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Biomedical subjects

T C Hardin

Publications and source records attributed to T C Hardin.

At least 19 recordsLinked to original sources
PubMed1997

Key issues concerning fungistatic versus fungicidal drugs.

Are there any fungicidal drugs available today? A critical issue in answering this question is that of definition. The simplest, most stringent definitions identify fungistatic drugs as those that inhibit growth, whereas fungicidal drugs kill fungal pathogens. The immunocompetent host is usually far better equipped to eliminate fungal pathogens than the immunosuppressed host. Therefore, it would be especially desirable to have a truly fungicidal drug, one that absolutely kills and fungi, as a treatment option for the immunosuppressed patient. The critical question would be whether a fungicidal drug can be delivered to the target site in a concentration high enough for a sufficient time to reduce the intralesional fungal counts to zero. By this simple definition, there are no fungicidal drugs available today. However, an accepted alternative definition is that often used by the bacteriologist: Fungicidal drugs are those that lead to a reduction of 99.9% of the initial inocula. Although this less restrictive in vitro standard is more easily met, it has serious limitations. Whether the 99.9% kill should be an acceptable standard remains uncertain. As an alternative, the minimum inhibitory concentration, though indicating static activity, has served well; perhaps it should be the only information reported for fungal susceptibility testing.

Adjuvants, Immunologic↗
PubMed1997

Therapeutic drug monitoring of systemic antifungal therapy.

The use of systemic antifungal therapy has significantly increased in recent years. Individualization of antifungal therapy through the use of serum or plasma concentrations has been suggested, although no specific recommendations have been developed. The important criteria for therapeutic drug monitoring and which of these criteria are satisfied by systemic antifungal agents are presented in this review. No one antifungal is ideally suited for application of therapeutic drug monitoring, but, under certain circumstances, obtaining serum or plasma concentrations can be justified. In patients who are susceptible to flucytosine toxicity, serum flucytosine concentrations should be monitored in an effort to avoid untoward side-effects. In contrast, therapeutic drug monitoring of amphotericin B is not recommended in the clinical setting. Demonstrating that ketoconazole and itraconazole are reaching the systemic circulation by obtaining serum concentrations may be clinically useful due to the large variability in their absorption and issues of patient compliance which may be seen with these agents. The bioavailability of fluconazole is much less varied although validation of compliance is a situation where obtaining serum concentrations may provide additional information.

Amphotericin B↗
PubMed1997

Amphotericin B enzyme-linked immunoassay for clinical use: comparison with bioassay and HPLC.

OBJECTIVE: To evaluate a new enzyme-linked immunosorbent assay (ELISA) for amphotericin B in serum samples. Results are compared with those obtained by HPLC and bioassay. DESIGN: Comparison of results obtained by ELISA, HPLC, and bioassay. METHODS: We developed a new ELISA using a polyclonal rabbit antibody to measure serum amphotericin B concentrations. Blinded samples of amphotericin B in concentrations of 0.15-78 micrograms/mL were prepared in human serum and assayed simultaneously by the ELISA, HPLC, and bioassay. The results of each assay were derived from standard curves and evaluated by using the Table Curve 2D computer program. These data were compared by using correlation analysis with evaluation of Pearson's correlation coefficient by Student's t-test. RESULTS: ELISA and bioassay compared favorably at amphotericin B concentrations of 0.3-20 micrograms/mL with a correlation coefficient of r = 0.993, while ELISA and HPLC compared with a correlation coefficient of r = 0.944. The average coefficient of variation over the range 0.3-20.0 micrograms/mL was 28% +/- 7% for HPLC, 26% +/- 9% for ELISA, and 13% +/- 4% for bioassay. Comparison of all three assays revealed the highest correlation with the ELISA assay (r = 0.998) for the range of concentrations (0.3-20 micrograms/mL) routinely achieved. Samples containing concentrations in excess of 20 micrograms/mL could be diluted. Desiccation for concentrations less than 0.3 microgram/mL was not tested. CONCLUSION: The determination of serum amphotericin B concentrations by ELISA gave results similar to those obtained by a bioassay and HPLC technique. Although variability appears greater with ELISA, the ease of performing yjis assay expedites the evaluation of amphotericin B concentrations from lipid formulations without interference from coadministered antibacterials of azole antifungals.

