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Introduction The past decade has been marked by a gradual expansion of the traditional primary care role of the pediatric nurse practitioner (PNP) into practice arenas that call for more acute and critical care of children. The purpose of the study was to explore the educational programming needs of dual (combined) track PNP programs that prepare graduates to provide care to children and adolescents across the continuum of health and illness. Method A two-phase, exploratory, mixed method design was utilized. An electronic survey was completed by 65% of PNP program directors in the country. Semi-structured telephone interviews were conducted with hospital-based PNPs who were practicing in roles that met a range of health care needs across the primary and acute care continuum. Results Primary care and acute care programs have more common than unique elements, and the vast majority of clinical competencies are common to both types of program. Only three competencies appear to be unique to acute care programs. Discussion The Association of Faculties of Pediatric Nurse Practitioner Programs should utilize existing evidence and develop guidelines for dual PNP programs that focus on the provision of care to children across a wide continuum of health and illness.

In increasing numbers, pediatric nurse practitioner (PNP) students seek educational programs that prepare them for dual certification in acute care and primary care. In 2008, an AFPNP research team of faculty experts was convened to examine areas of commonality and distinction between acute-care and primary-care PNP programs. This team surveyed all acute-care and primary-care PNP programs in the country and conducted interviews with hospital-based PNPs who were practicing in roles that met a range of health-care needs across the acute-care and primary-care continuum. Based on the results of the survey and interviews, an AFPNP task force created guidelines for combined educational programs that prepare students for dual certification as acute-care and primary-care PNPs.

OBJECTIVE: To review folic acid's mechanism of action, adverse effects, therapeutic recommendations, compliance, and cost. DATA SOURCES: A MEDLINE search was conducted through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included folate, folic acid, neural tube defect, homocysteine, and methylenetetrahydrofolate reductase. STUDY SELECTION: Animal and human studies examining the effects of folate were reviewed. DATA EXTRACTION: Data collected included mechanism of action, safety issues, dosing recommendations, compliance with recommendations, and economics. DATA SYNTHESIS: Folic acid decreases neural tube defect risk through an effect on methionine–homocysteine metabolism. In addition, increased folate intake may reduce cardiovascular morbidity and mortality. Since toxicity is minimal, everyone can potentially benefit from increased folate consumption. To help achieve this, the Food and Drug Administration has mandated that cereal grain be fortified with 140 μg of folic acid per 100 g of grain, which will add approximately 0.1 mg of folate to the average diet. Studies recommend supplementing with 0.2 mg to promote optimal homocysteine concentrations and for preventing neural tube defects. CONCLUSIONS: Despite fortification, most women will still receive less folate than the 0.4 mg/d recommended by the Public Health Service. All population groups would benefit from increased folate intake. Current studies indicate 200 μg/d may be the minimum effective amount of fortification needed for normalizing homocysteine concentrations and preventing a significant number of neural tube defects; thus, a higher level of food fortification may be warranted.

Objective: To review information regarding the dual and interdependent drug-nutrient interaction between phenytoin and folic acid and other literature involving phenytoin and folic acid. Data Sources: Information was retrieved from a MEDLINE search of English-language literature conducted from 1983 (time of the last review) to March 1995. Search terms included folic acid, phenytoin, and folic acid deficiency. Additional references were obtained from Current Contents and from the bibliographies of the retrieved references. Study Selection: All human studies examining the effects of phenytoin on serum folate concentrations and folic acid supplementation on serum phenytoin concentrations were selected. These included studies of patients with epilepsy and healthy volunteers as well as case reports. Case reports were included because of the extensive length of time needed to study this drug interaction. Data Extraction: Data extracted included gender, dosing, serum folate concentrations if available, pharmacokinetics, and adverse events. Data Synthesis: Serum folate decreases when phenytoin therapy is initiated alone with no folate supplementation. Folic acid supplementation in folate-deficient patients with epilepsy changes the pharmacokinetics of phenytoin, usually leading to lower serum phenytoin concentrations and possible seizure breakthrough. Folate is hypothesized to be a cofactor in phenytoin metabolism and may be responsible for the “pseudo-steady-state,” which is a concentration where phenytoin appears to be at steady-state, but in reality, is not. Phenytoin and folic acid therapy initiated concomitantly prevents decreased folate and phenytoin obtains steady-state concentrations sooner. Conclusions: Folic acid supplementation should be initiated each time phenytoin therapy commences because of the hypothesized cofactor mechanism, decreased adverse effects associated with folate deficiency, and better seizure control with no perturbation of phenytoin pharmacokinetics.

