Controlling drug effects through improved oral formulations. The pharmacokinetics of the prazosin gastrointestinal therapeutic system.

Influences that determine a drug's effects include pharmacokinetic factors (the serum concentrations of drug as determined by the drug dose, absorption, distribution, and excretion) and pharmacodynamic factors (the intensity of drug effect). Most assessments of drug effect focus on the therapeutic range, i.e., the serum concentrations below which therapeutic effects are unlikely and above which toxic effects may be seen. A goal for many treatment regimens is to maintain serum drug concentrations within the therapeutic range. Maintenance of drug concentrations within the therapeutic range can be difficult with many traditional oral dosage formulations. Soon after administration of standard tablets, capsules, or liquids, a pronounced peak level is observed in serum. At the end of a dosage interval, serum concentrations are frequently below those needed to exert therapeutic effect. One reason for the wide range in serum concentrations with standard oral formulations is that these products usually exhibit first-order drug absorption, in which the rate of absorption from the gastrointestinal tract continually varies following a dose (from high to low) and is directly determined by the amount of drug remaining in the gastrointestinal tract. First-order absorption, therefore, results in changing absorption rates, wide swings in serum drug concentrations, a relatively short duration of action, and often, inconsistent drug effects over a dosage interval. One way to address the problems with standard oral products that have first-order absorption is to produce products that control drug release and absorption. A large number of controlled-release oral products are now on the market and use a variety of technologies. The ideal controlled-release formulation would result in zero-order drug absorption, in which the rate of drug absorption from the gastrointestinal tract would be constant and not determined by the amount of drug in the gastrointestinal tract. Zero-order absorption, therefore, results in an unchanging absorption rate, consistent serum levels, a longer duration of action, and more steady drug effect. Zero-order absorption is particularly preferable in situations that require a consistent, long-term therapeutic effect, e.g., in patients with hypertension, asthma, or arrhythmias. Of all the controlled-release preparations on the market, however, very few exhibit zero-order absorption; most can be categorized somewhere between first- and zero-order kinetics. An advanced-technology tablet has been invented to produce zero-order drug absorption for prazosin and nifedipine.(ABSTRACT TRUNCATED AT 400 WORDS)

Novel drug-delivery systems for hypertension.

Although novel controlled-release drug-delivery systems have been used in other areas of medicine, their application in the treatment of hypertension has been relatively recent. Biotechnical use of chemical-dispensing systems has been applied to propranolol, clonidine (the transdermal therapeutic system), nifedipine (the gastrointestinal therapeutic system), verapamil (the sodium alginate and spheroidal oral-delivery absorption system), felodipine (the hydrophilic gel principle), metoprolol succinate (the multiple-unit pellet system), and diltiazem (one system comprising sustained-release beads and the other utilizing the patented Geomatrix extended-release system). Oral drug-delivery systems allow antihypertensive agents that previously had to be administered two to four times daily to be administered once each day. Potential disadvantages of the oral controlled-release products include delayed attainment of pharmacodynamic effect, unpredictable or reduced bioavailability, enhanced first-pass hepatic metabolism, dose dumping, sustained toxicity, dosing inflexibility, and increased cost. Potential advantages include reduced dosing frequency, enhanced compliance and convenience, reduced toxicity, stable drug levels, uniform drug effect, and decreased total dose. Although skin reactions are common, the transdermal drug delivery of clonidine provides another innovative approach to supplying transcutaneous, controlled, continuous delivery of drug for 7 days. It is possible that future research will prove that the agents that provide complete 24-hour control may reduce the cardiovascular events associated with the early-morning blood pressure surge. This evolution in antihypertensive therapy to achieve once-daily dosing may prove to be of great value to both physicians and patients in the 1990s.

Drug interactions: theory versus practice.

