Showing papers in "The Journal of Clinical Pharmacology in 1991"

Nonsteroidal anti-inflammatory drugs: Effects on kidney function

Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are capable of inducing a variety of renal function abnormalities, particularly in high-risk patients with decreased renal blood perfusion who depend on prostaglandin synthesis to maintain normal renal function. Fluid retention is the most common NSAID-related renal complication, occurring to some degree in virtually all exposed individuals; however, clinically detectable edema occurs in less than 5% of patients and is readily reversible on discontinuation of the NSAID. Other electrolyte complications, notably hyperkalemia, are seen infrequently and occur in specific at-risk patients. The next most worrisome complication is acute deterioration of renal function, which occurs in high-risk patients and is also reversible. Nephrotic syndrome with interstitial nephritis is a rare problem of NSAID use and is reversible. Papillary necrosis is the only permanent complication of NSAIDs and is very rare. Altogether, these renal function abnormalities, with the exception of mild fluid retention, are clinically detectable in approximately 1% of exposed patients. Given the number of patients who take NSAIDs on a prescription or over-the-counter basis, the absolute number of at-risk patients is relatively large. Consequently, an appreciation for the risk factors and pathophysiology of NSAID-induced renal function abnormalities is required for optimal use of these drugs.

Drug delivery systems. 6. Transdermal drug delivery.

Abstract: Transdermal drug delivery system has been in existence for a long time. In the past, the most commonly applied systems were topically applied creams and ointments for dermatological disorders. The occurrence of systemic side-effects with some of these formulations is indicative of absorption through the skin. A number of drugs have been applied to the skin for systemic treatment. In a broad sense, the term transdermal delivery system includes all topically administered drug formulations intended to deliver the active ingredient into the general circulation. Transdermal therapeutic systems have been designed to provide controlled continuous delivery of drugs via the skin to the systemic circulation. The relative impermeability of skin is well known, and this is associated with its functions as a dual protective barrier against invasion by micro-organisms and the prevention of the loss of physiologically essential substances such as water. Elucidation of factors that contribute to this impermeability has made the use of skin as a route for controlled systemic drug delivery possible. Basically, four systems are available that allow for effective absorption of drugs across the skin. The microsealed system is a partition-controlled delivery system that contains a drug reservoir with a saturated suspension of drug in a water-miscible solvent homogeneously dispersed in a silicone elastomer matrix. A second system is the matrix-diffusion controlled system. The third and most widely used system for transdermal drug delivery is the membrane-permeation controlled system. A fourth system, recently made available, is the gradient-charged system. Additionally, advanced transdermal carriers include systems such as iontophoretic and sonophoretic systems, thermosetting gels, prodrugs, and liposomes. Many drugs have been formulated in transdermal systems, and others are being examined for the feasibility of their delivery in this manner (e.g., nicotine antihistamines, beta-blockers, calcium channel blockers, non-steroidal anti-inflammatory drugs, contraceptives, anti-arrhythmic drugs, insulin, antivirals, hormones, alpha-interferon, and cancer chemotherapeutic agents). Research also continues on various chemical penetration enhancers that may allow delivery of therapeutic substances. For example, penetration enhancers such as Azone may allow delivery of larger-sized molecules such as proteins and polypeptides.

Pharmacokinetics and oral bioavailability of hydrocortisone.

Abstract: The pharmacokinetics of 20 mg hydrocortisone were studied after IV and oral administration. Endogenous hydrocortisone was suppressed by dexamethasone administration. Hydrocortisone concentrations were measured in plasma and saliva. After IV administration, hydrocortisone was eliminated with a total body clearance of 18 L/hr and a half-life of 1.7 hr. The volume of distribution was 34 L. Oral bioavailability averaged 96%. Absorption was rapid, achieving maximum hydrocortisone levels of 300 ng/mL after 1 hour. Saliva levels were not proportional to plasma levels, but could be shown to reflect free, non-protein bound hydrocortisone concentrations in plasma.

Cardiovascular adaptation to spaceflight.