Phenytoin (PHT) therapy to control seizures decreases serum folate levels in half of epileptic patients, thus increasing the risk of folate depletion. Supplementation with folic acid prevents deficiency but also changes PHT pharmacokinetics. Kinetic monitoring of PHT when folic acid is provided as a supplement has not been reported in women of child-bearing age. This study of six fertile women examined the interdependence of PHT and folic acid in a randomized crossover study of two treatments: treatment 1 consisted of 300 mg sodium PHT per day and treatment 2 consisted of 300 mg sodium PHT plus 1 mg folic acid per day. Dietary folic acid intake was calculated daily. During treatment 1, serum folate level decreased 38.0 +/- 18.6% (mean +/- standard deviation) and serum PHT concentration was in the low therapeutic range (43.92 +/- 14.52 mumol/L). During treatment 2, serum folate level increased 26.0 +/- 33.4%, and serum PHT level (39.04 +/- 14.16 mumol/L) was similar to that in treatment 1. Only one subject attained PHT steady state during treatment 1, but four subjects achieved steady state during treatment 2. Dietary folate intakes during treatments 1 and 2 were not significantly different. This study suggests an interdependence between PHT and folic acid and supports the observation that fertile women treated with PHT require folic acid supplementation to maintain a normal serum folate level.

The in vivo phenobarbital removal characteristics of three brands of activated charcoal (Actidose, Charcoaid, Superchar) were studied in normal volunteers using a system analysis approach. The subjects received a 200-mg dose of oral or intravenous phenobarbital followed by a single oral dose of 30 g of one of the three charcoals in a randomized crossover design. The relative merits of the three charcoals in enhancing the removal of oral and intravenous phenobarbital were assessed using a system analysis approach. The removal clearance, time to peak (tp), peak removal clearance (Rmax), percentage of dose removed (PCT∞), and phenobarbital removal clearance (CLr) were calculated for the oral and intravenous treatments. Superchar had a pulse-like effect, with the shortest tp and the largest Rmax. Actidose and Charcoaid had similar effects, with Actidose inducing slightly greater phenobarbital removal. Superchar has the highest surface area and relative percentage of surface hydroxyl groups, whereas Actidose has the lowest surface area and relative percentage of surface hydroxyl groups of the three charcoals studied. Although correlations between the in vitro and the in vivo phenobarbital adsorption characteristics of the three charcoals may be difficult due to the presence of preservatives and palatibility enhancers in the commercial preparations, it appears that the in vivo effectiveness decreases as the surface area and the concentration of surface hydroxyl groups decrease. The proposed system analysis approach requires fewer assumptions than methods based on compartmental or physiologic approaches and has the advantage of describing the phenobarbital removal in a dynamic manner.

The climate of health care in the United States continues to be tumultuous, with widespread calls for change. Concerns about health care costs are matched by public demands for quality, safety, efficiency, and appropriate access for all (Institute Of Medicine [IOM], 2001; Sorian, 2006). Nurse practitioners (NPs) are increasingly recognized as providing a level of care comparable to physicians (Brooks, 2009), prompting the design of newmodels of care delivery that integrate NPs. This growing recognitionofeffectivenesshasgiven rise to a myriad of new NP positions in diverse settings ranging from community-based to high-acuity critical care. Nursing educators are challenged to effectively deliver NP educational programs to meet the demand for highly skilled advanced practice registered nurses (APRNs). Recent landmark collaboration between theNational Council of State Board of Nursing (NCSBN) and the APRN Joint Dialogue Group has resulted in the widely supported document, ‘‘Consensus Model for APRN Regulation: Legislation, Accreditation, Certification, and Education’’ (NCSBN, 2008). This publication establishes common language around titles, scopes of practice, and patient populations; it clarifies terminology, regulation, and roles of all types of APRNs, including primary care and acute care NPs. The consensus document lays the groundwork to create a consistent approach to APRN credentialing by logically linking the

Phenytoin (PHT) exhibits linear and Michaelis-Menten pharmacokinetics. PHT decreases serum folate; the vitamin folic acid (FA) is hypothesized to be a cofactor in the metabolism of PHT. The depletion of serum folate may explain the unpredictability of measured total serum PHT concentrations and time to steady state as compared with the Michaelis-Menten predictive calculations. We examined PHT pharmacokinetics before and after FA supplementation in 13 healthy male volunteers. The study was divided into two phases. Phase I determined V(max) (mg/day) and Km (micrograms/ml) of PHT to calculate PHT doses needed for the second phase. Phase II was a four-way cross-over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 microgram/ml less and 5 micrograms/ml greater than the subject's Km, Km - 1 and Km + 5, respectively. Predicted versus measured total serum PHT concentrations, t90% (days to steady state), and the effect of FA were calculated for Km - 1 and Km + 5 before and after 1 or 5 mg FA. The measured total serum PHT concentration was always greater than the calculated concentration (p less than 0.05), and t90% was always longer than the calculated t90% (p less than 0.05) for Km - 1 before FA (all subjects decreased serum FA); the same was observed for Km + 5. If folate is assumed to be a cofactor in PHT metabolism, these results are expected, because depletion of the vitamin would indicate less folate to drive the metabolism of PHT, resulting in higher total serum PHT concentrations and longer time to reach steady state.(ABSTRACT TRUNCATED AT 250 WORDS)

X-ray photoelectron spectroscopy (XPS) was used to identify the functional states of carbon existing on the surfaces of various activated charcoals. The relative percentages of carbon, oxygen, and detectable trace elements comprising the activated charcoal surfaces were determined. Analysis of the carbon core-electron binding energy region revealed the existence of one hydrocarbon state (C-H, C-C are indistinguishable) and three oxygen-containing functional states. These states were hydroxyls or ethers (C-O), carbonyls (C = O), and carboxylic acids or esters (O-C = O). The C-O functional state contributed approximately 60-70% to the total percentage of oxygen-containing states. A very good correlation existed between the apparent areas occupied on the adsorbent surface per phenobarbital molecule and the relative percentages of the C-O functional state. Previously reported heat of displacement results for phenobarbital adsorption are now explained since the C-O state appears to be the primary site involved in the binding of phenobarbital by the activated charcoals.