Cimetidine inhibition of P-450 oxidative metabolism results in interactions with many drugs, leading to clinically significant drug toxicity. A one-year survey of inpatient prescribing practices revealed a 32.6 percent incidence of concomitant cimetidine and interacting drug use. Retrospective chart review showed statistically significant increased toxic drug plasma levels in patients receiving theophylline and cimetidine, and a strong trend to increased rates of drug toxicity in phenytoin-cimetidine treated patients. Ranitidine appears to be a superior choice in patients receiving drugs metabolized by P-450 oxidation. When cimetidine and known interacting drugs are prescribed together, more frequent assessment of blood levels of the affected drug will be required, increasing substantially the cost to patients. Drug interactions of clinical significance occurring due to altered absorption because of effects of H2-receptor antagonists on gastric secretion are reviewed.

Renal transplant patient compliance with free immunosuppressive medications.

BACKGROUND: Noncompliance with immunosuppressive medications after renal transplantation is believed to be a major cause of allograft rejection and graft loss, with the impressive costs of these agents considered a significant reason for noncompliance. Our purpose was to determine the compliance rates of renal transplant patients who received their immunosuppressant therapy free of charge and evaluate their patterns of compliance. METHODS: All patients who received a renal transplant and received their immunosuppressant medications at our institution for their first year posttransplant were included in the study. Compliance rate was calculated and serum immunosuppressant concentrations were obtained to validate compliance assessments. RESULTS: Eighteen patients were included in the study. Approximately 48% of noncompliant patients were found to have subtarget drug concentrations, although only 14% of compliant patients had subtarget levels (chi2=12.9, P<0.001). At 5 months posttransplant, 95% of the patients remained compliant; however, by 12 months posttransplant, only 48% of the patients remained compliant. The mean time to the first noncompliant month was 9.8 months (95% confidence intervals=8.60-11.0). CONCLUSIONS: Patients who received their immunosuppressants free of charge were generally compliant within their first year of transplantation, however, compliance tended to decrease over time. This suggests that drug cost alone does not explain noncompliant behavior. Intensive efforts to increase medication compliance before month 8 posttransplantation should be implemented.

Intraoperative serum and tissue activity of cefazolin and cefoxitin.

We determined the intraoperative serum and wound-muscle concentrations of cefazolin and cefoxitin in 40 patients who were undergoing cholecystectomies. The study employed an open-label design in which all of the patients randomly received cefazolin sodium (20 mg/kg) or cefoxitin sodium (30 mg/kg) intravenously while the patient was in the ward ("on call") or with the induction of anesthesia. Multiple blood and wound-muscle samples were collected intraoperatively and assayed for their cephalosporin concentrations. Considerable differences in intraoperative serum and tissue concentrations between antibiotics were apparent; there were usually higher levels of cefazolin. In all of the patients who received cefazolin sodium, the antimicrobial was detectable in wound tissue at wound closure, while it was detectable in 86% and 38% of patients who received cefoxitin sodium with anesthesia and on call, respectively. Because cefoxitin has a much shorter elimination half-life than cefazolin it seems prudent to administer the agent as close to the start of the operation as possible, and readminister the agent every two to three hours until the wound is closed. For cefazolin, on-call administration appears to be acceptable, with readministration not required for at least four hours.

Association of interleukin-4 plasma levels with traumatic injury and clinical course.

OBJECTIVES: To determine if interleukin-4 (IL-4) could be detected in plasma of trauma patients and if IL-4 activity is associated with patterns of clinical events, complications, or outcomes. METHODS: A prospective case series conducted in a tertiary care referral center with a level I trauma center. One hundred patients admitted to the trauma intensive care unit for at least 3 days were included. Plasma concentrations of IL-4 and IgE were determined from admission to intensive care unit discharge. Data on clinical outcome were collected, including death, sepsis, severe sepsis, adult respiratory distress syndrome, pneumonia, and renal dysfunction. RESULTS: Interleukin-4 was detected in the plasma of 87 patients. Patients with an Injury Severity Score of greater than 25 had higher admission IL-4 levels (P = .03) and greater maximal IL-4 levels (P < .001). Admission hypotension (P = .04) and age 30 years or younger (P < .001) were also associated with higher admission IL-4 levels. Increases in IL-4 levels were significantly greater for patients in whom sepsis, severe sepsis, or pneumonia developed (P < .05). A low admission IL-4 level was associated with a greater incidence of nosocomial pneumonia (P < .001). Additional indirect evidence of IL-4 activation included increased plasma IgE levels. CONCLUSIONS: Anti-inflammatory cytokine mechanisms are activated after injury and are associated with the development of infectious complications (sepsis, severe sepsis, and pneumonia). Exogenous administration of interleukin-4 should be evaluated as an experimental therapeutic approach after trauma and associated sepsis.

