Showing papers in "The Journal of Clinical Pharmacology in 1994"
TL;DR: The authors believe that closer hemodynamic monitoring of orthostatic hypotension patients would considerably increase understanding and aid in the diagnosis of this condition.
Abstract: The authors' objective was to review previous studies of immediate (first 30 seconds) and stabilized (30 seconds to 20 minutes) hemodynamic responses of healthy adults to the head-up posture, with particular reference to alteration of such responses in the elderly and the usefulness of such data in the diagnosis of orthostatic hypotension. The immediate response in healthy young adults is characterized by a prompt rise in heart rate, which peaks at about 8 to 15 seconds and then tapers; the arterial pressure and total vascular resistance decrease sharply at 5 to 10 seconds, followed by a rapid rebound and overshoot. Over the first 30 seconds there is a steady parallel decline of thoracic blood volume and stroke volume; there is also an initial surge of cardiac output followed by a steady decrease. During the stabilized response (30 seconds to 20 minutes), the hemodynamic variables are relatively steady, showing average increases in heart rate of about 15 to 30%, in diastolic pressure of 10 to 15%, and in total vascular resistance of 30 to 40%; during the 5th to 20th minutes there are also decreases in thoracic blood volume averaging about 25 to 30%, in cardiac output 15 to 30%, and in pulse pressure about 5 to 10%. It is evident that in normal human subjects, assumption of the upright posture results in profound hemodynamic changes, most of them occurring during the first 30 seconds. In elderly subjects (aged 60-69 years), there are, in the upright posture, lesser increments of heart rate and diastolic pressure, but no significant differences from younger age groups in the response of thoracic blood volume, cardiac output or total vascular resistance. However, beginning at about age 75, there is an increasing incidence of orthostatic hypotension, which averages about 14 to 20% at age 75 and older. The tendency toward orthostatic hypotension in the elderly is due (1) to the structural and functional changes in the circulation itself, (2) to a decline in autonomic function, and (3) to a probable functional deficiency of the skeletal muscle pump. The authors believe that closer hemodynamic monitoring of orthostatic hypotension patients would considerably increase our understanding and aid in the diagnosis of this condition.
294 citations
TL;DR: Data from studies of drug metabolism in vitro can be used to predict and thereby possibly avoid clinically important drug interactions and explain the potentially life‐threatening ventricular arrhythmias reportedly associated with terfenadine‐ketoconazole cotherapy.
Abstract: 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.
115 citations
TL;DR: This research highlights the need to understand more fully the role of emotion in the decision-making process and the role that emotion plays in the development of new treatments for multiple sclerosis.
Abstract: This report derives from the conference on ‘The Integration of Pharmacokinetic, Pharmacodynamic and Toxicokinetic Principles in Rational Drug Development,’ held on April 24–26, 1991 in Arlington, VA. The conference was sponsored by the American Association of Pharmaceutical Scientists, U.S. Food and Drug Administration and American Society for Clinical Pharmacology and Therapeutics. The objectives of the conference were: (1) To identify the roles and the interrelationships between pharmacokinetics (PK), pharmacodynamics (PD) and toxicokinetics (TK) in the drug development process. (2) To evolve strategies for the effective application of the principles of pharmacokinetics, pharmacodynamics and toxicokinetics in drug development, including early clinical trials. (3) To prepare a report on the use of pharmacokinetics and pharmacodynamics in rational drug development as a basis for the development of future regulatory guidelines.
109 citations
TL;DR: A combination of methods should be used in the evaluation of medication compliance during the investigation of a new drug, given the limitations of the available techniques for monitoring compliance.
Abstract: The assessment of compliance is critical in the evaluation of the effectiveness of a new therapeutic agent. Fifteen patients with transfusion-dependent beta-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.(ABSTRACT TRUNCATED AT 250 WORDS)
103 citations
TL;DR: Although lithium has been used in a variety of psychiatric and medical illnesses, its FDA approved indications include the acute treatment of mania and maintenance treatment of bipolar disorder.