The clinical variability of teratogenic response to fetal drug exposure has been well documented. Metabolic differences in biotransformation have been shown to extend to multiple drugs and may involve many steps in drug metabolism with alterations of key intermediates. Although metabolic differences have been reported to be associated with complications of medication use, it has only recently been appreciated that such differences also may be associated in the unborn with the potential for the disruption of normal embryologic development and the production of congenital malformations. It has long been suspected that the teratogenicity of phenytoin may be mediated not only by the parent compound, but also by toxic intermediary metabolites that are produced during the biotransformation of the parent compound. Recent work elucidating differences in isoenzyme forms of cytochrome P-450 enzyme systems, glutathione, and microsomal epoxide hydrolase has provided increased interest in the multiple individual pharmacogenetic differences that may be significant factors affecting increased susceptibility to birth defects in individuals and families with fetal exposure to phenytoin.

Activated charcoal is known to adsorb a wide variety of substances from solution, and several equations have been used to fit the resulting adsorption data. The determination of the correct model to fit phenobarbital adsorption onto activated charcoal was made using a calorimetric method. The differential heats of displacement of water by phenobarbital for four activated charcoals were determined and found to be linearly related to the amount of phenobarbital adsorbed. The activated charcoals studied had statistically similar heats of displacement. The linear relationship between heat evolved and the amount of phenobarbital adsorbed is consistent with the assumptions implicit in the Langmuir model.

PURPOSE. To describe the relationship between pain-sensitive temperament and self-report of pain intensity following surgery. DESIGN AND METHODS. Fifty-nine adolescents and young adults (average age 14 years) undergoing spinal fusion for adolescent idiopathic scoliosis completed the Sensitivity Temperament Inventory for Pain–Child version (STIP-C). The Pearson correlation between STIP-C scores and the highest pain intensity for each of the first three postoperative days was investigated. RESULTS. There was a small but significant correlation between the Perceptual Sensitivity and Symptom Reporting subscales of the STIP-C and pain intensity measured on the third postoperative day. PRACTICE IMPLICATIONS. Aspects of the pain-sensitive temperament may be important in understanding the variability in postoperative pain. This is the first investigation of the relationship between pain-sensitive temperament and surgical pain. More research is needed in this area.

Publisher Summary This chapter reviews the pharmacological differences between men and women. There is a higher rate of medication use among women and different adverse event reporting rates for men and women. Drug–drug, drug–nutrient, drug–herbal, and drug–smoking interactions may also alter pharmacokinetics (PK) or pharmacodynamics (PD) and may lead to possible differences in adverse drug events. Some studies discussed in the chapter show that gastric emptying is slower in women than in men, thus slowing drug absorption from a distal gastrointestinal site. Sex differences in other gastrointestinal enzymes have been postulated to account for the differences observed in first-pass metabolism and bioavailability. The volumes of distribution of lipophilic drugs are expected to be greater in women after normalization for body weight. Conjugation is reported to be greater in men than in women for chlordiazepoxide, oxazepam, and temazepam. It has been observed that women use herbal and dietary supplements at higher rates than men do. This rise in the use of alternative therapies places women at increased risk of significant drug interactions, specifically drug–herb and drug–nutrient interactions. Women appear to be at an increased risk of torsades de pointes because the baseline heart rate–corrected QT interval in women is, on average, longer than it is in men.

This chapter examines the effects of antiepileptic drugs (AEDs) on selected vitamins and minerals, including folic acid, vitamin D, calcium, and vitamin K. Where known, gender analysis is included. It will be noted in relationship to the AEDs if nutritional status is important for one gender. However, the major emphasis is on the impact of AEDs on folate status.

There are specific pharmacology issues related to women's unique physiology, including the hormonal changes that occur throughout their life span. Studies have shown alterations in drug metabolism in relation to phase of menstrual cycle, during pregnancy, or after menopause. In the brain, hormones can alter the response to drugs through various mechanisms. Estrogen and other compounds can bind to the estrogen receptor and modulate a wide range of activities within the cell. In addition, animal studies have demonstrated sexual dimorphism in the brain in terms of both the type of response to estrogen and the response as related to timing of administration. Many normal physiological changes that occur during pregnancy can affect pharmacokinetics and pharmacodynamics. These changes during pregnancy are dramatic rises in levels of estrogen and progesterone, increases in maternal blood volume, altered protein binding resulting from a drop in albumin levels, and a rise in levels of other plasma proteins. The field of chronobiology offers a way to study these changes in biological functions. Chronopharmacology is the study of how biological rhythms, particularly 24-hour, menstrual cycle, and annual rhythms, impact the pharmacokinetics and pharmacodynamics of drugs as a function of their timing. Chronopharmacokinetics is the study of the absorption, distribution, metabolism, and elimination of medicines according to the time of day, menstrual cycle, or year. In addition to applying chronobiology to the study of drugs used in women, new technologies were addressed from computer modeling, pharmacogenetics (genetics of the response to drugs), and in vivo drug metabolism studies.

