranged from approximately 15 to 150 minutes. The authors conclude that there is limited uptake of tobramycin into the systemic circulation when administered by nebulizer aerosol into the lungs even in high doses. Absorption of tobramycin from the alveolar space into the pulmonary vasculature appears to be rate limited, but this may be characteristic for adults with cystic fibrosis. The authors also conclude that high doses of tobramycin administered by aerosolized nebulizer in these patients would contribute little to the risk of toxicity because of the poor systemic uptake of this drug.
Critical Comparison of Novel and Existing Methods of Compliance Assessment During a Clinical Trial of an Oral Iron Chelator
Authors: Matsui Doreen , Hermann Christine , Klein Julia , Berkovitch Matitiahu , Olivieri Nancy , Koren Gideon
Published: March 2013

The assessment of compliance is critical in the evaluation of the effectiveness of a new therapeutic agent. Fifteen patients with transfusion‐dependent β‐thalassemia, many of whom had previously demonstrated erratic compliance with deferoxamine, were enrolled in a clinical trial of a new oral iron chelator, 1,2‐dimethyl‐3‐hydroxypyrid‐4‐one (L1). Their compliance with this medication was estimated by several existing methods and the novel Medication Event Monitoring System (MEMS). Overall compliance as assessed by the MEMS was 78.5 ± 13.0% of prescribed doses taken, significantly lower than the corresponding rates calculated by pill counts and diaries (91.5 ± 9.2% and 94.1 ± 4.3%, respectively). However, several serious problems were encountered with the MEMS, mostly in the form of incorrect use of the device by the patients. Disclosure of the nature of the MEMS and the compliance monitoring process did not alter the rate of adherence with L1 therapy. Compliance as determined by pill counts did not differ between the 1st and 2nd 6‐month periods. Although not reaching statistical significance, a trend towards better L1 compliance occurred in those patients in whom serum ferritin levels decreased. Patients who filled at least 50% of their diaries had significantly better compliance by pill counts than those who completed less than 50% of their diaries (95.9 ± 4.1% and 86.5 ± 11.1%, respectively). Steady‐state L1 trough concentrations and 24‐hour urinary iron excretion did not correlate with L1 compliance. Given the limitations of the available techniques for monitoring compliance, including the new MEMS device, a combination of methods should be used in the evaluation of medication compliance during the investigation of a new drug.
Atrial Natriuretic Peptide and Its Potential Role in Pharmacotherapy
Authors: Deutsch Adam , Frishman William H. , Sukenik Dmitry , Somer Bradley G. , Youssri Ayman
Published: March 2013

Atrial natriuretic peptide (ANP) is a 28 amino‐acid polypeptide secreted into the blood by atrial myocytes after atrial pressure and distension. Although its role in humans is not clear, it can produce a variety of physiologic effects including vasodilatation, natriuresis, and suppression of the renin‐angiotensin‐aldosterone axis. These actions are potentially useful in a variety of pathologic states such as hypertension and congestive heart failure, and diverse methods to augment the effects of ANP in these states have been devised. The results are exciting and, despite some problems, may lead to the pharmacologic use of enhancement of ANP actions in several clinical disorders.
Sequential Monotherapy of Hypertension
Authors: Kochar Mahendr S. , Trottier Dee , Kotecki Gloria , Forbes Marshall , Bamrah Virinderjit S.
Published: March 2013

In most cases, the antihypertensive therapy for an individual patient is selected through a process of trial and error. This study determined if, by treating each hypertensive patient sequentially, with six antihypertensive drugs, one from each of the major classes, one could decide on the best possible drug for control of hypertension. In a randomized open‐label crossover study, 19 patients (16 male and 3 female), 28–70 years of age with a sitting diastolic blood pressure of 95–110 mm Hg were given atenolol, captopril, clonidine, indapamide, prazosin, and verapamil in a sequential manner. Each drug was started at the minimum recommended or lower dose and titrated upwards every 2 weeks, if well tolerated, until blood pressure was controlled (diastolic BP <90 mm Hg). If blood pressure was controlled, the drug was continued for another 2 weeks. A washout period of at least 2 weeks was allowed between drugs. Both systolic and diastolic blood pressures were reduced significantly with all of the six drugs. In 18 of the 19 patients, blood pressure was controlled with at least one of six drugs, frequently with the lowest dose. The authors conclude that if hypertension is not controlled with the lowest recommended dose of a drug, other antihypertensive drugs should be tried sequentially rather than increasing the dose or adding a second drug.
Inhibition of Angiotensin‐Converting Enzyme with Libenzapril in Normotensive Males
Authors: Morgan John M. , Piraino Anthony J. , Saris Steven D. , Graham Camilla S. , Hirschhorn William L. , Kochak Gregory M. , Choi R. Les
Published: March 2013