Abstract: Data are presented on the rate of adaptation of the human cardiovascular system to conditions of spaceflight, with particular attention given to data obtained during spaceflight in the U.S. Space Shuttle Program. It is pointed out that many of the cardiovascular changes that occurred during spaceflights that lasted from 2 to 11 days can be traced directly to changes in the body fluid volume. The beneficial effects of a fluid loading countermeasure (oral rehydration) and of the supine body position on the heart rate during the spaceflight are demonstrated. It is noted that, after hours or a few days of spaceflight, a state of adaptation is reached, in which the subject is well adapted and appropriately hydrated for the weightless environment. However, the return to the normal gravity of the earth leaves the individual especially sensitive to orthostatic stress.

AICA-riboside: safety, tolerance, and pharmacokinetics of a novel adenosine-regulating agent.

Abstract: AICA-riboside (5-amino-4-imidazole carboxamide ribonucleoside) is a novel adenosine-regulating agent that is currently being investigated for the treatment of ischemic heart disease. In a placebo-controlled, double-blind study in healthy men, we evaluated the safety and kinetics of the drug after oral and IV administration of 10, 25, 50, and 100 mg/kg doses. At each dose level, four subjects received active drug and two subjects received placebo with a 1-week wash-out period between the IV and oral doses. The drug was well tolerated at all dose levels with only mild and transient side effects reported in some instances by the subjects who received placebo and those patients who received the drug. The post-infusion plasma concentrations of AICA-riboside declined rapidly in a biphasic fashion, and the terminal elimination phase had a harmonic mean t1/2 beta of 1.4 hours. Total plasma clearance (CL), mean residence time (MRTIV), and volume of distribution at steady-state (VSS) were 2.5 L/hr/kg, 0.7 hr, and 1.6 L/kg, respectively. The drug was not protein bound, and there was rapid uptake and phosphorylation in RBCs to its 5'-monophosphate nucleotide. Renal clearance (CLR) was 0.2 L/hr/kg with only 8% of the IV dose excreted in the urine as intact AICA-riboside. Although there was a trend towards a decrease in CL with increasing dose, there were no significant differences (P greater than .05) in the mean estimates of t1/2 beta, CL, CLR, MRTIV and VSS associated with dose. The drug was poorly bioavailable (less than 5%) when administered orally in solution.

Pharmacology and pharmacokinetics of amiodarone.

Abstract: Amiodarone is a unique antiarrhythmic agent originally developed as a vasodilator. Classified electrophysiologically as a Type III antiarrhythmic, it also has both nonspecific antisympathetic and direct, fast channel-membrane effects. Hemodynamic effects of orally administered amiodarone (a negative inotropic agent) are usually negligible, and are usually compensated for by induced vasodilation. Effects on thyroid and hepatic function may help to explain some of the unique pharmacologic as well as toxicologic effects of the drug. Amiodarone is poorly bioavailable (20-80%) and undergoes extensive enterohepatic circulation before entry into a central compartment. The principal metabolite, mono-n-desethyl amiodarone is also an antiarrhythmic. From this central compartment, it undergoes extensive tissue distribution (exceptionally high tissue/plasma partition coefficients). The distribution half-life of amiodarone out of the central compartment to peripheral and deep tissue compartments (t1/2 alpha) may be as short as 4 hours. The terminal half-life (t1/2 beta) is both long and variable (9-77 days) secondary to the slow mobilization of the lipophilic medication out of (primarily) adipocytes. A pharmacokinetically based loading scheme is described, and data suggesting a role for routine amiodarone plasma levels are presented.

Echocardiographic Evaluation of the Cardiovascular Effects of Short‐Duration Spaceflight

Abstract: Results are presented of echocardiographic investigations and hemodynamic measurements performed on 24 astronauts before and after short-duration (4-5 days) spaceflight, including data on the heart rate, blood pressure, and cardiac volumes. Cardiovascular changes which were found to occur after 4-5 day long spaceflight included decreased the left ventricular end-diastolic volume and the stroke volume indices, with a compensatory increased heart rate and the cardiac output being maintained; in addition, altered total peripheral vascular resistance was found to occur, with an apparent reduction in the ability to augment the peripheral vascular tone upon assuming the standing position. These cardiovascular characteristics normalized within 48 hrs of landing.