Amphotericin B↗
PubMed1993

Cytokine mediators of malnutrition: clinical implications.

During the past decade, the relationships that exist between inflammatory cytokines and the metabolic changes associated with critical illness have been the focus of extensive research efforts. Alterations in protein metabolism, characterized by increased peripheral protein catabolism and increased hepatic synthesis of acute-phase proteins, have been reported with tumor necrosis factor, interleukin-1, and interleukin-6 administration in animals and humans. Hyperlipoproteinemia has also been observed, particularly in association with increases in very-low-density lipoproteins and hepatic fatty acid synthesis. The release of counter-regulatory hormones in response to cytokine activity contributes to these metabolic changes as well. An understanding of the complex interactions of cytokines as mediators of intermediary metabolism is important to clinicians caring for critically ill patients.

Critical Illness↗
PubMed1993

Treatment of aspergillosis with itraconazole.

OBJECTIVE: To review the role of itraconazole as oral therapy for the major infections caused by Aspergillus spp.: allergic bronchopulmonary aspergillosis, aspergilloma, and invasive aspergillosis. DATA SOURCES: A MEDLINE search of articles published in the English language between 1986 and 1993 was used to identify relevant citations, including review articles. In addition, a search of the published abstracts of the past two Interscience Conferences on Antimicrobial Agents and Chemotherapy (ICAAC) was performed. STUDY SELECTION: Clinical trials that evaluated itraconazole therapy in either allergic bronchopulmonary aspergillosis, aspergilloma, or invasive aspergillosis were critically reviewed. Trials were evaluated based upon entry criteria for the diagnosis of each type of aspergillosis, risk factors for the development of aspergillosis (neutropenia, transplant recipient, hematologic malignancy), prior antifungal chemotherapy, and dose and duration of itraconazole therapy. DATA SYNTHESIS: Overall, the clinical trials of itraconazole therapy for aspergillosis are limited and of variable quality. In the treatment of allergic bronchopulmonary aspergillosis, itraconazole has been reported to prompt a reduction in corticosteroid dosage in selected patients. There have been no controlled trials of itraconazole as treatment for aspergilloma, but data from several open-label trials suggest that this agent may be of clinical benefit in aspergilloma, primarily as an alternative to surgery. The use of itraconazole for invasive aspergillosis has been evaluated in several trials, most often in patients who were intolerant to amphotericin B treatment. Response to oral itraconazole has generally been promising. CONCLUSIONS: Although itraconazole offers promise for oral therapy against infections caused by Aspergillus spp., it should not presently be regarded as primary therapy for any of these diseases. Amphotericin B, in doses ranging from 1 to 1.5 mg/kg to a total dose of 1.5-4.0 g, should remain the treatment of choice in both aspergilloma and invasive aspergillosis. Itraconazole use should be restricted to patients who experience severe toxicity with amphotericin B therapy. Corticosteroids continue to be first-line therapy for allergic bronchopulmonary aspergillosis, with the use of itraconazole reserved for those patients who would benefit from a reduction in corticosteroid dose.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Pharmacokinetics of SCH-39304 in human immunodeficiency virus-infected patients following chronic oral dosing.