Reconstituted high density lipoprotein inhibits physiologic and tumor necrosis factor alpha responses to lipopolysaccharide in rabbits.

OBJECTIVE: To determine the effect of reconstituted human high density lipoprotein (rHDL) on physiologic and cytokine responses to infusion of lipopolysaccharide. DESIGN: A blinded, randomized trial of three preparations of a purified human rHDL with apolipoprotein A-I-phosphatidyl choline-cholesterol molar ratios of 1:100:10, 1:150:10, and 1:200:0 and placebo in a rabbit lipopolysaccharide intravenous infusion model. INTERVENTIONS: Groups of six New Zealand white rabbits received either placebo or one of the three human rHDL preparations above as a single, 75-mg/kg (apolipoprotein A-I equivalent) dose intravenously over 10 minutes ending 5 minutes before the start of a 3-hour infusion of lipopolysaccharide. MAIN OUTCOME MEASURES: Mean arterial pressure, base excess, and plasma tumor necrosis factor alpha (TNF-alpha) production were determined. RESULTS: The human rHDL suppressed TNF-alpha production with the products having the highest fraction of phosphatidyl choline producing the greatest suppression of TNF-alpha production. The human rHDL 1:200:0 group maintained a low, near-baseline TNF-alpha concentration and minimal decline in mean arterial pressure and base excess throughout the lipopolysaccharide infusion in contrast to the placebo group. CONCLUSION: Reconstituted human high density lipoprotein appears to be useful in inhibiting the physiologic effects and cytokine release associated with endotoxemia and may provide adjunctive treatment for patients with gram-negative sepsis.

Relationship of plasma clonidine to growth hormone concentrations in children and adolescents.

The relationships of plasma clonidine to increases in growth hormone, blood pressure response and degree of sedation were studied in nine children with short stature after a 0.15 mg/m2 oral clonidine tolerance test. A direct correlation was found between the peak plasma clonidine concentration and the increase in plasma growth hormone (P = 0.055). The patients experienced varying degrees of blood pressure reduction and sedation that were unrelated to age. No correlation was found between the plasma clonidine concentration and degree of blood pressure reduction or degree of sedation. The half-life of oral clonidine ranged from 1.75 to 2.38 hours, which is significantly less than that for adults.

Efficacy of a single intravenous dose of amphotericin B for Candida urinary tract infections: further favorable experience.

Studies in experimental animals and humans have shown that Amphotericin B (AmB) persists in urine for days to weeks after a single IV dose in levels that should inhibit candidal organisms and thereby obviate the need for frequent dosing. Including data from four previously described patients, we have now treated a total of 11 patients (12 episodes) with Candida urinary tract infections with single-dose AmB (six, Candida albicans; two, C. tropicalis; four, other nonalbicans Candida). The duration of candiduria prior to entry ranged from 18 to 180 days. Predisposing conditions included renal transplantation (1), diabetes mellitus (8), genitourinary stones (1) or anomalies (4), catheterization (2), and antibacterial therapy (11). A single patient was intolerant of AmB. Out of 11 evaluable candiduric episodes, eight resolved. Failure occurred in one patient with a chronic indwelling bladder catheter and in the allograft recipient. The data suggest that the sustained urinary excretion of AmB may permit successful single- or paucidose therapy of Candida urinary tract infections in some patients with a minimum of toxicity.

Considerations for therapy of mixed infections: focus on intraabdominal infection.