Effects of Gravity on Gastric Emptying, Intestinal Transit, and Drug Absorption

Abstract: The effects of microgravity on the physiologic response of the human body, the physical properties of gastrointestinal contents, and the influence these responses have on drug absorption are becoming more and more critical as the duration of humans in the hostile space environment dramatically increases. In this environment, some conventional oral dosage forms may be severely limited as an effective drug regimen. To understand the effects of microgravity, one must first understand the basic forces acting on a particle moving through a walled-tube such as the small intestine: gravity (FG), buoyancy (FB), and drag (FD). These forces can be combined and rearranged into a dimensionless ratio of gravitational forces to viscous forces. This is the most important dimensionless group influencing the motion of a particle relative to the fluid. Gastric emptying is highly influenced by several factors: volume, calories, exercise, size, density, temperature, viscosity, osmolality as well as those factors associated with physiologic responses: splanchnic blood flow, body position, and electrolyte balance. This array of factors can lead to variability in drug plasma levels. In the absence of gravity, the factors of size and density would appear to be most directly altered due to their dependence on the force of gravity. Intestinal transit rate in a gravity environment is highly dependent on the motility state of the GI tract either fasted or fed partly due to the higher viscosities of chyme in the fed state. In space, the absence of gravity may tend to increase the transit rate along the small intestine by decreasing the dimensionless ratio of gravitational forces to viscous forces. In zero gravity, therefore, these alterations in GI emptying and intestinal transit rate could lead to erratic plasma levels and inefficient absorption.

Changes in total body water during spaceflight

Abstract: Total body water (TBW) changes occurring in humans as a consequence of prolonged exposure to microgravity were measured in five male crewmembers of Space Shuttle missions STS-61C and STS-26. It was found that the inflight mean TBW values were significantly different from the preflight and postflight values, while the preflight TBW values were not significantly different from the postflight values. It was also found that individuals may differ in the rate at which they respond to weightlessness. Of the three crewmen who reported experiencing no symptoms of space motion sickness (SMS), two had not exhibited a decrease of TBW at the time of measurements (24 hrs after launch), while the two crewmen who reported SMS of intermediate severity showed a decrease of several kg by 24 hrs, suggesting that dehydration might be an important factor affecting the rate of TBW decrease.

Effects of gemfibrozil and other fibric acid derivatives on blood lipids and lipoproteins.

Abstract: Fibric acid derivatives (FADs) are a class of drugs that have been shown to reduce the production of very low-density lipoprotein (VLDL) while enhancing VLDL clearance due to the stimulation of lipoprotein lipase activity. The drugs can reduce plasma triglyceride levels while raising high-density lipoprotein (HDL) cholesterol levels. Their effects on low-density lipoprotein (LDL) cholesterol levels are less marked and more variable. There is evidence that oral gemfibrozil (Lopid, Parke-Davis, Morris Plains, NJ) can reduce the risk of serious coronary events, specifically in those patients who had elevations of both LDL cholesterol levels and total plasma triglyceride levels with lower HDL cholesterol levels. Newer FADs (bezafibrate, ciprofibrate, fenofibrate) have been shown to have greater efficacy in reducing LDL cholesterol than gemfibrozil but, in general, these drugs are not as effective as the other primary drugs used to lower LDL levels. The FADs are also used to treat adult patients with very high levels of triglycerides who have pancreatitis and whose disease cannot be managed with dietary therapy. The FADs are well tolerated, with dyspepsia and abdominal pain the most common adverse effects. A small risk of cholelithiasis exists with these drugs, and caution should be used when combining these drugs with HMG-CoA reductase inhibitors because the combination increases the incidence of hyperlipidemic myositis and rhabdomyolysis.

Lovastatin therapy in hypercholesterolemia : effect on fibrinogen, hemorrheologic parameters, platelet activity, and red blood cell morphology

Abstract: The effect of lovastatin therapy on blood rheology was investigated in 26 hypercholesterolemia patients. Treatment with lovastatin was associated with a significant improvement in whole blood filtration time and a tendency toward normalization in red blood cell morphology. A significant increase was observed in fibrinogen level, in ADP-induced platelet aggregation, in the percentage of “big” platelets, and in platelet count. The viscosity of whole blood and plasma and the percentage of aggregated platelets did not change significantly. The cause for these hemorrheologic changes and their role in influencing the coronary risk of lovastatin-treated hypercholesterolemia patients should be further investigated.

Gender-related differences in xenobiotic metabolism.

Abstract: This review will focus on the possible mechanisms for such differences, will briefly review the current state of the literature as it relates to humans, and will make recommendations for future research

Significance of classifying antiarrhythmic actions since the cardiac arrhythmia suppression trial.