The pharmacokinetics of SCH-39304, an investigational, orally active, broad-spectrum antifungal agent, were evaluated in 17 adult, human immunodeficiency virus-positive males. Patients were studied on days 1 and 16 and were divided into the following three treatment groups: (i) patients with culture-proven oropharyngeal candidiasis who were not receiving concurrent zidovudine therapy and who were treated with 50 mg of SCH-39304 daily (n = 6); (ii) patients with culture-proven oropharyngeal candidiasis who were receiving concurrent zidovudine therapy and who were treated with 50 mg of SCH-39304 daily (n = 5); and (iii) patients with or without oropharyngeal candidiasis who were receiving concurrent zidovudine therapy and who were treated with 200 mg of SCH-39304 daily (n = 6). All patients received a single daily dose of the study medication for 16 days. Plasma samples for SCH-39304 concentration measurement were collected for 6 h following the initial dose and for 504 h following the day 16 dose. Urine was collected for 24 h following SCH-39304 administration on days 1 and 16. All samples were assayed for SCH-39304 by gas chromatography. Wide intersubject variations in SCH-39304 plasma concentration-versus-time profiles were observed on each study day. Absorption appeared to be slow, with mean day 1 peak plasma SCH-39304 concentrations of 1.2 micrograms/ml at 2.1 h (50 mg) and 3.9 micrograms/ml at 4.0 h (200 mg) after drug administration. Mean peak plasma SCH-39304 concentrations on day 16 were 7.6 micrograms/ml at 4.3 h (50 mg) and 17.2 micrograms/ml at 3.2 h (200 mg) after drug administration. Mean elimination half-lives on day 16 for the 50- and 200-mg daily dosages were 100 and 89 h, respectively. SCH-39304 was cleared primarily unchanged in the urine. Mean areas under the plasma concentration-versus-time curve (from 0 to 24 h) on day 16 reflect a lower than expected increase with the 200-mg/day regimen (314.5 microgram.h/ml) compared with that for the 50-mg/day regimen (139.9 microgram.h/ml), suggesting the potential for reduced bioavailability at higher dosages. No significant effect of concurrent zidovudine therapy on the kinetics of SCH-39304 was observed.

Administration, Oral↗
PubMed1992

Aminoglycosides, imipenem, and aztreonam.

The aminoglycosides continue to be the cornerstone of antibiotic therapy for serious infections caused by gram-negative aerobic pathogens, even with the recent introduction of potent beta-lactams and the fluoroquinolones. Two of these newer agents are imipenem and aztreonam. Imipenem is the most expensive commercially available antibiotic, but it has the broadest range of activity, including most gram-negative and gram-positive, aerobic and anaerobic bacteria. Aztreonam, the first monobactam antibiotic to be released, has excellent activity against aerobic, gram-negative bacteria. It is not, however, simply a nonnephrotoxic replacement for aminoglycoside therapy. This article reviews the basic pharmacology and clinical utility of the aminoglycosides, imipenem, and aztreonam.

Aminoglycosides↗
PubMed1991

High-dose itraconazole in the treatment of severe mycoses.

Eight patients with systemic mycoses and with prior treatment failures were treated with itraconazole (600 mg/day) for a mean duration of 5.5 months. All six patients without AIDS experienced improvement or stabilization of their fungal infections while receiving high-dose itraconazole, although two patients later experienced treatment failures, one by relapse and one by progression, on lower doses. Treatment failures also occurred in the two patients with AIDS and cryptococcal meningitis. The failures were associated with low serum itraconazole concentrations (less than 2.5 micrograms/ml) in both patients. All other patients had mean trough levels in serum above 5 micrograms/ml. One patient who was improving on 600 mg/day developed a progressive infection after reduction of the dose to 400 mg/day. Side effects included reversible adrenal insufficiency in one patient; severe hypokalemia, mild diastolic hypertension, and rhabdomyolysis in one patient; mild hypokalemia and hypertension in four other patients; and breast tenderness in one patient. The mean decrease in serum potassium during treatment was statistically significant (P = 0.05). Selected patients with severe systemic mycoses may benefit from prolonged high-dose itraconazole treatment. However, 600 mg/day may be approaching the upper limits of acceptable dosing for long-term treatment.

Acquired Immunodeficiency Syndrome↗
PubMed1990

The use of vasopressin in the treatment of upper gastrointestinal haemorrhage.

