Disposition of vessel dilator and long-acting natriuretic peptide in healthy humans after a one-hour infusion.

The present investigation was designed to determine half-lives, distribution phases and metabolic clearance of two new cardiac peptide hormones in humans. Long-acting natriuretic peptide (LANP) and vessel dilator were infused at 100 ng/kg of b.wt./min concentrations for 60 min with their respective concentrations measured by specific radioimmunoassays in plasma during and for 3 hr after infusion. The half-life of vessel dilator was 107 min, whereas the half-life of LANP was 28 min. The average time that the respective peptides were retained in the body (mean residence time) was 214 +/- 34 min for vessel dilator and 178 +/- 12 min for LANP, which indicates that they are widely distributed outside the initial space (i.e., circulation). The metabolic clearance normalized to 1.73 m2 body surface area was 241 ml/min for vessel dilator and 249 ml/min for LANP. The total body clearance normalized to 1.73 m2 body surface area was 130 ml/min for vessel dilator and 293 ml/min for LANP. The significantly (P < .001) longer half-lives and slower metabolic clearance of LANP and vessel dilator compared with atrial natriuretic factor (half-life, 2.5 min, metabolic clearance, 582-2,581 ml/min/1.7 m2) explain why these peptides circulate at concentrations 15- to 24-fold higher than atrial natriuretic factor in healthy humans.

The fluconazole era: management of hematogenously disseminated candidiasis in the nonneutropenic patient.

Hematogenously disseminated candidiasis arising from nosocomial fungal infection is a life-threatening complication in critically ill, nonneutropenic patients. The overall nosocomial fungal infection rate in United States hospitals doubled from 1980-1990. Until recently, amphotericin B was the only agent available for the treatment of life-threatening candidal infections, but its use is plagued by toxicities including nephrotoxicity and infusion-related reactions such as rigors and hypotension. The availability of fluconazole, which is regarded as much less toxic than amphotericin B, prompted a surge in research to determine if it is as efficacious in the management of candidemia and hematogenously disseminated candidiasis. Complicating the interpretation of studies is the broad range of infection severity, from candidemia that may be transient and self-limiting to life-threatening hematogenously disseminated candidiasis. Clinical trials comparing fluconazole and amphotericin B demonstrate the efficacy of fluconazole for catheter-associated candidemia in critically ill patients when the likely pathogen is Candida albicans. Amphotericin B should remain the first-line agent for the management of candidemia and hematogenously disseminated candidiasis in all other patients.

Disturbances of taste and smell induced by drugs.

We reviewed the current literature (1980-1990, 1991-1996) concerning drugs associated with anosmia, hyposmia, dysgeusia, parageusia, and ageusia, and the impact of these adverse effects. Case reports of patients with sudden and delayed onset of one of these disorders with evidence for implication of a drug were included. Disturbances of taste and smell among the elderly and chronically ill, including those with thermal injury, decreases interest in eating and secondarily impairs healing of wounds. Mechanisms involved with these sensory disturbances include deposition of silver sulfate in nerves after use of topical agents containing silver, altered influx of calcium and other ions, chelation or depletion of tissue-bound zinc, disturbed bradykinin catabolism and second messenger synthesis, catabolism, and altered prostaglandin systems. Other mechanisms, particularly prolonged chemosensory disorders after early drug discontinuation, remain unknown.

In vitro testing of antibiotics.

To enhance knowledge in the area of in vitro testing of antibiotics and to understand the limitations of available methods for susceptibility testing, we conducted a MEDLINE literature search in the English language to accumulate relevant articles. Headings searched included microbial sensitivity tests; Kirby-Bauer; laboratory tests; antiinfective agents; antibiotics, combined; microbiological techniques; blood bactericidal assay; and pharmacology, clinical. The management of patients with serious life-threatening infections can be complicated by recent changes in organism nomenclature, newly marketed antibiotics, and new isolation and sensitivity testing methods. With the addition of formulary constraints, many problems and controversies arise regarding interpretation of antibiotic sensitivity results. Comprehensive care for infected patients requires assessment of current antibiotic therapy and options for alternative therapy. By applying pharmacodynamic and pharmacokinetic knowledge to known limits of in vitro testing results, the clinician is able to select the most efficient antibiotic or antibiotic combination.

Intravenous ketorolac for pain management in a ventilator-dependent patient with thermal injury.