Abstract: L ithium, a monovalent cation, was discovered in 1817 and first used medically to treat gout in 1858. In the 1940s it was used as a salt substitute with fatal results.1 It was first reported beneficial in psychiatric patients in 1949 by Cade.2 Lithium became available in the United States in 1970. Although lithium has been used in a variety of psychiatric and medical illnesses, its FDA approved indications include the acute treatment of mania and maintenance treatment of bipolar disorder.3 Lithium is available in the United States as rapid and slow release preparations. Products marketed include rapid release dosage forms: lithium carbonate 150, 300, or 600 mg/ tablet or 300 mg/capsule (8.l2mEq [mmolj lithium ion per 300 mg lithium carbonate) and lithium citrate syrup (8mEq/5mL); and slow release dosage forms: lithium carbonate 300 mg and 450 mg (12.l5mEq) tablets. The pharmacologic activity resides in the lithium ion.
94 citations
TL;DR: Transition to patient's unit dose is likely to decrease calculation errors, because pharmacists commit fewer errors, and Hazardous drugs that are not required on a stat basis should be removed from the wards.
Abstract: Tenfold errors in pediatric doses are not uncommon. Because the needed volume of stock solution is generally small, even a tenfold higher volume may still appear deceivingly normal. Such errors are much less likely to occur in adults, because it would result in unacceptably large volumes of stock solution. Other sources of tenfold errors are communication difficulties with parents and illegible writing of orders by physicians. Testing health professionals may identify subgroups of individuals who are prone to commit such errors. Independent double checking of calculations and a mechanism to resolve disagreement is being practiced in most academic institutions. Transition to patient's unit dose is likely to decrease calculation errors, because pharmacists commit fewer errors. Hazardous drugs that are not required on a stat basis should be removed from the wards.
91 citations
TL;DR: It is suggested that sudden death due to cocaine is proarrhythmic in nature, occurring under similar circumstances as that due to specific antiarrhythmmic drugs.
Abstract: Sudden, unexpected death due to cocaine in young otherwise healthy individuals occurs in an idiosyncratic manner and is commonly felt to be arrhythmogenic in nature, although the exact cause of death is rarely documented. In addition to indirect sympathomimetic actions, cocaine is a potent sodium channel blocking drug and, in this regard, most closely resembles agents such as flecainide. We suggest that sudden death due to cocaine is proarrhythmic in nature, occurring under similar circumstances as that due to specific antiarrhythmic drugs.
87 citations
TL;DR: The studies show that the cardiovascular responses to standing differ, in some respects, between the sexes and with age, and suggest that the sex differences are related to greater decrease of thoracic blood volume with standing in women than in men.
Abstract: 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.
86 citations
TL;DR: Overall, CL 284,846 was well tolerated in the normal volunteers, causing no significant changes in vital signs, EEG, ECG, hematologic, or clinical chemistry laboratory parameters, and the authors recommend repeating dose safety and pharmacokinetic studies in healthy volunteers.
Abstract: This report describes the first evaluation in humans of CL 284,846, a non-benzodiazepine compound with a preclinical profile indicative of sedative/hypnotic properties. Healthy, normal male volunteers were assigned randomly to receive single oral doses of 1, 5, 15, 30, or 60 mg of CL 284,846 or placebo on a double-blind basis. Observations were made over the subsequent 25 hours to determine the safety, pharmacokinetic profile, and psychometric effects of the test compound. CL 284,846 was well tolerated in the normal volunteers, causing no significant changes in vital signs, EEG, ECG, hematologic, or clinical chemistry laboratory parameters. Although few adverse events were noted at doses less than 60 mg, at the highest dose (60 mg), all volunteers reported transient neurologically related adverse events (e.g., impaired concentration, difficulty focusing, and impaired coordination), reflecting the central nervous system action of the compound. Although determination of hypnotic efficacy was not an objective in this Phase I study, daytime treatment with 60 mg of CL 284,846 was associated with greater reports of drowsiness and impaired performance on psychomotor tests. However, memory, as assessed by a word recall test, was not affected at any dose of the compound. Pharmacokinetic analyses revealed CL 284,846 to be absorbed and eliminated rapidly (Tmax = 0.9-1.5 hr, T 1/2 = 0.9-1.1 hr), with a dose-proportional AUC (area under cure). Plasma levels of CL 284,859, the primary desethylated metabolite of CL 284,846, were much lower in humans than in other species, indicating that the metabolism of CL 284,846 in humans may differ from that of rodents and dogs. Overall, CL 284,846 was well tolerated, and the authors recommend repeating dose safety and pharmacokinetic studies in healthy volunteers.
85 citations
TL;DR: In patients with hypercholesterolemia, lovastatin and pravastatin have nearly identical effects on lipids and no significant effects on sleep and cognitive performance.