The effect of intravenous (IV) libenzapril was studied in six healthy males by administering IV angiotensin I (AI) administered in stepwise increments of 20 ng/kg/5 min until the subjects' systolic blood pressure (SBP) had increased 20–30 mm Hg above baseline. The mean baseline infusion of 63 ng/kg/5 min resulted in a significant (P <0.05) increase in the ratio of AII to AI plasma levels from 0.52 ± 0.46 to 7.92 ± 4.48 and a SBP increase of 120 ± 7.1 to 147 ± 5.6. Within 15 minutes of starting the 1‐mg infusion of libenzapril over 1.5 hours, the AII/AI ratio decreased to baseline values, and the SBP had returned to baseline in 1 hour. Repeat AI challenges at 3.5 and 5 hours postdose did not increase SBP significantly. Even the 6.5‐hour challenge demonstrated only a slight increase in SBP, with an AII/AI ratio of 0.26. At 24 hours, SBP was only 40% of the baseline response, demonstrating that libenzapril is a potent long‐acting ACE inhibitor.
A Dose‐Ranging Pharmacokinetics Study of Sodium Diethyldithiocarbamate in Normal Healthy Volunteers
Authors: Awni Walid M. , Hoff Julie V. , Shapiro Bruce E. , Halstenson Charles E.
Published: March 2013

Sodium diethyldithiocarbamate (DDTC) is an investigational modulator of the toxicity produced by cisplatin. The pharmacokinetics of DDTC were evaluated after administration of 200 mg/m2/hr (n=8) and 400 mg/m2/hr (n=7) DDTC as 4‐hour intravenous infusions to normal male healthy volunteers. Diethyldithiocarbamate concentration at steady‐state (Cpss) increased disproportionally from 27.0 ± 7.6 μM for the low dose to 74.8 ± 19.3 μM for the high dose, whereas total body clearance decreased from 23.83 ± 8.23 mL/min/kg for the low dose to 15.48 ± 2.72 mL/min/kg for the high dose (P <0.05). However, the volume of distribution in the terminal phase remained unchanged. Diethyldithiocarbamate terminal elimination half‐life (t1/2β) increased from 3.74 ± 1.10 minutes for the low dose to 6.08 ± 1.07 minutes for the high dose (P <0.005). The data were then fitted using a one‐compartment open model with zero‐order infusion and Michaelis‐Menten elimination kinetics. The Km for DDTC was estimated to be 124.3 ± 19.9 μM, whereas the Vm was estimated to be 3.67 ± 1.15 μmol/min/kg. However, DDTC t1/2β was independent of DDTC concentrations, suggesting that the nonlinearity in DDTC kinetics does not exactly follow Michaelis‐Menten elimination kinetics. Thus, DDTC pharmacokinetics are dose dependent and may not be concentration dependent. Clinically, DDTC Cpss will increase nonlinearly with an increase in dose.
Absorption of Isosorbide‐5‐Mononitrate at Specific Sites in the Gastrointestinal Tract
Authors: Kramer William G.
Published: March 2013

As part of a development program for controlled‐ and extended‐release formulations of isosorbide‐5‐mononitrate (ISMN), the rate and extent of drug absorption was evaluated after site‐specific delivery in the gastrointestinal (GI) tract. Seven healthy male subjects received, on separate occasions, 20 mg of ISMN solution orally and via nasogastric tube to the jejunum, terminal ileum, and ascending colon. Compared with oral administration (AUC 2,963 hr × ng/mL, Cmax 442 ng/mL, Tmax 0.81 hr), placement of drug directly into the jejunum did not change the extent (AUC 2,844 hr × ng/mL) but increased the rate of absorption (Cmax 630 ng/mL, Tmax 0.28 hr) due to direct placement of drug into the intestine. Administration to the terminal ileum resulted in a rate of absorption comparable to that from the jejunum (Tmax 0.28 hr) but a reduction in extent (mean AUC 2,377 hr × ng/mL). Delivery to the ascending colon resulted in a further decrease in the extent (AUC 2,017 hr × ng/mL) and a “slowing” of the rate of absorption compared with the two intestinal sites (Cmax 392 ng/mL, Tmax 0.68 hr). Overall, bioavailability throughout the GI tract was sufficient to support development of controlled‐ and extended‐release formulations.
In Vitro Prediction of the Terfenadine‐Ketoconazole Pharmacokinetic Interaction
Authors: von Moltke Lisa L. , Greenblatt David J. , Duan Su Xiang , Harmatz Jerold S. , Shader Richard I.
Published: March 2013