Intraabdominal infections are a wide range of diseases that include penetrating abdominal trauma, appendicitis, peritonitis, and abscess. Most are polymicrobic, involving aerobic and anaerobic bacteria. The primary treatment is surgery, but important issues regarding administration of antimicrobials may affect patient outcome. Evaluation of an antimicrobial regimen must include consideration of outcomes--survival, organ failure, adverse drug effects, and superinfection. Single-agent regimens have demonstrated benefit in patients with acute intraabdominal contamination and established infections. Guidelines for selecting antimicrobial agents are available from the Surgical Infection Society. Regimens are effective when active against most bacteria isolated from the focus of abdominal infection. The patient's clinical response, not culture results independent of clinical findings, is the primary guide for directing changes in therapy.

Cytokine networks with infection: mycobacterial infections, leishmaniasis, human immunodeficiency virus infection, and sepsis.

Distinct cytokine profiles are clearly associated with and relate to the severity of several types of infections. Cytokine networks are apparent with selected human infectious diseases, such as mycobacterial infections (leprosy, tuberculosis), the parasitic infection leishmaniasis, human immunodeficiency virus (HIV) infection, and gram-negative sepsis. Cytokine profiles are determined to some extent by two functional subsets of T lymphocytes, Th1 and Th2. The Th1 cytokines (interferon gamma, interleukin-2 [IL-2], IL-12) enhance cell-mediated immunity, inhibit humoral immunity, and result in protective effect for pathogens that are removed primarily through cell-mediated immunity (Mycobacterium tuberculosis, Mycobacterium leprae, Leishmania). The Th2 cytokines (IL-4, IL-5, IL-10, IL-13) enhance humoral immunity and inhibit cell-mediated immunity, and result in protective effect for pathogens removed primarily through humoral mechanisms. Progression of HIV infection is associated with a switch from a Th1 to a Th2 profile. For sepsis, uncontrolled activation of proinflammatory cytokines (IL-1, tumor necrosis factor-alpha, interferon-gamma) may be a fundamental defect that promotes the detrimental aspects of inflammation, whereas Th2 cytokines may be beneficial in controlling inflammation. Knowledge of basic cytokine immunopharmacology, networks, and relationships with infectious processes will aid clinicians in determining treatment approaches that are likely to be effective.

Single-agent versus combination antibiotic therapy in the management of intraabdominal infections.

For the treatment of intraabdominal infection, single-agent antimicrobial regimens such as beta-lactams with good antianaerobic activity are frequent alternatives to combination regimens such as aminoglycosides or aztreonam plus an antianaerobic agent such as clindamycin or metronidazole. The major issues in selecting a regimen are relative efficacy, potential for adverse drug effects, and cost. Single agents are clearly equivalent to combinations in preventing infectious complications after penetrating abdominal trauma and in treating established intraabdominal infections of mild to moderate severity or in relatively low-risk patients. A few trials demonstrated their equivalency in patients at high risk of mortality, although experience is limited. Single-agent regimens may reduce the risks of adverse drug effects compared with combination regimens, but they are not always less expensive.

Vancomycin: an update.

Vancomycin is a narrow-spectrum glycopeptide antibiotic with potent antistaphylococcal activity. It is primarily active against gram-positive organisms. Bacterial resistance rarely develops due to its numerous modes of action. The toxic potential of vancomycin is less significant than previously thought. "Red neck syndrome" seems to be the most common side effect and appears to be caused by rapid intravenous infusion. It is characterized by erythema at the base of the neck and the upper back; hypotensive episodes may also occur. Nephrotoxicity and ototoxicity are rare. Relationships between toxicities and serum concentrations have not been established. The disposition of vancomycin after intravenous administration proceeds biphasically--rapid distribution followed by elimination. The drug is excreted primarily unchanged in the urine by glomerular filtration. Vancomycin clearance is reduced and elimination half-life is prolonged in patients with renal insufficiency. Various methods have been published to aid in dosing the drug in these patients. Vancomycin is the drug of choice in the treatment of methicillin-resistant staphylococcal infections. It is also useful in the treatment of gram-positive endocarditis and has been used as alternative therapy in the treatment of prophylaxis of gram-positive infections in penicillin-allergic patients. Oral vancomycin is the preferred therapy in antibiotic-associated colitis.