Abstract: Sleep disturbances and decrements of daytime performance have been attributed to HMG-CoA reductase inhibitors. As a rule, lipophilic compounds more readily cross the blood-brain barrier and are more likely to affect central nervous system function. The authors compared the effects of lovastatin (40 mg), a lipophilic compound, to pravastatin (40 mg), a hydrophilic compound, in a 6-week, double-blind, randomized, placebo-controlled, three-way Latin square design, cross-over study on 22 men with hypercholesterolemia. Patients had LDL cholesterol of more than 165 mg/dL and triglyceride of less than 350 mg/dL after 6 weeks of a low-fat (< 30%), low-cholesterol (< 300 mg/day) diet. Compared with placebo, there were no significant effects of lovastatin or pravastatin on the following subjective and polysomnographic sleep measures: changes in total sleep time, time in each sleep stage, sleep efficiency, sleep latency, REM density, REM activity, and number of arousals. Similarly, there were no effects of the two drugs on measures of cognitive performance. A significant increase in the duration of nocturnal tumescence (NPT) was observed after 2 weeks of treatment with both study drugs. This effect was not significant after 6 weeks of treatment. Both lovastatin and pravastatin caused significant (P < .05 compared with placebo) decreases in total cholesterol (by 20.9 and 20.6%, respectively), LDL cholesterol (by 27.8 and 29.9%), and triglycerides (by 13.6 and 3.7%). Subjects' HDL increased by 2.3% with lovastatin (NS) and by 3.1% with pravastatin (P < .05). Lipoprotein(a) increased by 20.5% with lovastatin and by 1.1% with pravastatin; these changes were not significantly different from placebo.(ABSTRACT TRUNCATED AT 250 WORDS)
78 citations
TL;DR: Angiotensin‐converting enzyme inhibitors (ACE‐I) have become the mainstem of antihypertensive therapy and first‐choice agents for vasodilatation in congestive heart failure (CHF) and should be continued in most patients despite the cough, which will subsequently regress in intensity or disappear.
Abstract: Angiotensin-converting enzyme inhibitors (ACE-I) have become the mainstem of antihypertensive therapy and first-choice agents for vasodilatation in congestive heart failure (CHF). A typical dry cough is the main cause for discontinuation of ACE-I therapy. Data about the incidence, course, and clinical significance of this side effect are conflicting. This study determined the incidence of cough in ACE-I treated patients with hypertension and with CHF and to appreciate its clinical significance; 268 ACE-I treated patients, 164 with hypertension and 104 with CHF were prospectively followed for at least 1 year and specifically questioned about cough and other side effects. In those in whom cough developed, a second and then a third ACE-I were tried. Cough developed in 50 (18.6%) of the 268 patients; 23 patients with hypertension (14%) had coughs 24.7 +/- 17.1 (SD) weeks after initiation of therapy; 27 patients with CHF (26%) had coughs 12.3 +/- 12 (SD) weeks after the start of ACE-I therapy (P = 0.005). All but three patients had coughs also on the second and third ACE-I. The time from the beginning of therapy to the onset of cough was significantly shorter with the second than the first drug. ACE-I agents had to be discontinued in 50% of the patients in whom coughs developed, most of them in the CHF group. In the others, cough was well tolerated or disappeared during subsequent months. The incidence of cough, which necessitated discontinuation of ACE-I treatment, was 4% among patients with hypertension and 18% among patients with CHF (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Drug dosing in renal insufficiency needs to be individualized whenever possible to optimize therapeutic outcomes and to minimize toxicity.
Abstract: Drug dosing in renal insufficiency needs to be individualized whenever possible to optimize therapeutic outcomes and to minimize toxicity. Although a number of published tables that provide dosing guidelines and nomograms exist to assist in dose modification, individualization of therapy should be based on pharmacokinetic principles whenever possible. The basis equations to estimate the pharmacokinetic parameters of clearance, volume of distribution, and half-life for intravenous drug administration of drugs with first-order kinetics are not difficult to understand and apply. Their use should be encouraged in patient care.
TL;DR: The diuretic effects, pharmacokinetics, and safety of CI‐977, a new centrally acting selective kappa‐opioid agonist, were determined in 16 healthy subjects and decreases in negative free water clearance and urine osmolality and increases in urine volume were observed after administration of 15‐ and 25‐μg doses.