Biotransformation of the peripherally acting H‐1 histamine antagonist, terfenadine, to its desalkyl and hydroxy metabolites was studied in vitro using microsomal preparations from six separate human livers. These metabolic reactions are mediated by the specific cytochrome P450‐3A4. Addition of ketoconazole to the reaction mixtures reduced the rate of formation of both metabolites in a manner consistent with competitive inhibition. Ketoconazole inhibition constants (Ki) averaged 0.024 μM for the desalkyl terfenadine pathway, and 0.237 μM for the hydroxy terfenadine pathway. A mathematical model, based on the in vitro Ki values and the usual clinical range of plasma ketoconazole concentrations (1–5 μg/mL; 1.88 − 0.94 μM), predicted that plasma terfenadine levels during coadministration of ketoconazole would increase by a factor ranging from 13‐fold to 59‐fold relative to the same dose of terfenadine given without ketoconazole. Actual plasma terfenadine levels during terfenadine‐ketoconazole coadministration in a clinical pharmacokinetic study were close to those predicted by the model. These plasma levels were associated with prolongation of the corrected QT interval, thereby explaining the potentially life‐threatening ventricular arrhythmias reportedly associated with terfenadine‐ketoconazole cotherapy. Thus, data from studies of drug metabolism in vitro can be used to predict and thereby possibly avoid clinically important drug interactions.
Improving the Diagnosis of Hypersensitivity Reactions Associated with Sulfonamides
Authors: Lanctôt Krista L. , Ghajar Bahram M. , Shear Neil H. , Naranjo Claudio A.
Published: March 2013

The differential diagnosis of idiosyncratic adverse drug reactions (ADRs) is difficult because symptoms are seldom pathognomonic. The authors compared the performance of two new diagnostic aids in the differential diagnosis of 27 cases of skin reactions associated with sulfonamide therapy. One test, the Bayesian Adverse Reaction Diagnostic Instrument (BARDI), calculates the posterior probability (PsP) of a drug being the etiology of an idiosyncratic ADR. The other, the lymphocyte toxicity assay (LTA), is a biochemical test that determines the percent of cell death because of toxic metabolites of a drug. Cases were assessed independently and blindly by BARDI and then the LTA. Skin reactions consisted of 19 exanthematous eruptions, 2 vasculitis, 1 erythema multiforme, and 5 urticarial rashes. BARDI indicated that the drug was very likely associated with 20 adverse events (PsP = 0.59 to 0.99); and unlikely to have caused 7 (PsP = 0.02 to 0.38). The LTA showed that 19 patients (70%) were test positive, and 8 were test negative. Comparing BARDI to LTA showed that BARDI had 79% sensitivity and 67% accuracy, but only 38% specificity. However, when the results of the LTA were incorporated into the calculation of the PsP based on this comparison, BARDI indicated that the drug was very likely associated with 18 reactions (PsP = 0.61 to 0.99) and unlikely to have caused 9 reactions (PsP = 0.003 to 0.47). The agreement increased from 67% to 96%. These findings indicate that the accuracy of diagnosis of idiosyncratic ADRs improved when the results of BARDI and LTA were combined. These findings also crossvalidate the results obtained by using BARDI.
Autonomic Control of Cardiovascular Function: Clinical Evaluation in Health and Disease
Authors: Taylor Addison A.
Published: March 2013

The high‐ and low‐pressure baroreceptor reflexes are integral to the control of blood pressure by the autonomic nervous system. Tests of the integrity of these baroreflexes make it possible to identify the site of autonomic dysfunction in patients with orthostatic hypotension. Clinical characteristics and typical results of autonomic testing in patients with autonomic failure, with carotid sinus hypersensitivity, and with hyperadrenergic autonomic dysfunction are described in this review.
Cardiovascular Responses to Postural Changes: Differences with Age for Women and Men
Authors: Frey Mary Anne Bassett , Tomaselli Clare Marie , Hoffler Wyckliffe G.
Published: March 2013

The cardiovascular responses to postural change, and how they are affected by aging, are inadequately described in women. Therefore, the authors examined the influence of age and sex on the responses of blood pressure, cardiac output, heart rate, and other variables to change in posture. Measurements were made after 10 minutes each in the supine, seated, and standing positions in 22 men and 25 women who ranged in age from 21 to 59 years. Several variables differed, both by sex and by age, when subjects were supine. On rising, subjects' diastolic and mean arterial pressures, heart rate, total peripheral resistance (TPR), and thoracic impedance increased; cardiac output, stroke volume, and mean stroke ejection rate decreased; and changes in all variables, except heart rate, were greater from supine to sitting than sitting to standing. The increase in heart rate was greater in the younger subjects, and increases in TPR and thoracic impedance were greater in the older subjects. Stroke volume decreased less, and TPR and thoracic impedance increased more, in the women than in the men. The increase in TPR was particularly pronounced in the older women. These studies show that the cardiovascular responses to standing differ, in some respects, between the sexes and with age. The authors suggest that the sex differences are, in part, related to greater decrease of thoracic blood volume with standing in women than in men, and that the age differences result, in part, from decreased responsiveness of the high‐pressure baroreceptor system.
Acute Effects of Head‐Down Tilt and Hypoxia on Modulators of Fluid Homeostasis
Authors: Whitson Peggy A. , Cintron Nitza M. , Pietrzyk Robert A. , Scotto Pietro , Loeppky Jack A.
Published: March 2013