Folate was first isolated in an unknown form in 1941. The pharmaceutical form of folate is folic acid (pteroylglutamic acid). The major source of folate in the USA is food, with primary sources being grain products, especially fortified cereals, citrus fruits, and dried beans and lentils. However, the estimation of dietary intake of folate by food tables may not reflect actual intake because naturally occurring folate in the diet may be rendered inactive by cooking and food processing.

OBJECTIVE: To present a review of the literature and research on the pharmacogenetics of congenital defects, with a focus on the need for predictive maternal genotype assays. DATA SOURCE: MEDLINE searches (January 1985–January 1999), past reference reviews, and unpublished research. STUDY SELECTION: Review of relevant human, animal, and basic science studies. DATA EXTRACTION: Data on research on polymorphisms, genotyping, cytochrome P450 enzyme systems, epoxide hydrolase, folate metabolism, metabolism of anticonvulsant medications, molecular genetics of neural tube defects, variations in drug metabolism, and environmental exposures were evaluated. DATA SYNTHESIS: Data synthesis includes not only a review of the literature but suggests ways such data might be used to facilitate the development of maternal genotype assays, with the goal of preventing birth defects. CONCLUSIONS: Individuals vary in how they metabolize drugs and handle toxic environmental exposures. In an ideal pregnancy, there is no or limited exposure to medications and environmental agents. However, in women with chronic medical conditions such as heart disease and seizures, this is often not possible. Unfortunately, no techniques have been available to identify those at risk in this population. Gene polymorphisms for a specific enzyme may result in an absence or reduction in the level of enzyme activity or in no change at all, with little effect on the structure/function of the gene product(s); they are not associated with clinical phenotypes in either the mother or the fetus. Other polymorphisms may be only markers. Thus, developing genotyping assays for women that are predictive of phenotype expression in the fetus is the key to screening for polymorphisms. As more mutations are identified and clinical, pharmacologic, biologic, and pharmacokinetic relationships are established, using these polymorphisms to develop a genotyping assay for women may become a clinical reality, possibly leading to preventive prepregnancy or prenatal treatment that may play an increasingly effective role in maternal care.

OBJECTIVE:Part I of this review examines the relationship between antiepileptic drugs (AEDs) and pregnancy outcomes. Drug-induced folate deficiency and the role of AED metabolism are emphasized. Part II will discuss periconceptional folate supplementation for prevention of birth defects. Part III will discuss the mechanism of folate's protective effect, therapeutic recommendations, compliance, and cost.DATA SOURCES:A MEDLINE search was conducted for journal articles published through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included phenytoin, carbamazepine, phenobarbital, primidone, valproic acid, oral contraceptives, clomiphene, drug-induced abnormalities, spina bifida, anencephaly, neural tube defect, folate, folic acid, and folic acid deficiency.STUDY SELECTION:Relevant animal and human studies examining the effects of AEDs, smoking, and oral contraceptives on folate status and pregnancy outcome are reviewed.DATA EXTRACTION:Studies and case reports were interpreted. Data extracted included dosing, serum and red blood cell folate concentrations, teratogenicity of anticonvulsant medications, metabolism of AEDs and folate, and genetic susceptibility to AED-induced teratogenicity.DATA SYNTHESIS:Low serum and red blood cell folate concentrations are associated with adverse pregnancy outcomes. Decreases in serum folate are seen with AEDs, oral contraceptives, and smoking. Since similar birth defects are observed with multiple AEDs, metabolism of aromatic AEDs to epoxide metabolites and genetic factors may play a role in teratogenesis.CONCLUSIONS:Adequate prepregnancy planning is essential for women who have epilepsy. Women receiving folate-lowering drugs may be at increased risk of adverse pregnancy outcomes. Therefore, epileptic women contemplating pregnancy should be treated with the minimum number of folate-lowering drugs possible and receive folic acid supplementation.

OBJECTIVE: The purpose of this review is to update clinicians with recent advances in the management of parkinsonism, including drug therapy, transplantation, and diet. DATA SOURCES: Pertinent articles were obtained from an English-language literature search using MEDLINE (1970–1991), Index Medicus (1987–1991), Current Contents (1990), and bibliographic reviews of review articles. Index terms included parkinsonism, selegiline, pergolide, vitamin E, and transplantation. Fifty-five articles (representing 85 percent of the complete literature search) were selected by multiple reviewers for their contribution to the stated purpose. Emphasis was placed on double-blind, placebo-controlled, and randomized studies. Data from cited articles were examined by multiple reviewers for support of their stated hypothesis and were included as background for justification of major points in this article; critical studies were abstracted in more detail. RESULTS: New therapeutic measures have been added to the treatment of parkinsonism. Selegiline, a monoamine oxidase inhibitor type B, has shown beneficial results, especially in early stages. Pergolide, a dopamine agonist, may be an efficacious alternative to bromocriptine resistance or intolerable adverse effects. Vitamin E may have protective antioxidant properties, but very few clinical data are available. Fetal tissue transplantation needs continued research and remains very controversial. Diet modification may maximize the results of therapy with exogenous dopamine therapy. CONCLUSIONS: Clinicians should familiarize themselves with new alternatives for the management of parkinsonism in order to be reliable consultants for both professional and lay persons.