Abstract: The Cardiac Antiarrhythmic Suppression Trial (CAST) showed flecainide and encainide induced excess mortality compared with placebo. Labeling drugs as Class 1C is based on clinical observations, comprising measurements of the electrocardiographic parameters QRS. H-V and J-T intervals and of effective refractory period (ERP) as follows: 1--(QRS) wide, 2--(HV) long, 3--(ERP) unchanged, 4--(JT) unchanged. In vitro electrophysiology helped to explain the clinical findings. Flecainide and encainide rendered Na channels as nonconducting, but F and E were only slowly released from the channels after repolarization. At any given drug concentration, a proportion of total channels were eliminated, and the steady-state proportion increased at rising heart rate. It is not proven that the properties that lead to classification of a drug as 1C were those that caused excess deaths in the CAST. The proarrhythmic tendency of 1C drugs can be reduced by beta-blockade, and the mechanisms of adrenergic arrhythmogenicity are discussed. Propafenone is both a 1C drug and a beta-blocker, and its pharmacologic profile is reviewed to illustrate how it resembles and differs from flecainide and encainide. Some features of the CAST are assessed with particular reference to the extent to which conclusions drawn from the results may be justifiably extrapolated to other drugs classified as 1C.

Induction of fluconazole metabolism by rifampin: in vivo study in humans.

Abstract: The effects of rifampin on the pharmacokinetics of fluconazole were analyzed in an open-label, placebo-controlled, parallel study. Sixteen healthy male volunteers, randomized into two groups, received 200 mg of oral fluconazole on days 1 and 22. On days 8 through 27, group I received oral rifampin, 600 mg/d, and group II received placebo. Fluconazole in serum was analyzed by HPLC. On days 1 and 22, respectively, the AUC (micrograms.hr/mL) (mean +/- SD) was 160.5 +/- 19.5 and 124 +/- 22.2 in group I, 152 +/- 25 and 152.8 +/- 33.9 in group II; the Kel (hr-1) was .0211 +/- .0030 and .0264 +/- .0040 in group I, .0219 +/- .0036 and .0216 +/- .0053 in group II. Cmax and Tmax did not change significantly in either group. Urinary 6 beta-hydroxycortisol/cortisol increased from 3.47 +/- 1.04 to 15.2 +/- 5.07 in group I, but was unchanged (3.54 +/- 1.33-4.26 +/- 2.36) in group II on days 1 and 22, respectively. The findings in this study indicate that rifampin induces the metabolism of fluconazole.

Drug delivery systems 5B. Oral drug delivery.

Abstract: 247. 46. Lejoyeux F, Ponchel C, Wouessidjewe D, Peppas NA, Duchene D: Influence of the composition of the testing medium on the adhesion of a bioadhesive tablet to a biological fabric. 15th Inter Symp Control Bel Bioactive Mater controlled Release Society Inc. 1988, Abstract 261. 47. Eckenhoff B, Theeuwes F, Urquhart J: Osmotically actuated dosage forms for rate-controlled drug delivery. Pharmaceutical Technology 1987;(June):96-105. DRUG DELIVERY SYSTEMS 5B DRUG DELIVERY SYSTEMS SERIES 115 48. Yacobi A. Halperin-Walega E: Oral Sustained Release Formulations: Design and Evaluation. A. Wheaton & Co., Exeter, UK,

Human autonomic responses to actual and simulated weightlessness.

Abstract: Orthostatic dysfunction occurs after exposure to microgravity, and is not completely understood. The authors developed a device for stimulating carotid baroreceptors to test the hypothesis that exposure to microgravity leads to impairment of arterial baroreflex mechanisms. Data obtained before and after two head-down bedrest studies and before and after brief Space Shuttle missions indicate that baroreceptor-cardiac reflex control is impaired by simulated or actual weightlessness. The authors speculate that arterial baroreflex derangements combine with blood volume reductions and increased venous compliance to provoke orthostatic hypotension after microgravity exposure. Altered baroreflex function after missions may result from autonomic neuronal plasticity that develops during missions secondary to changes of cardiopulmonary and arterial dimensions and consequent changes of autonomic sensory input proxies.