In an effort to understand the interaction between acute postural fluid shifts and hypoxia on hormonal regulation of fluid homeostasis, the authors measured the responses to head‐down tilt with and without acute exposure to normobaric hypoxia. Plasma atrial natriuretic peptide (ANP), cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP), plasma aldosterone (ALD), and plasma renin activity (PRA) were measured in six healthy male volunteers who were exposed to a head‐down tilt protocol during normoxia and hypoxia. The tilt protocol consisted of a 17° head‐up phase (30 minutes), a 28° head‐down phase (1 hour), and a 17° head‐up recovery period (2 hours, with the last hour normoxic in both experiments). Altitude equivalent to 14,828 ft was simulated by having the subjects breathe an inspired gas mixture with 13.9% oxygen. The results indicate that the postural fluid redistribution associated with a 60‐minute head‐down tilt induces the release of ANP and cGMP during both hypoxia and normoxia. Hypoxia increased cGMP, cAMP, ALD, and PRA throughout the protocol and significantly potentiated the increase in cGMP during head‐down tilt. Hypoxia had no overall effect on the release of ANP, but appeared to attenuate the increase with head‐down tilt. This study describes the acute effects of hypoxia on the endocrine response during fluid redistribution and suggests that the magnitude, but not the direction, of these changes with posture is affected by hypoxia.
Long‐Duration +Gz Acceleration on Cardiac Volumes Determined by Two‐Dimensional Echocardiography
Authors: Tripp Lloyd D. , Jennings Thomas J. , Seaworth John F. , Howell Lora L. , Goodyear Chuck
Published: March 2013

To enhance protection of humans exposed to long‐duration low‐gravity environments such as the Space Shuttle and National Aerospace Plane during re‐entry or in the short‐duration high‐+Gz environment of fighter aircraft, the effects of +Gz acceleration on cardiovascular hemodynamics must be understood. This study reports the use of two‐dimensional echocardiography in normal men during +Gz acceleration. The heart's position in relation to the chest did not change during acceleration up to +7 Gz. The success in maintaining high‐quality images during exposures to G‐forces of this magnitude may he attributed to the relatively low rate of G onset. End‐diastolic volumes (EDV) and stroke volumes (SV) decreased during a +Gz acceleration ramp that increased until the subject experienced peripheral light loss (PLL) (P > .05). An inflated G‐suit partially counteracted this effect. By 30 seconds of a +3 Gz acceleration plateau, the protective effects of the inflated G‐suit to maintain EDV is lost and the EDV of the inflated G‐suit was lower than the EDV of the uninflated G‐suit (P > .05).
Losartan Does Not Affect the Pharmacokinetics and Pharmacodynamics of Warfarin
Authors: Kong Ah‐Ng Tony , Tomasko Lisa , Waldman Scott A. , Osborne Barbara , Deutsch Paul J. , Goldberg Michael R. , Bjornsson Thorir D.
Published: March 2013

Losartan, an orally active, nonpeptide angiotensin II receptor antagonist is being developed as a therapeutic agent for the treatment of hypertension and heart failure. Many patients requiring anticoagulant therapy with warfarin also may have hypertension or heart failure, and thus, are potential candidates for losartan therapy. This study was designed to investigate whether losartan at likely dosage levels would alter the anticoagulant response to warfarin. In a two‐period, placebo‐controlled, randomized, crossover study, ten healthy male subjects received a single oral dose of 30 mg warfarin sodium on the seventh day of a 13‐day treatment with losartan, 100 mg daily by mouth, or placebo. Multiple plasma samples were collected over a 6‐day period after both warfarin doses for the measurements of R‐ and S‐warfarin concentrations and prothrombin times. The pharmacokinetics of R‐ and S‐warfarin were comparable in the absence and presence of losartan (no significant effects of losartan on area under the curve, Cmax, or tmax). Losartan also had no significant effect on the anticoagulant effect of warfarin, as assessed by the area under the prothrombin time versus time curve and the maximum response for prothrombin time. The lack of pharmacokinetic or pharmacodynamic interaction between warfarin and losartan observed in this investigation suggests that a clinically important interaction between these drugs is unlikely to occur in patients requiring concomitant administration of both drugs.
Can Chronic Maternal Drug Therapy Alter the Nursing Infant's Hepatic Drug Metabolizing Enzyme Pattern?
Authors: Toddywalla Villi S. , Patel Shahnaz B. , Betrabet Shrikant S. , Kulkarni Ramesh D. , Kombo Indira , Saxena Badri N.
Published: March 2013