High-performance capillary electrophoresis in the pharmaceutical sciences.

High-performance capillary electrophoresis (HPCE) is a new separation technique that is applied in the pharmaceutical sciences. Separations by HPCE occur in a narrow-bore capillary under the influence of an applied electrical field. Components of the sample matrix are separated and migrate at different rates based on physicochemical properties, including ionic charge, charge to mass ratio, lipid solubility, and spatial orientation. Detection is achieved through an on-line capillary detection window. The technique has several advantages, such as rapid analysis times, automation, and minute sample volume requirements. However, a significant disadvantage of HPCE is the high concentration limit of detection. Although HPCE will not displace traditional separation techniques, it will add another dimension to existing laboratories.

Oral neomycin sulfate and erythromycin base before colon surgery: a comparison of serum and tissue concentrations.

It is accepted that the use of oral neomycin sulfate and erythromycin base before colon surgery results in decreased numbers of intestinal bacteria. Intraluminal levels of these agents are reported to be very high, but systemic availability is still debated. The systemic levels were studied in 8 patients undergoing colon surgery. Each patient received neomycin sulfate and erythromycin base, 1 g each, 19, 18 and 9 hours preoperatively. Twelve samples from serum, one from wound muscle and one from the intestinal wall were obtained from each patient in the 26 hours after the initial dose. Considerable variation was observed among levels. The following means were calculated: peak serum levels were 3.4 and 0.59 micrograms/ml, muscle levels were 1.68 and 0.23 micrograms/g and intestinal wall levels were 6.4 and 12.9 micrograms/g for erythromycin and neomycin respectively. Observed times to peak levels were 19 and 12 hours after the initial dose for erythromycin and neomycin respectively. The detectable systemic concentrations that result when these agents are given orally for bowel preparation before colon surgery may contribute to the drugs' efficacy.

Sepsis syndrome and associated sequelae in patients at high risk for gram-negative sepsis.

We conducted a prospective surveillance study of 80 hospitals across the United States to determine the incidence of sepsis syndrome and its associated sequelae in hospitalized patients over age 18 years who were administered antibiotics for suspected or documented gram-negative infection. A sample of 1754 hospitalized patients were followed from onset of antimicrobial therapy to discharge or death. Mortality rates (MR) varied depending on the suspected source of sepsis syndrome. For patients in whom the syndrome was associated with community-acquired urinary tract infections, mortality was 20% (relative risk [RR] = 0.51, p < 0.05), for those with trauma 20.6% (RR = 0.51, p < 0.05), and patients with nosocomial respiratory tract infections 57.1% (RR = 1.66, p < 0.05). More than two complications occurred in 65.2% of patients under age 60 years (MR 31%), 40.8% of those age 60-80 (MR 42%), and 35.6% of patients older than 80 years (MR 33.3%, p > 0.05). Various patient populations had significant differences in both the incidence of the syndrome and its complications, and consequent mortality. Perhaps morbidity as well as mortality should be used as outcomes when testing the efficacy of innovative therapies for sepsis.

Combination antibiotic therapy in the management of intra-abdominal infection.

Combination antimicrobial regimens consisting of an agent with activity against gram-negative bacilli (an aminoglycoside) plus an agent with anaerobic activity (usually clindamycin or metronidazole) have traditionally been accepted as the standards for the treatment of intra-abdominal infection. Because of the problems of nephrotoxicity and ototoxicity in patients treated with aminoglycosides, clinical trials have been conducted using alternative combination therapy (e.g., aztreonam plus clindamycin) or single beta-lactam antimicrobial agents. Most clinical trials of intra-abdominal infections have been conducted in relatively small patient populations with a variety of low- and high-risk patients. The newer regimens have demonstrated efficacy equivalent to traditional combination therapy in selected patient populations. When selecting an antimicrobial regimen for treatment of intra-abdominal infection, multiple issues should be considered, including demonstrated efficacy in clinical trials, potential for adverse effects, and cost.