Abstract: The diuretic effects, pharmacokinetics, and safety of CI-977, a new centrally acting selective kappa-opioid agonist, were determined in 16 healthy subjects. Subjects received single intramuscular doses of CI-977 (5, 15, or 25 micrograms) or placebo 1 week apart according to a randomized, double-blind, placebo-controlled, four-period, crossover design. Serial blood and urine specimens were collected after each dose. Significant dose-related decreases in negative free water clearance and urine osmolality and increases in urine volume were observed after administration of 15- and 25-micrograms doses of CI-977. CI-977 had no effect on urine electrolyte excretion or serum antidiuretic hormone. Absorption of CI-977 was rapid with individual tmax values ranging from 0.17 to 1.5 hours. Cmax and AUC(0-infinity) increased proportionally with dose. Individual elimination half-life values ranged from 0.6 to 3.3 hours and were independent of dose. Changes in free water clearance were related to CI-977 Cmax (r2 = 0.29, P = 0.0001) and AUC(0-4 hr) (r2 = 0.32, P = 0.0001) values. The most frequently reported adverse events after CI-977 administration were dizziness, fatigue, paresthesia, headache, vasodilatation (facial flushing), emotional lability, high feeling, and abnormal thinking. The frequency and intensity of adverse events increased with increasing CI-977 dose. In conclusion, CI-977 Cmax and AUC(0-infinity) increased in proportion to dose over the range of 5 to 25 micrograms; decreases in negative free water clearance were related to CI-977 dose and Cmax and AUC(0-4 hr) values; and the frequency and intensity of adverse events increased with increasing CI-977 dose.
TL;DR: This review summarizes and comments on the current understanding of both the biochemical and clinical implications of the epimerization of R‐aryl propionic (APA) class (1) nonsteroidal anti‐inflammatory agents (NSAIDs) to S‐enantiomers in humans.
Abstract: This review summarizes and comments on the current understanding of both the biochemical and clinical implications of the epimerization of R-aryl propionic (APA) class (1) nonsteroidal anti-inflammatory agents (NSAIDs) to S-enantiomers in humans. This article focuses principally on rac-ibuprofen and its enantiomers. In the United States, five commercialized NSAIDs are APAs. Only two of them, rac-ibuprofen and rac-fenoprofen, are subject to significant epimerization in humans. The remaining three, rac-flurbiprofen, rac-ketoprofen, and S-naproxen, are not of interest in this context.
TL;DR: The advantage of betaxolol vis‐à‐vis systemic side effects is more clearly established than that of carteolol, and further systematic study is needed to determine what advantages, if any, are conferred by the presence of ISA.
Abstract: Since the late 1970s, topical beta-adrenergic blockers have been the drugs of choice in treating ocular hypertension and associated glaucoma. The currently available drugs are timolol, betaxolol, levobunolol, metipranolol, and carteolol. All reduce intraocular pressure by decreasing the production of aqueous humor. Although these drugs are applied locally in the eye, they may enter the general circulation and reach concentrations high enough to cause systemic effects, including alterations in heart rate and rhythm, bronchoconstriction, dyslipidemia, and central nervous system abnormalities. Interactions with other drugs may also occur. Ocular beta- blockers differ in beta 1-selectivity (betaxolol is beta 1-selective, whereas the other drugs are nonselective) and in intrinsic sympathomimetic activity (ISA) or partial agonist properties (only carteolol possesses ISA). These differences give betaxolol and carteolol potential advantages in minimizing certain side effects. The advantage of betaxolol vis-a-vis systemic side effects is more clearly established than that of carteolol. Further systematic study is needed to determine what advantages, if any, are conferred by the presence of ISA.
TL;DR: Improving protein and fat absorption in patients with cystic fibrosis relates to the amount of biologically active enzyme reaching the duodenum.
Abstract: Improving protein and fat absorption in patients with cystic fibrosis relates to the amount of biologically active enzyme reaching the duodenum. Microencapsulated formulations are more effective than conventional products but differ in content, ability to retard acid inactivation and the pH at which they release enzymes. Contaminants in these products contribute to hyperuricosuria.
TL;DR: The hypothesis was tested that women, who naturally have a higher blood estrogen content compared with men, will have a smaller loss of PV during bed rest, and it is possible that women may experience less cardiac and circulatory strain on reambulation.