This study was carried out to investigate whether minute quantities of maternal drugs ingested over an extended period of time by a breast‐feeding infant can alter the activity pattern of the infant's hepatic drug metabolizing enzyme (HDME). The HDME activity patterns of 12 breast‐fed infants whose mothers were not on drug therapy were compared with those of 11 infants whose mothers had been taking 30 μg levo‐norgesterel daily for 90 to 195 days (oral contraceptives group) and of 10 infants whose mothers had been taking ethambutol and isoniazid daily since pregnancy (tuberculosis group). As 6β hydroxycortisol in urine is considered to be a good and acceptable reflector of HDME activity, it was estimated from the infants' urine using enzyme‐linked immunosorbent assay (ELISA) technique. A comparison of the patterns between 90 days of age and 195 days of age of the infants in the control group and the two study groups indicated an increase from 36.6 ng/mL to 58.4 ng/mL at 195 days in the control group. An initial decrease from 36.6 ng/mL to 26.2 ng/mL was noted with commencement of maternal levo‐norgesterel therapy, followed by a slow and steady rise to 47.8 ng/mL at 195 days of age, with a shift in the peak from 120 to 135 days of infants age in the oral contraceptive group. A suppressed pattern with decreased levels of 6β hydroxycortisol ranging from 19.3 ng/mL to 26.5 ng/mL at 195 days was found in the tuberculosis group. The data were analyzed by two‐way analysis of variance (ANOVA) coupled with Duncan's Multiple range test. Both treatment groups showed significant differences from the control group at the 0.050 level. The HDME plays an important role in determining the final outcome of any drug in humans, as it controls the metabolism of drugs. Hence, alterations in its activity caused by the transfer of maternal drugs over a prolonged period of time could pose a serious problem to nurslings when they require drugs for their own benefit.
Ceftizoxime Use In Trauma Celiotomy: Pharmacokinetics and Patient Outcomes
Authors: Rosemurgy Alexander S. , Dillon K. R. , Kurto H. A. , Albrink M. H.
Published: March 2013

Seriously injured patients undergo vigorous resuscitation upon arrival at the emergency department and through the immediate perioperative period. Although resuscitation leads to volume loading and fluid shifts, drug dosing and dosing intervals are often not altered to account for changes in total body volume or circulatory volume. To address this, a prospective study of pharmacokinetics of ceftizoxime in 53 injured adults who underwent emergency celiotomy was conducted. Further, the relationship between serum ceftizoxime concentrations and infectious outcomes was evaluated. Per protocol, injured adults undergoing emergency celiotomy received prophylactic ceftizoxime treatment according to standard dosing regimens. Of the patients, 6 (11.5%) experienced postoperative infections and had lower peak serum ceftizoxime levels in the recovery room than patients not experiencing infection. For severely injured adults with extensive blood loss or undergoing lengthy operations requiring rigorous volume resuscitation, doses of ceftizoxime, and indeed all antibiotics, may need to be increased beyond conventional standards to minimize infectious complications.
The Effect of Food, Time of Dosing, and Body Position on the Pharmacokinetics and Pharmacodynamics of Verapamil and Norverapamil
Authors: Gupta Suneel K. , Yih Betty M. , Atkinson Linda , Longstreth James
Published: March 2013

To evaluate the influence of food, time of dosing, and body position on the steady‐state pharmacokinetics of an osmotically controlled formulation of verapamil (COER‐verapamil), each of 29 healthy men received one tablet a day at specified times in an open‐label, multiple‐dose, four‐period, crossover study. The verapamil tablets were administered in a randomized, balanced, crossover design: 240 mg at 8:00 AM on an empty stomach, subjects remaining ambulatory;240 mg at 8:00 AM on an empty stomach, subjects remaining supine for 8 hours; 240 mg at 10:00 PM with a standardized meal, subjects remaining supine for 8 hours; and 240 mg at 10:00 PM on an empty stomach, subjects remaining supine for 8 hours. Plasma verapamil concentrations were measured at steady state over the dosing interval. Steady‐state plasma concentrations were achieved by the fourth administration of the drug. Neither food nor posture had any effect on the pharmacokinetics of verapamil or norverapamil, or on hemodynamic measurements. Time of dosing did affect the rate of appearance and elimination of verapamil, but had no effect on the extent of verapamil absorption, norverapamil appearance, or hemodynamic measurements.
Pharmacokinetic and Pharmacodynamic Evaluation During Coadministration of Nefazodone and Propranolol in Healthy Men
Authors: Salazar Daniel E. , Marathe Punit H. , Fulmor I. Edgar , Lee Jim S. , Raymond Ralph H. , Uderman Howard D.
Published: March 2013