The effect of folic acid (1 mg/day orally) on phenytoin steady-state pharmacokinetics was studied in four male folate-deficient epileptic patients who were treated with only one anticonvulsant. Each patient served as his own control before and after starting folic acid replacement therapy. The Michaelis-Menten parameters, Vmax and Km, were calculated for each patient, and compliance with the single anticonvulsant drug (phenytoin) regimen was documented. Blood and urine samples were collected just before (day 1) and after 180 or 300 days of vitamin administration. Total and free phenytoin were measured in plasma; and phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), 5-(3,4-dihydroxyphenyl)-5-phenylhydantoin (DHD) were measured in 24-h urine. After the addition of folic acid, total phenytoin plasma concentration decreased 7.5-47.6% in three of the four patients, and the extent of this change correlated with Km (r2 = 0.99). Ratios of urinary metabolites to parent drug increased in those patients showing a decrease in plasma phenytoin caused by folic acid supplementation. This indicated that a folic acid-associated increase in phenytoin oxidative metabolism had occurred.

A patient with severe liver disease and mildly obnormal but stable renal function was given cimetidine on two occasions for gastrointestinal hemorrhage. In each course, dosing was initiated at half the recommended dosage of 600 mg daily, and mental status deteriorated shortly after dosing began. A further dosage decrease to 300 mg daily allowed continuation of cimetidine therapy in absence of mental status alterations. In this patient, mental status changes occurred at lower serum concentrations than we have previously reported. This discrepancy was explained by analysis of cimetidine CSF concentrations, as this patient had abnormally high cimetidine blood to CSF permeability. Although the cause of increased CSF concentrations is unclear, cimetidine-associated mental confusion was dose related and completely reversible upon a decrease in dosage. Patients who develop cimetidine-associated mental status changes and who cannot have treatment stopped may be safely treated by individualizing the dosing rate.