Abstract: This paper reviews a series of studies that indicate that estrogens play an important role in blood volume regulation. The first study illustrates that the plasma volume (PV) of ambulatory women fluctuates during the menstrual cycle, increasing during periods of elevated estrogens. In the second study, it was shown that exogenous and endogenous elevations in blood estrogens attenuate the decrease in PV during bed rest. In the third study, the hypothesis was tested that women, who naturally have a higher blood estrogen content compared with men, will have a smaller loss of PV during bed rest. Ten men and ten women underwent a 13-day, 6 degrees head-down bed rest. Plasma volume and red cell mass (RCM) were measured before and after bed rest using 125I and 51Cr labeling, respectively. Before bed rest, the men and women had similar blood volume (BV) and PV (mL/kg body weight), but the women had a smaller (P < .01) RCM (22.2 +/- 0.9 versus 26.2 +/- 0.8 mL/kg, mean +/- SE). During bed rest, the decrease in RCM (mL/kg) was similar in men and women. However, the decrease in BV was greater in men (8.0 +/- 0.8 mL/kg versus 5.8 +/- 0.8 mL/kg), because of a greater reduction in PV (6.3 +/- 0.6 mL/kg versus 4.1 +/- 0.6 mL/kg). Because the decline in BV has been proposed to contribute to the cardiovascular deconditioning after bed rest, it is possible that women may experience less cardiac and circulatory strain on reambulation.
TL;DR: Overall, the in‐flight adaptive modification of head stabilization strategies, changes in head/eye coordination, illusionary motion, and postural control are maladaptive for a return to the terrestrial environment.
Abstract: Space flight represents a form of sensory stimulus rearrangement requiring modification of established terrestrial response patterns through central reinterpretation. Evidence of sensory reinterpretation is manifested as postflight modifications of eye/head coordination, locomotor patterns, postural control strategies, and illusory perceptions of self or surround motion in conjunction with head movements. Under normal preflight conditions, the head is stabilized during locomotion, but immediately postflight reduced head stability, coupled with inappropriate eye/head coordination, results in modifications of gait. Postflight postural control exhibits increased dependence on vision which compensates for inappropriate interpretation of otolith and proprioceptive inputs. Eye movements compensatory for perceived self motion, rather than actual head movements have been observed postflight. Overall, the in-flight adaptive modification of head stabilization strategies, changes in head/eye coordination, illusionary motion, and postural control are maladaptive for a return to the terrestrial environment.
TL;DR: Molecular mechanisms, ontogeny and clinical implications of genetically determined intersubject variation in some of the polymorphic enzymes, including N‐acetyl transferase, cytochromes P4502D6 and 2C, are presented.
Abstract: Genetic polymorphisms of drug metabolizing enzymes are well recognized. This review presents molecular mechanisms, ontogeny and clinical implications of genetically determined intersubject variation in some of these enzymes. Included are the polymorphic enzymes N-acetyl transferase, cytochromes P4502D6 and 2C, which have been well described in humans. Information regarding other Phase I and Phase II polymorphic pathways, such as glutathione and methyl conjugation and alcohol and acetaldehyde oxidation continues to increase and are also discussed. Genetic factors effecting enzyme activity are frequently important determinants of the disposition of drugs and their efficacy and toxicity. In addition, associations between genetic differences in these enzymes and susceptibility to carcinogens and teratogens have been reported. Ultimately, the application of knowledge regarding these genetic factors of enzyme activity may guide medical therapy and minimize xenobiotic-induced disease.
TL;DR: There is limited uptake of tobramycin into the systemic circulation when administered by nebulizer aerosol into the lungs even in high doses, according to the authors, which may be characteristic for adults with cystic fibrosis.
Abstract: 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, 29 mg/kg every 6 hours) and after an inhalational dose (56 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 913% (+/- 382), 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(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: The present attempt is to seek out the primary sources of information in the hope that this effort would not only yield more reliable data, but would also provide an opportunity for reconsidering methodological problems which are possibly even more important.
Abstract: To define and evaluate the attention devoted to drug use in children rather than just review existing reviews, the present attempt is to seek out the primary sources of information in the hope that this effort would not only yield more reliable data, but would also provide an opportunity for reconsidering methodological problems which are possibly even more important. An English-language literature search for drug use in children from 1988 was conducted on two databases and a manual search was made of the literature, with a check of references quoted in main original articles, reviews and textbooks. The review was then organized in two main sections: an overall evaluation of the recent literature concerning drug use in children; the epidemiological profile of drug exposure as described cumulatively by the drug-utilization studies. A substantial lack of systematic attention to this area of drug epidemiology was found: drug use in the children is a ‘hidden’ reality in the literature; the wealth of methodologic developments that have taken place in the general field of drug use monitoring has scantly reached children. Children can be considered still “methodologic orphans” with respect to the transferable knowledge on the benefit/risk profile of therapies they receive. A network has to be developed to monitor clinical problems, including drug use, as part of an “audit” of the overall management of children.