Potential interactions between nefazodone (200 mg every 12 hours) and propranolol (40 mg every 12 hours) were assessed in 18 healthy male volunteers in an open‐label, randomized, three‐way crossover study. The nature, frequency, and severity of adverse events during coadministration of nefazodone and propranolol were similar to those observed with either treatment alone. There were no clinically significant effects on vital signs, electrocardiographic results, or laboratory parameters. With coadministration, the maximum peak concentration (Cmax) and area under the concentration‐time curve over the dosing interval (AUCτ) of propranolol decreased 29% and 14%, respectively; Cmaxand AUCτof 4‐hydroxy‐propranolol decreased 15% and 21%, respectively. Despite decreased plasma concentrations of the β‐antagonists, the reduction in exercise‐induced tachycardia and post‐exercise double product was slightly greater with coadministration than with propranolol alone. Administration of nefazodone alone did not significantly affect either pharmacologic parameter. The pharmacokinetics of nefazodone and its metabolites were largely unaffected during coadministration. Coadministration of propranolol and nefazodone results in modest pharmacokinetic inequivalencies, but no clinically significant alterations of the pharmacodynamics of propranolol.
5‐Fluorouracil Modulates the Toxicity of High Dose Methotrexate
Authors: White Robert M.
Published: March 2013

Pretreatment with 5‐fluorouracil (FU) attenuated the toxicity of high dose methotrexate (MTX) in in vitro and in vivo models. Because dose intensification of the MTX reversed the fluoropyrimidine antagonism of MTX activity in these models, administering FU before the MTX offered the potential advantage of MTX dose intensity and low toxicity without the confounding effects of leucovorin rescue. The current study was conducted to determine the maximum dose of MTX tolerated after a priming dose of FU without leucovorin rescue, and to determine the toxicities of this combination. Subjects (n = 42) received a constant dose of FU followed in 2 hours by MTX; treatment was repeated every 3 weeks. Subjects initially received five doses of leucovorin (10 mg/m2 every 6 hours); this was reduced to two doses, then to zero doses (no rescue) if less than grade 2 toxicity occurred in prior treatments. Cohorts of subjects received escalating doses of MTX in a Fibonacci fashion. At the 1250 mg/m2 dose level, almost all previously untreated subjects tolerated the elimination of leucovorin rescue, without the occurrence of severe toxicity; this was 6 to 8 times the MTX dose that generally requires leucov órin rescue to avoid severe and lethal toxicity. The 24‐ and 48‐hour MTX levels were at a level that usually requires leucovorin rescue. Previously treated subjects were less tolerant; 400 mg/m2 of MTX was the approximate maximum tolerated dose. Prior FU exposure appeared to protect tissues normally susceptible to MTX toxicity, and allowed safe administration of high dose MTX without leucovorin rescue.
Intrapulmonary and Systemic Pharmacokinetics of Aerosolized Pentamidine Used for Prophylaxis of Pneumocystis carinii Pneumonia in Patients Infected with the Human Immunodeficiency Virus
Authors: Conte John E. , Golden Jeffrey A.
Published: March 2013

A study was conducted to determine the intrapulmonary and systemic pharmacokinetics of aerosolized pentamidine prophylaxis (APP) in patients infected with human immunodeficiency virus (HIV). 151 patients received high‐dose (300 mg twice a month or 600 mg once a month) APP as part of a previously published clinical trial, and 29 additional patients received standard‐dose (300 mg once a month) APP. Serial blood samples were obtained from the first cohort: 577 samples were obtained from 76 patients in the group given 600 mg once a month, and 554 blood samples were obtained from 75 patients in the group given 300 mg twice a month. In 9 of the 151 patients, bronchoscopy and tri‐lobar (right upper, middle, and lower lobe) bronchoalveolar lavage (BAL) were performed 6 and 12 months after initiation of APP. Unilobar (right middle lobe) BAL was performed in the 29 patients infected with HIV who underwent bronchoscopy for diagnostic purposes. Pentamidine was measured using a chromatographic (HPLC) assay. The concentrations (mean ± SD) of pentamidine in plasma in the groups given 300 mg twice a month and 600 mg once a month were 5.3 ± 6.1 ng/mL and 8.8 ± 9.6 ng/mL, respectively, and accumulation did not occur. The BAL supernatant and alveolar cell pentamidine concentrations were not significantly different in the 3 lobes and ranged from 16.5 ± 7.7 ng/mL to 29.2 ± 19.5 ng/mL and 1255 ± 1142 ng/mg protein to 1572 ± 1161 ng/mg protein in the group gien 300 mg twice a month; and from 5.5 ± 2.9 ng/mL to 9.4 ± 7.7 ng/mL and 339 ± 201 ng/mg protein to 571 ± 681 ng/mg protein in the group given 600 mg once a month. The intrapulmonary concentrations of pentamidine at 6 and 12 months were not significantly different. In 18 of the 29 patients who received 1 to 7 prior monthly doses of standard APP, drug concentrations in BAL increased linearly (y = 2.05x) with the number of doses administered before bronchoscopy. These data indicate that intrapulmonary drug concentrations continue to increase for approximately 6 months after the initiation of APP, at which time steady state is achieved, and that administration of high dose APP is probably safe.
The Dose Proportionality of the Pharmacokinetics of Ardeparin, a Low Molecular Weight Heparin, in Healthy Volunteers
Authors: Troy Steven , Fruncillo Richard , Ozawa Tsunenori , Mammen Eberhard , Holloway Scott , Chiang Soong
Published: March 2013