Summary: The effect of phenytoin (PHT) on serum folate and the effect of additional oral folic acid (FA) on serum folate during continued treatment with PHT were studied in 13 healthy male subjects 20–35 years of age. The study was divided into two phases: Phase I determined Vmax (mg/kg/day) and Km (μg/ml) of PHT in order to calculate the PHT doses needed for the second phase. Phase II was a four-way cross-over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 μg/ml less and 5 μg/ml greater than the subject's Km, Km-1 and Km+ 5, respectively. Both phases examined the effect of PHT on serum folate. In Phase I, serum folate decreased by a mean and standard deviation of 42.15 ± 21.44% after an average of 24.15 ± 5.63 days of PHT administration, with a mean steady-state total serum PHT concentration of 8.45 ± 2.70 μg/ml. Mean percentage decreases in serum folate before the addition of 1 and 5 mg FA in Phase II were 12.80 ± 31.45% and 23.24 ± 21.24% for Km-1 and Km+5, respectively. The average numbers of days of PHT administration and total serum PHT concentrations before FA administration were 9.52 ± 3.34 and 15.84 ± 7.02 days, and 2.60 ± 2.18 and 8.64 ± 3.44 μg/ml, for Km-1 and Km+5, respectively. The percentage increases in serum folate after taking FA while continuing PHT in Phase II were as follows: 38.78 ± 72.84%, Km-1 (1 mg FA): 81.38 ± 72.75%, Km+5 (1 mg FA); 138 ± 93.43%, Km-1 (5 mg FA); and 169.67 ± 69.67%, Km+5 (5 mg FA). Five milligrams FA increased the serum folate more than the 1-mg dose. The higher total PHT concentration was associated with a greater decrease in the serum folate. Therefore, serum folate may decrease early with PHT therapy and should be monitored at that time. RESUME Nous avons etudie l'effet de la phenytoine (PHT) sur les taux seriques de folates, et l'effet d'une supplementation orale d'acide folique (FA) sur les taux seriques de folates pendant le maintien de la PHT chez 13 volontaires sains de sexe masculin âges de 20 a 35 ans. L'etude s'est deroulee en deux temps: la phase la servi a determiner la Vmax (mg/kg/j/) et la Km (μg/ml) de PHT pour calculer les doses de PHT necessaires a la phase II. La phase II est une etude croisee a quatre voies visant a determiner l'effet de I et 5 mg de FA sur les concentrations seriques de PHT inferieures de 1 μg/ml et superieures de 5 μg/ml au Km, Km-1 et Km+5, respectivement, chez chaque sujet. L'effet de la PHT sur les taux sanguins de FA a eteetudiee pendant toutes les phases de l'etude. Pendant la phase I, les taux de FA ont diminue de42.15 ± 21.44% (moyenne ± DS) apres 24.15 ± 5.63 jours de traitement par PHT, avec une concentration moyenne de PHT serique totale en phase stable de 8.45 ± 2.70 μg/ml. En phase II, le pourcentage moyen de diminution du taux de FA avant supplementation de 1 et 5 mg etait pour Km - 1 et Km + 5 respectivement de 12.80 ± 31.45% et de 23.24 ± 21.24%. Avant supplementation en FA. pour Km - 1 et Km + 5, la duree moyenne de l'administration de PHT etait de 9.52 ± 3.34 et de 15.84 ± 7.02 jours, et la concentration serique totale de PHT de 2.60 ± 2.18 et 8.64 ± 3.34 μg/ml respectivement. Le pourcentage d'augmentation des folates seriques apres supplementation en FA et maintien de la PHT en phase II etait le suivant: 38.78 ± 72.84%, Km - 1 (1 mg FA); 81.38 ± 72.75%, Km + 5 (1 mg FA); 138. ± 93.43%, Km - 1 (5 mg FA); 169.67 ± 69.67%, Km + 5 (5 mg FA). L'administration de 5 mg FA a entraine une augmentation des folates sanguins superieure a celle obtenue apres 1 mg FA. Les concentration elevees de PHT ont entrainea des diminutions plus importantes des folates sanguins. Les folates sanguins peuvent ectre abaisses precocement par le traitement par PHT, et doivent etre surveilles des l'instauration d'un tel traitement. RESUMEN En 13 sujetos varones de 20 a 35 anos de edad sin ningun tipo de enfermedad, se han estudiado los efectos de la fenitoina (PHT) sobre el folato serico y los efectos de la administracion adicional de acido folico por via oral (FA) sobre el folato serico mientras se continuaba tomando la PHT. Este estudio se ha dividido en dos fases: la Fase I determineo la Vmax (mg/Kg/d/ia) y la Km (μg/ml) de la PHT para calcular las dosis de PHT necesarias para la segunda fase. La Fase II consistio en un estudio cruzado de 4 dias para examinar el efecto de I y 5 mg de FA sobre las concentraciones sericas de FTA de menos de 1 μg/ml y mayores de 5 μg/ml que los sujetos Km, Km - 1 y Km + 5, respectivamente. Ambas fases examinaron los efectos de la PHT sobre el folato serico. En la Fase I el folato serico se redujo en un promedio y desviacion tipica de 42.15 ± 21.44% despues de un promedio de 24.15 ± 5.63 dias de administracion de la PHT con un promedio de situacion estable de concentraciones sericas de PHT de 8.45 ± 2.70 μg/ml. La reduccion media del porcen-taje del folato serico antes de la adicion de 1 y 5 mg de FA en la Fase II fue de 12.80 ± 31.45% y 23.24 ± 21.24% para los Km - 1 y Km + 5, respectivamente. El promedio del numero de dias de administracion de la PHT y de las concentraciones sericas de PHT antes de la administracion de FA fue de 9.52 ± 3.34 dias y 15.84 ± 7.02 dias y 2.60 ± 2.18 μg/ml y 8.64 ± 3.44 μg/ml para los Km - 1 y Km + 5 respectivamente. El incremento del porcentaje de folato serico despues de tomar el FA mientras se continuaba con la PHT en la Fase II, fue el siguiente: 38.78 ± 72.84%, en los Km - 1 (1 mgde FA); 81.38 ± 72.75% en ios Km + 5 (1 mg de FA); 138 ± 93.43% en los Km - 1 (5 mg de FA) y 169.67 ± 69.67 en los Km + 5 (5 mg de FA). Los 5 mg de FA incrementaron el folato serico mas que la dosis de lmg. Las concentraciones totales mas altas de PHT se asociaron a una reduccion mas intensa del folato serico. Por estas razones se deduce que el folato serico puede reducirse precozmente con la terapia de PHT y debe ser monitorizado en este momento. ZUSAMMENFASSUNG Der Einflus von Phenytoin (PHT) auf Serum-Folsaure und der Einflus von oraler Folsauregabe (FA) auf Serum-Folsaure unter PHT-Medikation wurde an 13 gesunden Mannern zwischen 20 und 35 Jahren untersucht. Die Studie wurde in zwei Phasen unterteilt; In Phase I wurde Vmax (mg/kg/d/) und Km (μ/ml) von PHT bestimmt, um die PHT-Dosen fur die zweite Phase zu ermitteln. Phase II war eine 4-Wege-Crossover-Studie um den Effekt von 1 und 5 mg FS auf PHT-Konzentration 1 μg/ml kleiner und 5 μg/ml groser als die jeweiligen Km, Km - 1 und Km + 5 der Patienten zu untersuchen. In beiden Phasen wurde der Einflus von PHT auf Serum-Folsaure untersucht. In Phase I sank Serum-Folsaure um einen Durchschnitt und eine Standar-dabweichung von 42.15 ± 21.44% nach durchschnittlich 24.15 ± 5.63 Tagen von PHT-Gabe mit einem durchschnittlichen PHT-Spiegel von 8.45 ± 2.70 μg/ml. Die durchschnittliche prozentuale Erniedrigung der Serum-Folsaure betrug vor der zusatzlichen Gabe von 1 und 5 mg FA in Phase II 12.80 ± 31.45% und 23.24 ± 21.24% fur jeweils Km - 1 und Km + 5. Die durchschnittliche Anzahl von Tagen unter PHT-Medikation und die PHT-Serum-Konzentrationen vor FA-Gabe war 9.52 ± 3.34 Tage und 15.84 ± 7.02 Tage und 2.60 ± 2.18 μg/ml und 8.64 ± 3.44 μg/ml fur jeweils Km - 1 und Km + 5. Der durchschnittliche Anstieg der Serum-Folsaure nach Einnahme von FA unter Fortfuhrung der PHT-Gabe in Phase II war folgender; 38.78 ± 72.84%, Km - 1 (1 mg FA); 81.38 ± 72.75%, Km + 5(1 mg FA) 138 ± 93.43%, Km - 1 (5 mg FA) und 169.67 ± 69.67, Km + 5 (5 mg FA). 5 mg FA erhohte die Serum-Folsaure starker als die 1 mg-Dosis. Eine hohere PHT-Konzentration war assoziiert mit einem groseren Abfall der Serum-Folsaure. Daraus folgt, das Serum-Folsaure-Werte eventuell schon zu Beginn einer PHT-Therapie erniedrigt werden und deshalb zu diesem Zeitpunkt uberwacht werden sollten.