A comparison of monobactam antibiotics in surgical infections.

The introduction of gentamicin almost 20 years ago provided an effective option for the treatment of gram-negative bacillary infections. During the past few years, the availability of aztreonam (a monobactam), imipenem (a carbapenem), and newer cephalosporins within vitro activities comparable with aminoglycosides against many gram-negative bacilli, has stimulated a reassessment of the role of aminoglycosides in treating these infections. When determining the role of new antimicrobials as potential replacements for more established agents, the clinical focus should be on three factors: comparative efficacy, safety, and cost. Consideration of cost is relevant only when efficacy and safety are equivalent. Other factors, such as comparative in vitro antimicrobial activity, pharmacokinetics, and effect on normal flora can also influence the selection of an antimicrobial regimen. A new class of antimicrobials, the monobactams, is the focus of this review. The only member of this class currently in clinical use is aztreonam. A comparison with aminoglycosides is particularly relevant because aztreonam is active against aerobic gram-negative bacilli. This review will discuss the acknowledged concerns with aminoglycoside use and compare the characteristics of aztreonam and currently marketed aminoglycosides.

Pharmacodynamics of antimicrobial therapy in surgery.

INTRODUCTION: "Pharmacodynamics" refers to the relationship of drug concentrations in serum or tissues to effects on biologic systems. Concepts used to describe antimicrobial pharmacodynamics include the minimal inhibitory concentration (MIC), the minimal bactericidal concentration (MBC), and serum bactericidal titers (SBT), as well as post-antibiotic effect. METHODS: Pertinent published literature was identified through a MEDLINE search. RESULTS: Aminoglycosides have a concentration-dependent effect on bacteria killing and possess a relatively long postantibiotic effect. Given these characteristics, single-daily dosing, where the total daily dose with a traditional aminoglycoside regimen is given as one dose, may be more efficacious compared with more frequent dosing. For beta-lactam antimicrobials, bacterial killing is related to the duration of time that the free drug concentration exceeds the bacterial MIC. Beta-lactam antimicrobials have been shown to have no, or a short postantibiotic effect. Beta-lactam antimicrobials may be more effective when administered as continuous intravenous infusions. CONCLUSIONS: Pharmacodynamic variation may result from differences in drug sensitivity among individuals and the nature of the interaction between antimicrobials and microorganisms. Proper use of pharmacokinetic and pharmacodynamic principles can result in more effective and less toxic antimicrobial regimens.

Drug interactions in surgical patients.

Drug interactions, defined as when the administration of a single substance (drug, nutrient, or tobacco) modifies the response to a drug, occur relatively frequently in surgical patients and may result in increased morbidity and lengthened hospital stay. Drug interactions also account for some instances of drug ineffectiveness or exaggerated pharmacologic response. There are many types of drug interactions. However, most of them are related to altered drug pharmacokinetic properties, where there are alterations in drug absorption, distribution, metabolism, or elimination; or altered drug pharmacodynamic actions, where two agents may have synergistic, additive, or antagonistic pharmacologic effects. The term, drug interaction, usually refers to pairs of drug substances administered concurrently, but more than two agents may be involved. When patients are taking a large number of different medications, there may be multiple drug interactions with additive or antagonistic effects, the overall effects of which are difficult to predict. There are hundreds of reported drug interactions, and some may be of important clinical consequence. In surgical patients, the majority of drug interactions involve histamine-2 blockers (particularly cimetidine), digoxin, warfarin, or a variety of agents that may be administered during anesthesia. Recognition of the potential for adverse drug interactions is of primary importance in minimizing their effects. Usually, potentially interacting drugs may be administered concurrently as long as appropriate patient or laboratory assessments are performed. For some agents, such as digoxin or theophylline, serum drug concentrations may aid in the avoidance of adverse drug interactions.