Ardeparin is a low molecular weight heparin currently being evaluated as an antithrombotic agent. The objective of this investigation was to assess the effects of dose on the pharmacokinetics of ardeparin after subcutaneous administration. Eighteen healthy subjects received doses of 30 U/kg, 60 U/kg, and 100 U/kg antifactor Xa (aXa) of ardeparin by subcutaneous injection. Plasma antifactor IIa (aIIa) activity levels after the 30‐ and 60‐U/kg doses of ardeparin were too low to reliably characterize the disposition of the drug. However, the pharmacokinetics of ardeparin could be characterized by using pharmacodynamic measurements of plasma aXa activity. The rate of absorption of ardeparin after subcutaneous administration did not change with increasing dose. The volume of distribution (Vd) of ardeparin was small, reflecting minimal distribution outside the intravascular space, and was independent of dose. The total clearance of ardeparin, however, decreased with increasing dose, and half‐life (t1/2) was prolonged at the higher doses. Within the observed dose range, a doubling of the ardeparin dose resulted in an area under the plasma aXa activity‐versus‐time curve (AUC) that was approximately 25% greater than expected on the basis of linear disposition. The differences in AUC and clearance between the three doses suggest that the mechanism of elimination of ardeparin is saturable.
Effects of Nonsteroidal Antiinflammatory Drugs on Platelet Function and Systemic Hemostasis
Authors: Schafer Andrew I.
Published: March 2013

Aspirin and nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs) inhibit platelet cyclooxygenase, thereby blocking the formation of thromboxane A2. These drugs produce a systemic bleeding tendency by impairing thromboxane‐dependent platelet aggregation and consequently prolonging the bleeding time. Aspirin exerts these effects by irreversibly blocking cyclooxygenase and, therefore, its actions persist for the circulating lifetime of the platelet. Nonaspirin NSAIDs inhibit cyclooxygenase reversibly and, therefore, the duration of their action depends on specific drug dose, serum level, and half‐life. The clinical risks of bleeding with aspirin or nonaspirin NSAIDs are enhanced by the concomitant use of alcohol or anticoagulants and by associated conditions, including advanced age, liver disease, and other coexisting coagulopathies.
Diltiazem: Ten Years of Clinical Experience in the Treatment of Hypertension
Authors: Weir Matthew R.
Published: March 2013

Diltiazem hydrochloride is a benzothiazepine derivative calcium‐channel blocker with proven antianginal and antihypertensive capabilities. Its primary mechanism of action is vasodilatation, which results in diminished vascular resistance and improved perfusion to various vascular beds and target organs. The antihypertensive efficacy of diltiazem in various demographic groups has been studied and compared with diuretics, β‐blockers, angiotensin‐converting enzyme inhibitors, and other calcium‐channel blockers. These studies have shown that the antihypertensive effect of diltiazem is similar to that of the other therapies. Diltiazem does not adversely affect electrolytes or carbohydrate or lipid metabolism, and it may have beneficial effects on the heart and kidneys. Diltiazem reduces myocardial hypertrophy and exerts antianginal effects on the heart through coronary vasodilation and reduction in the blood pressure double product. Diltiazem improves renal perfusion and attenuates proteinuria. These effects may be helpful in limiting the progression of renal injury. Overall, the efficacy and tolerability of diltiazem, as well as its salutary effects on the heart and kidneys, make it an important therapeutic consideration for patients with hypertensive disease.
The Effect of Atropine on Parasympathetic Control of Respiratory Sinus Arrhythmia in Two Ethnic Groups
Authors: du Plooy Willem J. , Venter Chris P.
Published: March 2013