A randomized crossover trial of the effect of oral activated charcoal on the kinetics of intravenous theophylline was carried out in six normal male subjects. After intravenous aminophylline (6 mg/kg), subjects received water or water with activated charcoal (140 gm) in divided doses over 12 hr. Serum theophylline concentrations were measured from 0 to 24 hr after the aminophylline infusion. Treatment with activated charcoal decreased the serum t 1/2 from 6.4 +/- 1.2 to 3.3 +/- 0.4 (SEM) hr and the serum AUC from 78 +/- 14 to 42 +/- 4 mg . hr/l. Percent decrease in AUC after treatment with charcoal correlated positively with the endogenous theophylline serum t 1/2 (r = 0.94). These results suggest that oral activated charcoal (1) enhanced the total body clearance of theophylline and (2) may be efficacious in the treatment of theophylline poisoning, especially in patients with prolonged serum t 1/2s of theophylline.

Fifteen patients diagnosed as bipolar I, bipolar II, unipolar, or bipolar I/schizophrenic, and each receiving prophylactic lithium carbonate, were studied for nine months in an outpatient clinic. Every four to six weeks, plasma and erythrocyte (RBC) lithium concentrations and RBC: plasma lithium ratios were monitored and mood scales were recorded. In those patients who showed a change in mood, a positive association was found between decreased RBC lithium concentration and depression ( p = 0.0156), and also between RBC: plasma lithium ratio and depression ( p = 0.0156). No relationship between plasma lithium concentration changes and depression could be determined.

The effects of two different oral charcoal suspensions on the elimination of a 200 mg/70 kg, 1 h intravenous (i.v.) infusion of phenobarbital and the tolerances of the two regimens were determined in a randomized crossover study in six healthy male volunteers. Phenobarbital was given i.v. alone or together with 105 g of oral activated charcoal suspension or with 105 g of a commercially available sorbitol-charcoal suspension over a 36-h period. A 13-34% decrease in the area under the serum concentration time curve (AUC) for 0-60 h occurred with the administration of the activated charcoal, and a 19-52% decrease occurred with the commercial sorbitol-charcoal regimen. The mean apparent systemic clearance of total phenobarbital increased from 0.089 +/- 0.019 ml/min/kg to 0.141 +/- 0.029 and 0.146 +/- 0.036 ml/min/kg with the charcoal and sorbitol-charcoal treatments, respectively. No significant change in the fraction of phenobarbital bound to protein was detected. The charcoal regimen caused constipation in one subject. All subjects taking the sorbitol-charcoal preparation experienced diarrhea; there were no changes in electrolytes with either charcoal suspension. All subjects preferred the sorbitol-charcoal preparation.

The purpose of this two-part review is to explain current drug treatment in part I and discuss investigational drug therapy and miscellaneous drugs in the management of parkinsonism in part II. The medical approach to this disease is still based on the imbalance between a deficiency of dopamine and a functional increase in acetylcholine. Anticholinergic agents are used to treat the tremors in the early stages of the disease.

Adsorption of phenobarbital from simulated intestinal and gastric fluids by two activated charcoals was studied. Adsorption isotherm data were analyzed by the linearized Langmuir equation and by nonlinear least-squares regression employing both Langmuir and Freundlich models. These analyses indicated differences in the capacities of the two charcoals for phenobarbital which could not be completely explained by surface-area considerations.