A patient with a long-standing history of chronic obstructive pulmonary disease suffered a thermal injury over 20% of his total body surface area. He required opiates for pain management and benzodiazepines for anxiety associated with dressing changes. The narcotics compromised his pulmonary function and level of consciousness, and interfered with several attempts to wean him from ventilator support. Intravenous ketorolac instead of narcotics before dressing changes alleviated the respiratory depression and returned his partial pressure of carbon dioxide-mediated respiratory drive to normal. With these changes, including changes in respiratory rate to tidal volume, he was successfully weaned from ventilatory support. In addition, the patient's level of consciousness improved. These changes increased his participation in his daily physical therapy sessions.

Comparison of fluid volumes with whole bowel irrigation in a simulated overdose of ibuprofen.

OBJECTIVE: To determine the effect of 2 different fluid volumes of polyethylene glycol whole bowel irrigation (WBI) solution on absorption of an ingested toxin in a simulated overdose model. DESIGN: Prospective, randomized, crossover trial. SETTING: Clinical research unit. PARTICIPANTS: Nine adult men. INTERVENTIONS: On 2 separate days, volunteers ingested approximately 75 mg/kg of ibuprofen. In treatment 1, 30 minutes after ingestion of ibuprofen, a 3-L WBI at 2 L/h was begun. This procedure was repeated in treatment 2 with an 8-L. WBI administered at 2 L/h. Fourteen timed serum samples were collected prior to and after drug ingestion for a 24-hour period and analyzed for ibuprofen concentration. The peak serum concentration, time to peak concentration, total area under the serum concentration-time curve (AUC), clearance, and volume of distribution were compared. RESULTS: The mean +/- SD AUCs did not differ between the 3-L (1185.3 +/- 216.9 mg.h/L) and 8-L (1153.5 +/- 251.5 mg.h/L) treatments (p = 0.710). Time to peak serum concentration, peak serum concentration, clearance, and volume of distribution were comparable for the 2 treatments (p > 0.05). CONCLUSIONS: These data indicated that a total WBI volume of 3 L would be expected to perform as well as 8 L administered at the same rate. We recommend that further research define the optimal dose of WBI in acute ingestion of toxins.

Toxic epidermal necrolysis after initiation of felbamate therapy.

A 33-year-old woman with a 13-year history of partial complex seizures experienced toxic epidermal necrolysis requiring management in a regional burn treatment center after 16 days of single-agent treatment for epilepsy with felbamate 3600 mg/day. Within 24 hours the target lesions involved 45% of her total body surface area. They coalesced and progressed to exfoliation involving the mucosa and the conjunctiva. The patient was hospitalized for 25 days. Reports in the literature describe life-threatening rashes after treatment with felbamate in combination with other anticonvulsant agents. We believe this to be the first reported case of felbamate-induced toxic epidermal necrolysis induced by single-agent therapy. Although felbamate provides many advantages as an anticonvulsant, its structure can be arranged to a conformation in space similar to that of hydantoins and barbiturates, and thus warrants careful patient monitoring for life-threatening rashes.

Vessel dilator is associated with survival after acute myocardial infarction.

To assess whether infarct size, ischemic area and/or survival correlates with circulating atrial natriuretic peptides (long acting sodium stimulator, vessel dilator, or atrial natriuretic factor), these peptides were measured in a canine model of acute myocardial infarction. Elevations in the circulating concentrations of atrial natriuretic factor, vessel dilator, and long acting sodium stimulator were significant (P < 0.05) within 6 min of coronary occlusion of the left anterior descending coronary artery. The percentage of ischemic myocardium ranged from 20 to 67% with a mean of 37 +/- 17%. The area of infarction ranged from 1 to 13% with the infarcted area of non-survivors being twice that of survivors. Both the ischemic and infarcted areas correlated (P < 0.05) with the circulating concentrations of these atrial natriuretic peptides. Survival correlated also with the circulating plasma concentrations of vessel dilator, atrial natriuretic factor and long acting sodium stimulator (P < 0.05). When these circulating concentrations were evaluated, however, by determining their area under their respective concentrations curves and expressing each as the log area under plasma concentration-time curve (area under the curve) per kg of weight (Y = 58.48X-23.62; r = 0.825; P = 0.0009), vessel dilator was the only atrial natriuretic peptide that correlated with survival.

Measurement of serum isopropanol and the acetone metabolite by proton nuclear magnetic resonance: application to pharmacokinetic evaluation in a simulated overdose model.