TL;DR: Yohimbine is not only a useful tool in the study of blood pressure regulation, but may offer a therapeutic option in autonomic dysfunction because patients with autonomic failure, even those with severe sympathetic deprivation, are hypersensitive to the pressor effects of yOHimbine.
Abstract: It has been postulated that alpha 2-adrenergic receptors play a modulatory role in the regulation of blood pressure. Activation of alpha 2-receptors located in the central nervous system results in inhibition of sympathetic tone and decrease of blood pressure. This indeed may be the mechanism of action of central sympatholytic antihypertensives such as alpha-methyldopa. Presynaptic alpha 2-receptors also are found in adrenergic nerve terminals. These receptors act as a negative feedback mechanism by inhibiting the release of norepinephrine. The relevance of alpha 2-adrenergic receptors for blood pressure regulation can be explored with yohimbine, a selective antagonist of these receptors. Yohimbine increases blood pressure in resting normal volunteers. This effect is associated with an increase in both sympathetic nerve activity, reflecting an increase in central sympathetic outflow, and in norepinephrine spillover, reflecting potentiation of the release of norepinephrine from adrenergic nerve terminals. These actions, therefore, underscore the importance of alpha 2-adrenergic receptors for blood pressure regulation even under resting conditions. Patients with autonomic failure, even those with severe sympathetic deprivation, are hypersensitive to the pressor effects of yohimbine. This increased responsiveness can be explained by sensitization of adrenergic receptors, analogous to denervation supersensitivity, and by the lack of autonomic reflexes that would normally buffer any increase in blood pressure. Preliminary studies suggest that the effectiveness of yohimbine in autonomic failure can be enhanced with monoamine oxidase inhibitors. Used in combination, yohimbine increases norepinephrine release, whereas monoamine oxidase inhibitors inhibit its degradation. Therefore, yohimbine is not only a useful tool in the study of blood pressure regulation, but may offer a therapeutic option in autonomic dysfunction.
TL;DR: It is concluded that fixed‐dose transdermal nicotine, tapered‐dose Transdermal Nicotine, and buspirone are associated with similar efficacy and safety when combined with behavior modification in smoking cessation.
Abstract: The authors compared the outcome of 208 smokers treated with fixed-dose transdermal nicotine (n = 69), tapered-dose transdermal nicotine (n = 71), or buspirone (n = 68). At baseline, there were no significant differences among the three treatment groups with regard to age, gender, educational level, duration of smoking, number of cigarettes smoked per day, concomitant disease states or drug use, or Fagerstrom score. All smokers participated in a behavior modification program. Fixed-dose transdermal nicotine was given at a dose of 21 or 22 mg/day for 6 weeks. Tapered-dose transdermal nicotine was given at a dose of 21 or 22 mg/day for 4 weeks, 14 mg/day for 4 weeks and 7 mg/day for 4 weeks. Both transdermal nicotine regimens were initiated on the evening before the attempted quit date. Buspirone was started 21 days before the quit attempt and continued for 7 days after the quit attempt. Buspirone was initiated at 5 mg TID for 7 days and then 10 mg TID for 21 days. Smoking cessation was assessed by patient diaries and random plasma thiocyanate determinations. Dropouts for any reason were considered treatment failures. Quit rates were as shown in the Table I. Discontinuation of treatment for perceived side effects and dropouts for all reasons were not significantly different among the treatment groups. The authors conclude that fixed-dose transdermal nicotine, tapered-dose transdermal nicotine, and buspirone are associated with similar efficacy and safety when combined with behavior modification in smoking cessation.
TL;DR: In this review, an overview of the mechanisms of adverse drug reactions will be presented, followed by a general review of the experience of adverseDrug reactions in neonates and some specific examples of current adverse drug reaction and a suggested approach for the prevention and evaluation of adverse Drug Reaction in Neonates are presented.