The pharmacokinetics and colonic tissue concentrations of cyclosporine after IV, oral, and enema administration

Abstract: This study compares pharmacokinetic parameters and colonic tissue concentrations of cyclosporine administered by olive-oil or water-retention enemas with conventional intravenous (i.v.) and oral dosing. Five medical students were enrolled in a prospective crossover study. All subjects received a single dose of cyclosporine on four separate occasions, once orally, once as an olive-oil enema, once as a water enema, and once i.v. Cyclosporine concentration was measured in blood and in colonic tissue obtained by flexible sigmoidoscopy. Bioavailability was 18 +/- 7% (mean +/- SD) for the oral dose and was unmeasurable for the oil and water enemas. The concentration of cyclosporine in colon tissue was 32,443 +/- 17,251 ng/g (mean +/- SD) for the i.v. dose, 2797 +/- 1812 ng/g for the oral dose, 21,727 +/- 14,090 ng/g for the oil enema, and 25,318 +/- 30,408 ng/g for the water enema. The authors conclude that the bioavailability of cyclosporine, and thus the systemic absorption after administration by a retention enema, is negligible. The colonic tissue concentration of cyclosporine after i.v. or rectal administration via an enema is tenfold higher than that for oral dosing. These findings suggest that cyclosporine-retention enemas produce high distal colonic tissue concentrations with negligible systemic absorption after a single dose in healthy subjects and should be evaluated as treatment for patients with left-sided colitis. Because cyclosporine administered by the i.v. route provided sharply higher colonic tissue concentrations than those seen with oral therapy, pulse i.v. cyclosporine should be tried for patients with severe ileitis and colitis.

Appropriate use and regulatory control of benzodiazepines.

Abstract: A nxiety, panic disorders, and insomnia are prevalent in the United States. Survey data from the National Institutes of Mental Health indicate that more than 12 million persons are afflicted.1-6 Pharmacologic intervention is one approach to the treatment of anxiety and sleep disorders. For centuries, patients have relied on using alcohol and patent medicines, and through 1960, barbiturates and meprobamate. In 1960, chlodiazepoxide, the first of the benzodiazepines, became available for the treatment of anxiety, soon followed by other related compounds including diazepam. In subsequent years, clinical experience with the benzodiazepines in the United States and elsewhere in the world became increasingly extensive, and the drug class likewise was the focus of numerous clinical and experimental studies.7’3 The emerging data base established several scientific principles. First, the anxiolytic efficacy of the benzodiazepines was clearly superior to placebo, and in many studies also superior to barbiturates or meprobamate.7 Second, the potential hazards of benzodiazepines in the context of intentional overdosage were clearly less than those of barbiturates or meprobamate.132#{176} Third, unlike the barbiturates, the b#{232}nzodiazepines did not posses clinically evident hepatic enzyme-inducing properties, and therefore were not a hazard to cause drug interactions by this mechanism.7 Attributable in part to this scientific and medical consensus, which remains essentially unchanged to the present, benzodiazepines largely replaced barbiturates and meprobamate as pharmacologic treatment for anxiety and sleep disorders. From 1973 to 1975-the years of peak benzodiazepine use-the yearly number of prescriptions dispensed in American retail pharmacies exceeded 80 million. During this time,

Fluoxetine-Induced Tricyclic Toxicity: Extent and Duration

Abstract: Combined fluoxetine-tricyclic medication has been recommended for patients who are partial responders or nonresponders to tricyclic medication alone. Three cases were encountered in which the addition of fluoxetine to tricyclic medication resulted in toxic, potentially dangerous elevations in tricyclic blood level, amounting to approximately 100-300% increases over recent tricyclic levels. In reducing the tricyclic dosage after fluoxetine, blood level decreases were behind dosage decreases; and blood level and dosage decreases were not well correlated with each other. Symptoms associated with toxic levels are described. Due to the long half-life of fluoxetine, such increases in tricyclic medication must be anticipated well in advance of initiating treatment with these two compounds. Based on these few cases, a procedure is tentatively recommended for patients on combined fluoxetine-tricyclic regimens, until such time as a definitive regimen can be developed.

New pharmacologic approaches to the prevention of space/motion sickness.