The effects of low and high doses of atropine on respiratory sinus arrhythmia were assessed to ascertain whether any differences exist in the degree of parasympathetic control on cardiac rhythm between two ethnic groups. The standard deviation of the R‐R interval (the R peak‐to‐peak interval of two QRS complexes of an electrocardiogram) has been used as a noninvasive parameter to measure the degree of parasympathetic cardiac control. Nine black and nine white healthy male volunteers took part in study after approval by the Research and Ethics Committee of the Medical University of South Africa. Thirty consecutive electrocardiographic complexes were recorded during each of the following: 3 deep inspirations and expirations, incremental cumulative atropine injections of 0.001 mg/kg until 0.005 mg/kg, followed by two injections of 0.01 mg/kg and 0.015 mg/kg of atropine each. After each of the last two injections the deep inspiration and expiration procedure was repeated. No significant differences could be found at any stage for any parameter between the groups. In both groups the R‐R interval variation increased threefold during voluntary induced respiratory sinus arrhythmia. This effect was blocked after 0.01 mg/kg of atropine. The degree of parasympathetic control was not affected by any respiratory maneuver, but was affected by atropine. A significant inverse quadratic relationship was found between parasympathetic control and heart rate change (R = .984 for whites, and R = .905 for blacks). A poor correlation was found between the R‐R interval variation and heart rate changes. In conclusion, ethnicity does not affect parasympathetic activity. It is suggested that R‐R interval variation be used as a good noninvasive parameter of cholinergic afferent reflexes that affect respiration, but that R‐R interval variation not be used as an indicator of parasympathetic control of heart rate.
In Vitro and In Vivo Evaluation of a Once‐Daily Controlled‐Release Pseudoephedrine Product
Authors: Hwang Stephen S. , Gorsline Jane , Louie John , Dye Dan , Guinta Diane , Hamel Larry
Published: March 2013

The functionality of a once‐daily, osmotic dosage form—gastrointestinal therapeutic system (pseudoephedrine HCl) or GITS (PeHCl)—was studied in vitro and in vivo. The in vitro release profiles were close to identical from pH 1 to 7.5 and between USP apparatus 2 and 7, independent of paddle speeds from 50 to 200 rpm; GITS also released drug at the normal rate in aqueous media after incubation in bile salts or fatty media. Both strengths of GITS (PeHCl)—240 and 120 mg—were then compared with a commercially available pseudoephedrine solution given every 6 hours and a timed‐release 12‐hour pseudoephedrine capsule given every 12 hours in a randomized 4‐way crossover study in 24 healthy men. All four formulations were equivalent in total drug absorbed. Both GITS treatments had AUCinf values equivalent to those of PeHCl solution and capsules, and Cmax values equivalent to PeHCl capsules. Cmax for GITS and capsule treatments were each significantly lower than for solution, but the differences were small (14–17%). A one‐to‐one correlation was shown between rate of absorption and in vitro release profiles for the GITS products, indicating that drug release from GITS controls absorption. Insensitivity to conditions of in vivo release accounts for the close in vitro/in vivo correlation of release rates. In a second randomized crossover trial (12 men), the effect of a high‐fat breakfast on GITS performance was evaluated. Mean pseudoephedrine concentrations in plasma were close to identical with or without the breakfast, and the treatments were bioequivalent. The validity of the in vitro/in vivo correlation was confirmed in a bioequivalence study in which GITS with similar in vitro release rate profiles, but manufactured under different conditions (batch size, quantitative core composition, manufacturing equipment, and manufacturing site), were shown to be bioequivalent.
Pharmacokinetics and Presystemic Gut Metabolism of Methyldopa in Healthy Human Subjects
Authors: Skerjanec Andrej , Campbell Norman R. C. , Robertson Susan , Tam Yun K.
Published: March 2013

This study examined the pharmacokinetics and metabolism of methyldopa after giving single 250‐mg oral and intravenous doses to 16 healthy human volunteers. A 48‐hour washout period was allowed between oral and intravenous treatments. Blood and urine samples were collected; methyldopa was assayed in blood and urine, and its metabolites (methyldopa sulfate, α‐methyldopamine, and α‐methyldopamine sulfate) were assayed in urine. Pharmacokinetic parameters were recorded as follows: half‐life was 2.0 ± 0.7 hours; total body and renal clearance were 268 ± 72 and 107 ± 35 mL/min, respectively; and volume of distribution at steady‐state was 33 ± 11 L. The absolute bioavailability of the drug was 42 ± 16%. The measurable metabolites in urine after oral and intravenous administration accounted for 27% and 17% of the dose, respectively. Methyldopa sulfate was the most abundant metabolite recorded; its quantity was higher after oral than after intravenous administration, 20.1 ± 5.7% versus 6.7 ± 5.3% of the dose (P < .05), suggesting significant presystemic gut metabolism. First‐pass gut metabolism for methyldopa was estimated to be 17.6 ± 6.9% of the dose given.