The theory of linear systems analysis is applied to the evaluation of induced drug removal processes. The rate and extent of removal are determined by deconvolution for the case of phenobarbital removal from the systemic circulation by orally administered activated charcoal. The proposed method is model independent in the sense that no specific models of intrinsic or induced pharmacokinetic processes are required, and it is readily adapted to the analysis of most types of induced removal processes (hemodialysis, peritoneal dialysis, etc.). Application of the approach indicates that phenobarbital was removed from the systemic circulation to an extent of 25–53% following multiple oral doses of activated charcoal in healthy human subjects.

To reach and maintain therapeutic drug concentrations, reliable estimates of the parameters describing the pharmacokinetic behavior of the drug are required. The accuracy and precision of the pharmacokinetic parameters are dependent upon the error associated with the time of specimen collection and the laboratory assay error. In this report, the determinate error and random error are analyzed independently and incorporated in calculations of regimens of two drugs, gentamicin and theophylline. The calculations show that, within a particular concentration range, there are better times for sampling to determine the elimination rate constant and, consequently, the dose. From the generalized, first-order equation for a one-compartment pharmacokinetic model, ln Ct = ln C0 - Kt, where C = plasma drug concentration, t = time, C0 = C at zero time, and the elimination rate constant, K = 0.693/t1/2, the determinate error, epsilon K, in K is epsilon = (1/C0t)epsilon C0 - (In C0/C)t-2 epsilon t, and the random error, assuming a gaussian distribution, is (formula; see text) where S2x is variance of parameter x. Therefore, the variances of the calculated quantity, C0, the measured quantity, C, and the time of sample collection, t, are initially of equal importance. However, with increasing t, the effect of S2t becomes small. In both random and determinate error cases, increased time of sampling after dose reduces the error in K, thus t1/2, as do recognized biological factors. However, increased relative analytical error may obliterate this advantage if analyses are not modified to obtain best quantitation at low, even subtherapeutic concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of folic acid supplementation on the disposition of phenytoin and the resultant loss of seizure control in a male folate-deficient epileptic is reported. Due to the increase in tonic-clonic seizures after the initiation of folic acid (1 mg, orally) the sodium phenytoin dosage was increased by 130 mg until control was achieved. Because of these dosage changes, the Vmax and Km were calculated before and after initiation of the folic acid. The Vmax remained relatively the same, but the Km decreased after folate supplementation.

Phenytoin decreases serum and red blood cell folates in 50% of the patients on the anticonvulsant. The supplementation of folic acid changes the disposition of phenytoin, a drug that exhibits Michaelis-Menten kinetics. In a retrospective study at the Veterans Administration Medical Center, seven adult male folate-deficient epileptic patients on phenytoin alone and compliant with the anticonvulsant were supplemented with 1 mg oral folic acid. Before and after the addition of the vitamin, Vmax and Km were calculated for phenytoin. With folic acid, the total serum phenytoin concentration decreased significantly by an average of 22.6 +/- 13.0%. The Km decreased significantly from 6.7 +/- 1.1 to 4.1 +/- 1.5 micrograms/ml. The Vmax remained unchanged. It is hypothesized that folic acid is a cofactor in the metabolism of phenytoin. A cofactor would be expected to alter the affinity (Km) of the enzymes for phenytoin with no change in the liver's total capacity (Vmax) to metabolize phenytoin. This retrospective study in seven male epileptic patients is a convincing argument for the hypothesis.

We investigated the effect of multiple oral doses of activated charcoal on the pharmacokinetics of intravenously administered phenobarbital in a randomized crossover trial. Six healthy men volunteered to take 200 mg of phenobarbital sodium per 70 kg of body weight intravenously on two separate occasions. On one occasion, each subject received oral activated charcoal (180 g) in divided doses over three days after the infusion of phenobarbital. Serum levels of phenobarbital were measured in all subjects up to 96 hours after the infusion, and urinary excretion of phenobarbital was measured in two subjects 24 to 96 hours after the infusion. A pharmacokinetic analysis showed that the charcoal decreased the serum half-life of phenobarbital form 110 +/- 8 to 45 +/- 6 hours (S.E.M.) (P less than 0.01), increased the total body clearance of phenobarbital from 4.4 +/- 0.2 to 12.0 +/- 1.6 ml per kilogram per hour (P less than 0.01), and increased the nonrenal clearance from 52 to 80 per cent of the total body clearance. We conclude that oral administration of activated charcoal enhances the nonrenal clearance of phenobarbital.

The pharmacologic effect of phenytoin is directly related to the unbound concentration in the serum, which previously has been reported in the literature to be approximately 10%. The results of 13 out of 14 20-35 year-old healthy male volunteers studied indicate that less than 10% unbound phenytoin is present in the majority of subjects taking two different doses of phenytoin.

The postabsorptive distribution of cimetidine is described. Assays by high pressure liquid chromatography (HPLC) of postmortem samples of cerebrospinal fluid, serum, and solid tissues were used to determine pharmacokinetic parameters as well as mean tissue: serum concentration (T:S) ratios in seven patients with renal and liver dysfunction. Correlations were calculated between the T:S ratio and the volume of distribution, and between the T:S concentration ratio and the time of sampling after death. The highest T:S ratios occurred in the eliminating organs, the liver and kidneys, and the lowest in fat. As the time of autopsy increased after death, the T:S ratios decreased.