Abstract: Three fundamental approaches used in the selection of new agents for the evaluation in the prevention of space-motion sickness (SMS) are reviewed, with emphasis on drugs under investigation at the Johnson Space Center. These approaches are: (1) the selection of agents from drug classes that possess pharmacologic properties of established antimotion sickness agents, (2) the selection of drugs that are used to prevent emesis caused by means other than the exposure to motion, and (3) basic research that characterizes individual differences in susceptibility to SMS. In the latter type of studies, it was found that subjects who were more resistant to SMS had higher plasma AVP after severe nausea than subjects with lower resistance. The review details the experimental data collected on AVP and adrenocorticotropin. It is noted that data support interrelated roles for AVP and opioid peptides in SMS.

Acute Hemodynamic Responses to Weightlessness During Parabolic Flight

Abstract: Pilots and astronauts experience fluid shifts in variable gravity. Acute effects of fluid shifts on the cardiovascular system were monitored on NASA's KC-135 aircraft during parabolic flight. The variability of R-R intervals in the electrocardiogram was measured as an indication of vagal cardiac neural activity. R-R intervals were measured during the gravity transition from 2-G to 0-G produced by parabolic flight to assess the involvement of the autonomic nervous system in regulating the acute effects of fluid shifts. In seven subjects, a BoMed noninvasive continuous cardiac output monitor (NCCOM 3) monitored thoracic fluid index (TFI, ohms), heart rate (bpm), and cardiac output (1/min). Data were stored on a lap-top computer with the subject in one of four postures: sitting, standing, supine, and semi-supine, during one of four sets of eight to ten parabolas. Five seconds of data were averaged: before parabola onset (1.3-G); parabola entry (1.9-G); 0-G; and parabola exit (1.7-G). Three to eight parabolas were averaged for subjects in each posture; the mean for each posture was calculated. In each of five additional subjects, the coefficient of variation was calculated by dividing mean value by the standard deviation of 3 to 15 R-R intervals. Eight to ten parabolas were averaged for each postural set. Compared with values collected before 0-G, standing values during 0-G showed that the thoracic fluid index decreased 2.5 ohms, heart rate decreased 22 bpm, and cardiac output increased 1 L/min. During sitting, thoracic fluid index decreased 1.25 ohms, heart rate decreased 10 bpm, whereas cardiac output increased 0.5 L/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic changes observed in astronauts

Abstract: Study of metabolic alterations that occur during space flight can provide insight into mechanisms of physiologic regulation. Results of medical experiments with astronauts reveal rapid loss of volume (2 L) from the legs and a transient early increase in left ventricular volume index. These findings indicate that, during space flight, fluid is redistributed from the legs toward the head. In about 2 days, total body water decreases 2 to 3%. Increased levels of plasma renin activity and antidiuretic hormone while blood sodium and plasma volume are reduced suggest that space flight-associated factors are influencing the regulatory systems. In addition to fluid and electrolyte loss. Skylab astronauts lost an estimated 0.3 kg of protein. Endocrine factors, including increased cortisol and thyroxine and decreased insulin, are favorable for protein catabolism. The body appears to adapt to weightlessness at some physiologic cost. Readaptation to Earth's gravity at landing becomes another physiologic challenge.

Diethyl phthalate: a perspective.

Abstract: Diethyl phthalate (DEP) is widely used as a solvent and fixative for cosmetic products and as a plasticizer for cellulose-based packaging materials that have broad applications in the food and pharmaceutical industries. Packaging composed of cellulose acetate plastics may contain up to 20% DEP. Considering the annual production of 26 million pounds of this compound1 and its varied uses, there is the potential for widespread, albeit low level, human exposure to DEP. It is thus important to determine what, if any, adverse health effects in humans might be expected due to these low levels of exposure. Until the 1930s, the main commercial thermoplastic material was celluloid, and the plasticizer of choice was camphor. During this decade, polyvinyl chloride (PVC) plastics became commercially available and di-(2-ethylhexyl) phthalate (DEHP), a PVC plasticizer, was first synthesized. The flexibility of polyvinyl chloride provided a significant advantage over celluloid and contributed to the rapid growth in its use. Although DEP could not be used in PVC fabrication, it also gained wide use as a plasticizer because it had two significant advantages compared with camphor-lower volatility and less odor. DEP and DEHP both belong to the general class of compounds known as phthalic anhydride esters (PAEs). There are approximately 20 different PAEs in current use, mostly as plasticizers, and they can be found in products representing virtually every major product category including construction materials, consumer goods, medical products, and packaging. U.S. production of these PAEs totaled approximately 1.6 billion pounds in 1988.1 DEP and DEHP are sometimes confused because of their similar uses and the single letter difference in the abbreviated forms of their chemical names. However, they have different toxic potencies as will be demonstrated in this article.