The purpose of this investigation was to 1) compare the performance of proton nuclear magnetic resonance spectroscopy to gas chromatography head-space analysis in the measurement of serum isopropanol and its metabolite, acetone, obtained during a simulated overdose, and 2) compare pharmacokinetic parameters obtained using the two analytical techniques. Three healthy volunteers ingested 0.6 mL/kg of 70% isopropanol and blood samples were obtained at baseline, 0.16, 0.33, 0.66, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours post-ingestion. Resulting sera were analyzed by gas chromatography head-space analysis and proton nuclear magnetic resonance spectroscopy for determination of isopropanol and acetone concentrations. A correlation between concentrations quantitated by gas chromatography head-space analysis versus proton nuclear magnetic resonance spectroscopy was determined using linear regression. Pharmacokinetic disposition parameters were determined from serum concentration-time data and compared using analysis of variance. For isopropanol, the linear regression equation which describes the relationship between gas chromatography head-space analysis and proton nuclear magnetic resonance spectroscopy was y = 1.041x - 2.180 (r2 = 0.995, p < 0.0001); for acetone, y = 1.022x - 0.946 (r2 = 0.984, p < 0.0001). Pharmacokinetic disposition parameters derived from the two analytical methods were comparable. Proton nuclear magnetic resonance spectroscopy can be used to rapidly quantitate serum isopropanol and acetone concentrations in the same sample when gas chromatography head-space analysis is unavailable. Also, proton nuclear magnetic resonance spectroscopy can be used to follow serial serum concentrations during an ingestion for the purpose of pharmacokinetic analysis.

Phenytoin and plasmapheresis: importance of sampling times and impact of obesity.

The effect of plasmapheresis (PP) on total and free phenytoin clearance is reported. An obese patient with the diagnosis of thrombotic thrombocytopenic purpura (TTP) was treated with PP. Twelve episodes of PP, having exchange volumes of 1.5-2.25 times the plasma volume with a mean +/- SD 7.7 +/- 0.8 L of plasma removed, were studied. A significant (p < 0.05) difference was observed with a mean change in plasma phenytoin concentrations from pre- to end-PP of 7.32 +/- 2.5 mg/L compared to 1.98 +/- 0.7 mg/L observed pre-PP to 1 h post-PP. These values corresponded to 48.4 +/- 11.6 and 15.0 +/- 6.7% decreases in phenytoin concentrations at the two aforementioned time periods. To prevent misinterpretation of plasma phenytoin concentrations, samples should not be obtained for at least 2 h after PP.

Low-volume whole bowel irrigation and salicylate absorption: a comparison with ipecac-charcoal.

STUDY OBJECTIVE: To evaluate two methods of gastrointestinal decontamination, low-volume whole bowel irrigation (WBI) and activated charcoal, for their ability to prevent absorption of salicylate. DESIGN: Randomized, two-phase crossover study. SETTING: A clinical research unit in a university-based teaching hospital. PATIENTS: Six healthy, volunteer men. INTERVENTIONS: Subjects were assigned to receive 3000 ml WBI or syrup of ipecac 30 ml followed by activated charcoal 50 g in sorbitol, and were crossed over to the other treatment phase after 1 week. All treatments began 30 minutes after ingestion of 3.25 g aspirin. Urine was collected over 24 hours for analysis of total urinary excretion of salicylate. Serial blood samples were collected for salicylate determination and were subjected to pharmacokinetic analysis. MEASUREMENTS AND MAIN RESULTS: Mean +/- SD recovery of salicylate were WBI 48.6 +/- 5.4% and ipecac-charcoal 37.0 +/- 2.6% from urine (p < 0.01). CONCLUSION: Ipecac-charcoal produced a significantly lower salicylate absorption (peak concentration, AUC) than WBI (p < 0.01) and thus was superior to low-volume WBI.

The use of delta osmolality to predict serum isopropanol and acetone concentrations.

We investigated whether serum delta osmolality will predict the total serum concentration of isopropanol and acetone metabolite. Three isopropanol ingestions were monitored by delta osmolality determinations followed by quantification of serum isopropanol and acetone concentrations. The delta osmolality was established by routine chemical analysis and standard freezing point depression osmometry. Serum isopropanol and acetone levels were quantified by gas chromatography-head space analysis (GC-HS). Patients were initially suspected of having isopropanol intoxication secondary to an elevated delta osmolality discrepancy (measured - calculated > 10 mOsm). Serum concentrations versus delta osmolality were analyzed by linear regression (correlation coefficient r = 0.713; p < 0.05). The delta osmolality paralleled and decreased relative to the total low molecular weight of volatile concentration in each case. In emergencies, delta osmolality may be a screening test to identify rapidly patients at risk for complications associated with isopropanol ingestion when GC-HS is not available.