Abstract: Adverse drug reactions (ADR) are uncommon causes of admission of neonates to the neonatal intensive care unit. The neonate, however, is potentially at significant risk for adverse drug reactions because of underdeveloped mechanisms and systems for handling drugs (the Gray Baby Syndrome with chloramphenicol as a classic example), the fact that infants in neonatal intensive care units are often critically ill with multiple organ system dysfunction, that they may be on multiple drugs, and that they may present with an adverse drug reaction as a result of exposure while still a fetus. There is also a history of misadventures in the neonatal intensive care unit and newborn nurseries due to exposure to antibacterial agents that produced systemic effects from percutaneous absorption. In this review, an overview of the mechanisms of adverse drug reactions will be presented, followed by a general review of the experience of adverse drug reactions in neonates and some specific examples of current adverse drug reactions and a suggested approach for the prevention and evaluation of adverse drug reactions in neonates.
TL;DR: Limited data from antiorthostatic bed rest and inflight studies provide preliminary evidence that the bioavailability of orally administered drugs in space may be decreased or subject to more interindividual variation than expected from ground‐based studies.
Abstract: Microgravity-induced changes in the bioavailability of drugs may influence the efficacy or toxicity of drugs The bioavailability of orally administered drugs may be altered by changes in dissolution rate, intestinal microflora, intraluminal enzymes, epithelial enzymes, rate of passage across the gastrointestinal epithelium, gastric emptying rate, intestinal transit time, hepatic first pass metabolism, and gastrointestinal and hepatic blood flow Limited data from antiorthostatic bed rest and inflight studies provide preliminary evidence that the bioavailability of orally administered drugs in space may be decreased or subject to more interindividual variation than expected from ground-based studies
TL;DR: The pharmacokinetic data suggest that the dose dependency of methylprednisolone pharmacokinetics is related to dose‐dependent prodrug hydrolysis, whereas the time dependence possibly reflects auto‐induction of methyl predictionsolone metabolism.
Abstract: The pharmacokinetics of methylprednisolone were evaluated in 29 healthy volunteers after multiple intravenous doses of methylprednisolone sodium succinate or the novel prodrug, methylprednisolone suleptanate. Subjects were assigned randomly to one of four treatment groups (40, 100, 250, or 500 mg) and then randomly assigned to receive either the sodium succinate or suleptanate prodrugs. Doses were administered every 6 hours for 48 hours. Plasma and urine were assayed for methylprednisolone and unchanged prodrug using HPLC methods. Methylprednisolone pharmacokinetics exhibited both a dose and time dependency, which was similar for administration of both prodrugs. After first-dose administration, mean clearance increased from 19.5 L/hr for 40-mg doses to 27.7 L/hr after 500-mg doses of the sodium succinate ester, and from 20.1 to 31.7 L/hr after the suleptanate ester. After multiple dosing, mean clearance values increased from 31.1 to 44.7 L/hr for sodium succinate dosing, and from 31.5 to 46.0 L/hr for suleptanate dosing. Apparent systemic clearance values determined after multiple dosing were 1.5- to 1.8-fold greater than corresponding first-dose values. No dependence on time was apparent for any prodrug pharmacokinetic parameter. These data suggest that the dose dependency of methylprednisolone pharmacokinetics is related to dose-dependent prodrug hydrolysis, whereas the time dependence possibly reflects auto-induction of methylprednisolone metabolism. Based on comparison of methylprednisolone pharmacokinetic parameters derived for each prodrug, methylprednisolone suleptanate resulted in a faster and slightly more efficient conversion to methylprednisolone than methylprednisolone sodium succinate.
TL;DR: The results show that the 0.75% gel formulation may offer the advantage of fewer systemic adverse effects compared with other formulations for the treatment of bacterial vaginosis.
Abstract: The pharmacokinetics of a single 500 mg oral dose of metronidazole and 5 g of 0.75% metronidazole intravaginal gel (37.5 mg metronidazole) were compared in 12 adult volunteers in a randomized crossover manner. Serial serum samples were collected over a 48-hour period and analyzed for metronidazole and hydroxymetronidazole. Metronidazole serum concentrations after intravaginal administration were only 2% of concentrations seen with the standard 500-mg oral dose. The dose-adjusted maximum serum concentration (898 +/- 121 ng/mL vs. 237 +/- 69 ng/mL) and area under the serum concentration-time curve (9362 +/- 2873 ng * hr/mL vs. 4977 +/- 2671 ng * hr/mL) were significantly greater for the oral versus intravaginal dose of metronidazole. The time to reach maximum concentration (1.4 +/- 0.6 hr vs. 8.4 +/- 2.2 hr) was significantly shorter for the oral compared with the intravaginal dose. The mean bioavailability for the intravaginal gel was 56%. Our results show that the 0.75% gel formulation may offer the advantage of fewer systemic adverse effects compared with other formulations for the treatment of bacterial vaginosis.