Drug delivery systems 5A. Oral drug delivery.

Abstract: The two main advantages of controlled drug delivery systems are: maintenance of therapeutically optimum drug concentrations in the plasma through zero-order release without significant fluctuations; and elimination of the need for frequent single dose administrations. The oral and other therapeutic systems in human use have validated the concept that controlled continuous drug release can minimize the daily dose of a drug required to maintain the required therapeutic effect, while minimizing unwanted pharmacological effects. By minimizing patient intervention, a design feature of therapeutic systems, compliance is automatically enhanced. Oral drug delivery systems, in particular, have required innovation in materials science to provide materials biocompatible during prolonged contact with body tissues, bioengineering to develop drug delivery modules, and clinical pharmacology for elucidation of drug action under conditions of continuous controlled drug administration. Recent work in advanced oral delivery has been primarily focused on liposome technology and the concept that substances that are normally destroyed by the stomach can be protected long enough before they could be absorbed downstream. For cost and patient convenience, oral delivery certainly would be an attractive method. The nature of biologic substances, however, with their unique technical problems, will probably limit greatly those that can be delivered orally. Besides, where delivery rate control is critical, oral delivery, even when possible, would probably be insufficiently precise. Oral delivery would also limit the substance to bloodstream delivery to the disease site. Even so, oral controlled drug delivery systems will likely find primary usefulness in specific carefully controlled therapies and prophylactic situations with due regard for drug interactions. This system represents a potentially very significant therapeutic modality. These delivery systems will find usefulness primarily in certain well-defined and well-controllable areas with due regard for individual patient variations. The purpose of the present article is to review oral controlled-release drug delivery systems, with particular emphasis on the practical aspects of testing and fabricating these systems and the underlying mechanisms by which control over drug release rate is accomplished.

Nicotinic acid for the treatment of hyperlipoproteinemia.

Abstract: Nicotinic acid is a water-soluble B-complex vitamin that has been shown, in high doses, to lower total plasma cholesterol (C), LDL-C, and VLDL-triglycerides (Tg), while raising HDL-C in patients with type II, III, IV, and V hyperlipoproteinemia. Its exact mechanism of action is not known, but it appears to lower the production of VLDL in the liver while activating lipoprotein lipase. The drug may also influence the metabolism of HDL-C. The drug is a second or third choice for isolated hypercholesterolemia because of a high incidence of side effects. However, it has a therapeutic advantage as a monotherapy when reduction of both LDL-C and triglycerides are needed in patients with severe combined hyperlipidemia. The drug can be used in combination with other cholesterol-lowering agents to maximize lipid-lowering activity. Nicotinic acid has been associated with a reduced risk of cardiovascular morbidity in clinical trials.

Pharmacokinetics of intravenous immunoglobulin (Gammagard) in bone marrow transplant patients

Abstract: The pharmacokinetics of an intravenous immunoglobulin (IVIG), Gammagard (Baxter Healthcare Corp., Glendale, CA), were measured in 31 cytomegalovirus (CMV) antibody negative bone marrow transplant (BMT) patients as part of a multicenter efficacy trial of 2 weekly dose regimens. Since all patients lacked antibody to CMV and received only screened CMV negative blood products, the half-life of the exogenous CMV antibody could be measured with an ELISA assay. The CMV antibody titer was related to the immunoglobulin concentration using a standard curve. Compared with the 22-day half-life in normal subjects, the half-life in BMT patients was approximately 6 days for either the 250 mg/kg or 500 mg/kg dose regimen. The half-life did not change over the subsequent 3 weekly doses. Peak concentrations were 3.5 +/- 1.4 and 2.6 +/- 0.7 mg/mL of IVIG in week 1 as well as 5.5 +/- 2.6 and 3.4 +/- 1.2 mg/mL in week 3 after the 250 mg/kg and 500 mg/kg, respectively. Total body clearance of IVIG was 0.61 and 0.46 mL/kg/hr for the 500 mg/kg and 250 mg/kg, respectively.

The effects of an antacid or cimetidine on the serum concentrations of azithromycin.