Analysis of vancomycin time-kill studies with Staphylococcus species by using a curve stripping program to describe the relationship between concentration and pharmacodynamic response.

Mono- and biexponential killing curves for vancomycin over a 2- to 50-micrograms/ml concentration range were generated for 11 Staphylococcus aureus isolates and 12 coagulase-negative Staphylococcus species in the logarithmic phase of growth. Nonlinear least-squares regression of the initial growth rate and disappearance were not significantly different for lower or higher concentrations of vancomycin in broth.

Disseminated Nocardia asteroides diagnosed by blood culture in a patient with disseminated histoplasmosis.

We describe herein a provocative case involving an immunosuppressed patient with disseminated Histoplasma capsulatum and also disseminated Nocardia asteroides, which was documented by multiple routine blood culture samples. Nocardia asteroides was isolated from 15 routine blood cultures using the nonradiometric blood culture system (Bactec NR-660, Becton Dickinson, Towson, Md). Several different species of the genus Nocardia proved to thrive in blood culture bottles (Bactec) when experimental inoculations were performed. The paucity of reports in the literature of disseminated nocardiosis with positive blood cultures has led us to consider cause for the apparent poor recovery of these organisms from blood culture media. We suggest that the media (Bactec) can successfully support growth of Nocardia species and that other variables, such as incubation times and subculture, should be considered to optimize isolation of this pathogen in blood culture systems.

Pharmacokinetic characterization of the postdistribution phase of prohormone atrial natriuretic peptides amino acids 1-98, 31-67, and atrial natriuretic factor during and after rapid right ventricular pacing in dogs.

Release rate constants and disappearance rate constants were determined for three atrial natriuretic peptides consisting of amino acids 1-98 (i.e., proANF 1-98), the midportion of the ANF prohormone consisting of amino acids 31-67 (i.e., proANF 31-67) and amino acids 99-126 (i.e., ANF) after right ventricular pacing at 100, 125, 150, and 180 bpm in six male mongrel dogs. Right atrial and femoral vein blood was obtained at baseline, and at 5, 12, 19, 26, 56, 86, 116, 146, and 206 minutes after right ventricular pacing. Resulting plasma concentration-time data derived parameters were compared. The disappearance rate constants for atrial and femoral venous proANF 1-98 were 0.0144 +/- 0.0087 (X +/- SD) and 0.0175 +/- 0.0075 min-1, respectively (t = 0.6158) and release rate constants were 0.1569 +/- 0.1504 and 0.0670 +/- 0.0393 min-1, respectively (t = 1.8269; P greater than .05). The proANF 31-67 disappearance rate constants were 0.0139 +/- 0.0082 and 0.0148 +/- 0.0132 min-1, respectively (t = 0.1192) and release rate constants were 0.0957 +/- 0.0414 and 0.1984 +/- 0.1762 min-1, respectively (t = 1.4812). The ANF elimination phase disappearance rate constants were 0.0663 +/- 0.0273 and 0.1116 +/- 0.0539 min-1 (t = 2.0923, P greater than .05), respectively, and the release rate constants were 0.1335 +/- 0.0532 and 0.1638 +/- 0.0520 min-1 (t = 0.7878, P greater than .05), respectively. These data indicate that proANF 1-98 and proANF 31-67 circulating beta post-distribution half-lives are approximately 45 minutes whereas beta half-life of ANF is 10 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Monitoring chronic outpatient infections: providing comprehensive home healthcare pharmacy services.

Management of acute illness has been increasingly shifted to community practitioners. Expansion of community pharmacy into home healthcare has brought new opportunities and responsibilities to community practitioners. These practitioners are gaining expertise in total parenteral nutrition, intravenous infusion systems, intravenous catheters, parenteral antibiotics, and clinical pharmacokinetics--areas historically managed by hospital and long-term care facility pharmacists. This shift to community pharmacy-based care has brought with it the need for community pharmacists to develop expertise in therapeutic monitoring of chronic disease states. Dose adjustment of medications based upon careful analysis of blood concentrations is no longer limited to institutional pharmacy practice. Community pharmacists now must master basic infectious disease principles and possess internal medicine knowledge to ensure appropriate monitoring of their patients. This article discusses several disease states currently managed with community pharmacy-based home healthcare, summarizing basic monitoring parameters for comprehensive patient care, and provides sample supply lists and documentation forms for home healthcare providers.