TL;DR: Examination of the new drug approvals of 1990, 1991, and 1992 finds that in general, 1990 to 1992 figures are similar to those in the last half of the 1980s.
Abstract: Efforts to speed the development and review of new drugs have increased sharply in recent years. This report, which is the third in a series on trends in drug development, examines the new drug approvals of 1990, 1991, and 1992. During the 3-year study period, the Food and Drug Administration (FDA) approved 79 new drugs, 74 of which met the Center for the Study of Drug Development's definition of a new chemical entity (NCE). Of the 74 NCEs, 36 (49%) were considered by the FDA to represent notable therapeutic gains and were selected for "priority" review (i.e., drugs rated 1P, 1A, 1AA, and 1B), and 38 (51%) were considered to represent little or no gain and received "standard" reviews (i.e., drugs rated 1S and 1C). Investigational new drug application (IND) filing and new drug application (NDA) submission dates on all 74 drugs were obtained from responses to our manufacturer surveys as well as from FDA and public sources. The mean length of the clinical phase (IND filing to NDA submission) was 6.1 years and that of the review phase (NDA submission to approval) was 2.6 years. Of the 74 NCEs, 43 (58%) were available in foreign markets at least 1 year before U.S. approval, with a mean of 5.6 years of foreign marketing. In general, 1990 to 1992 figures are similar to those in the last half of the 1980s.
TL;DR: A summary of four ground‐based investigations using one of the PATs to determine the extent to which various novel sensory stimulus conditions produce changes in compensatory eye movement responses, postural equilibrium, motion sickness symptoms, and electrogastric responses are presented.
Abstract: Two part-task preflight adaptation trainers (PATs) are being developed at the NASA Johnson Space Center to preadapt astronauts to novel sensory stimulus conditions similar to those present in microgravity to facilitate adaptation to microgravity and readaptation to Earth. This activity is a major component of a general effort to develop countermeasures aimed at minimizing sensory and sensorimotor disturbances and Space Motion Sickness (SMS) associated with adaptation to microgravity and readaptation to Earth. Design principles for the development of the two trainers are discussed, along with a detailed description of both devices. In addition, a summary of four ground-based investigations using one of the trainers to determine the extent to which various novel sensory stimulus conditions produce changes in compensatory eye movement responses, postural equilibrium, motion sickness symptoms, and electrogastric responses are presented. Finally, a brief description of the general concept of dual-adopted states that underly the development of the PATs, and ongoing and future operational and basic research activities are presented.
TL;DR: FK506 is incompletely and erratically absorbed after oral administration and is rapidly distributed outside the blood compartment after IV dosing, and an extended sampling period seems necessary to accurately characterize the slow elimination phase of FK506.
Abstract: The authors examined the safety and pharmacokinetics of FK506, a new hepatically metabolized immunosuppressant, after single-dose intravenous (i.v.) infusion (20 micrograms.kg(-1) x 4 hours-1) and oral (80 micrograms/kg) administration in six nondialysis patients, aged 27 to 53 years, with chronic renal failure awaiting transplantation. A two-period, randomized, crossover study protocol was used with blood samples drawn for 72 hours after each dose and a washout period of 4 days. Whole-blood FK506 levels were determined using a standard, two-step, nonspecific enzyme immunoassay. There were no significant changes in vital signs, EKG, or complete laboratory test battery for any patient during the entire study period. No side effects were noted after i.v. or oral FK506 dosing. Mean +/- SD distribution half life was 0.9 +/- 0.2 hours, elimination half life (t1/2 beta) 33 +/- 8 hours, total body clearance (CL) 2.4 +/- 1.1 L/hour, and bioavailability 14 +/- 12%. There was no significant correlation between serum creatinine (Cr) and CL (r = 0.36) or between Cr and t1/2 beta (r = -0.30). It was found that FK506 is incompletely and erratically absorbed after oral administration and is rapidly distributed outside the blood compartment after IV dosing. An extended sampling period seems necessary to accurately characterize the slow elimination phase of FK506.