Abstract: The effects of an antacid and of cimetidine on the serum concentrations of azithromycin were examined in volunteers. Ten subjects were given 500 mg azithromycin alone and immediately after being given 30 mL Maalox (Rorer, Fort Washington, PA) in a crossover design. There were no statistically significant differences in Tmax or AUC0-48 after administration of azithromycin alone or with antacid, but mean values of Cmax were reduced by 24% (P = .015). Thus, although Cmax was decreased, the extent of absorption of azithromycin was not affected by coadministration with an antacid. Two groups of six volunteers were given 500 mg azithromycin on day 1. On day 8, one group was given 800 mg cimetidine 2 hours before a dose of azithromycin; the remaining group received placebo before azithromycin. There were no differences in the pharmacokinetic parameters produced by administration with cimetidine or placebo, relative to those on day 1. Thus, cimetidine administered 2 hours before a dose of azithromycin had no apparent effect on the serum concentrations of azithromycin.

Stereoselective disposition of etodolac enantiomers in synovial fluid.

Abstract: The synovial fluid (SF) uptake of the chiral nonsteroidal anti-inflammatory drug, etodolac, was studied in six arthritic patients, 2 hours (n = 1) or 12 hours (n = 5) after a single 200 mg dose of racemate. Marked stereoselectivity was seen in both SF and plasma; concentrations of pharmacologically inactive R-etodolac were up to 10-fold greater than active S-etodolac. Concentrations of S-etodolac were greater in SF than in plasma (SF:plasma ratio = 1.98 +/- 0.8): No such difference was seen for R-etodolac (SF:plasma = 0.91 +/- 0.3). Considerable concentrations of conjugated enantiomers were present in SF. In vitro equilibrium dialysis studies in drug-spiked samples showed that the unbound fraction of both enantiomers in SF was greater than in plasma; both fluids bound R more extensively than S etodolac. Therapeutically active S-etodolac has greater concentrations in synovial fluid than plasma during the post-distributive phase, which may be of possible clinical relevance.

Cerebral Blood Flow: Comparison of Ground-Based and Spaceflight Data and Correlation with Space Adaptation Syndrome

Abstract: The relationship between the cerebral blood flow velocity and the space adaptation syndrome (SAS), which includes symptoms of motion sickness, stuffy head, and/or headaches, was investigated by measuring (using a transcranial Doppler device) differences between the preflight and the inflight cerebral blood flow velocity in crew members who were motion sick and in those who were not sick during a flight aboard KC-135 It was found that the cerebral artery bloodflow inflight did not differ significantly from that recorded preflight, nor did the severity of SAS symptoms correlate directly with the cerebral blood flow

Efficacy of cardioselective beta-adrenergic blockade with intravenously administered metoprolol in the treatment of supraventricular tachyarrhythmias.

Abstract: The efficacy of intravenously administered metoprolol, a cardioselective beta-adrenergic blocking agent, was evaluated in the treatment of supraventricular tachyarrhythmias in 16 patients. The arrhythmias that were treated were atrial fibrillation (11 patients), atrial flutter (2 patients), supraventricular tachycardia (2 patients), and multifocal atrial tachycardia (1 patient). Mean dose of metoprolol was 9.5 mg (range: 2-15 mg) administered in one or two separate infusions of up to 7.5 mg each over a cumulative maximum interval of 25 minutes. In the 13 responders (81%), mean ventricular rate decreased from 134 +/- 6 to 106 +/- 7 beats/min 10 minutes after metoprolol administration and was controlled for 40 to 320 minutes without further therapy. Minimum ventricular rate (98 +/- 6 beats/min) was reached 48 minutes after initiation of metoprolol. Metoprolol reduced ventricular rate by greater than 15% (decrease of 26-60 beats/min) in 11 (69%) of 16 patients, including 9 (82%) of 11 patients with atrial fibrillation. In two other patients, one with atrial fibrillation and one with supraventricular tachycardia, ventricular rate was reduced by greater than 12%. Hypotension, occurring in five patients, was the most frequent side effect but was transient and readily managed. Cardioselective beta-adrenergic blockade by metoprolol was rapidly effective in controlling ventricular rate in a majority of patients with supraventricular tachyarrhythmias and may be of particular use in selected patients with chronic obstructive pulmonary disease in whom intravenous beta-adrenergic blockade is indicated. Hypotension is an important potential side effect.