Vasopressin is a potent vasoconstrictor which greatly reduces mesenteric blood flow. In patients with portal hypertension this results in decreased portal venous flow and portal pressure. Because of this property, vasopressin has been used for years in the therapy of variceal haemorrhage. A few controlled trials show that vasopressin causes a decrease in bleeding but has no effect on survival. It has been shown that intravenous vasopressin is just as effective as intra-arterial, and is associated with fewer complications. The inability to influence the outcome of variceal haemorrhage significantly may be related to suboptimal dosing due to the occurrence of systemic complications at higher doses. The combination of vasopressin with either sodium nitroprusside or nitroglycerin (glyceryl trinitrate) has resulted in a further decline of portal pressure, along with amelioration of most of the adverse haemodynamic effects of vasopressin. Whether or not clinical efficacy is increased when vasopressin is combined with sodium nitroprusside or nitroglycerin remains to be proven. Analogues of vasopressin, such as terlipressin, held early promise as agents which would be as effective as vasopressin, without the cardiac adverse effects. Recent data have not supported this and at present there is little to suggest any advantage of terlipressin over vasopressin. Virtually no adequate studies have yet been performed to support the use of vasopressin in the treatment of non-variceal haemorrhages. There is reason to suspect that vasopressin can effectively control bleeding from haemorrhagic gastritis, but the subsequent results of inducing gastric ischaemia in an already damaged gastric mucosa are unknown. In summary, vasopressin appears to have little effect on the mortality of patients with variceal haemorrhage. It may, however, help control the haemorrhage in some patients by lowering the portal pressure. Cardiovascular complications limit the dose that can be used but it is hoped that by combining vasopressin with nitroglycerin, a more effective and safe therapy will be available for variceal haemorrhages.

Gastrointestinal Hemorrhage↗
PubMed1989

A prospective double-blind trial of intracorporeal papaverine versus prostaglandin E1 in the treatment of impotence.

A randomized prospective, double-blind clinical trial was performed comparing intracorporeal injections of papaverine (30 mg. per ml.) with prostaglandin E1 (10 mcg. per ml.) as pharmacological treatment of impotence. A total of 15 men completed the study, receiving papaverine and prostaglandin E1 in a crossover design. Over-all, 9 of 15 evaluable patients had a full erection with either 1 or both drugs: 3 secondary to papaverine only, 2 to prostaglandin E1 only, and 4 to both drugs. No major complications were observed. We conclude that intracorporeal prostaglandin E1 may be used successfully to stimulate pharmacological erections and that it might be useful in patients not responding to intracorporeal papaverine.

Adult↗
PubMed1988

Pharmacokinetics of itraconazole following oral administration to normal volunteers.

The pharmacokinetics of itraconazole, an orally effective, broad-spectrum, systemic antifungal agent, were evaluated in five healthy male volunteers. Each subject was studied on days 1 and 15 at the following dosages: 100 mg once daily (regimen A), 200 mg once daily (regimen B), and 200 mg twice daily (regimen C). On each study day, itraconazole was administered with a standardized meal. Plasma samples were collected for 72 h postdose, and 24-h urine specimens were obtained. On day 1 of regimen C, plasma samples were collected following the second dose. Samples were assayed for itraconazole by a sensitive, reverse-phase, high-performance liquid chromatography method. Wide intersubject variations in itraconazole concentration in plasma versus time profiles were observed on all study days. Absorption appeared to be slow, with day 1 mean peak itraconazole concentrations in plasma of 110 ng/ml at 2.8 h (regimen A), 272 ng/ml at 3.0 h (regimen B), and 553 ng/ml at 3.4 h (regimen C). Mean peak itraconazole concentrations in plasma on day 15 were 412 ng/ml at 3.0 h (regimen A), 1,070 ng/ml at 4.4 h (regimen B), and 1,980 ng/ml at 6.0 h (regimen C). The steady state was achieved by day 13. Respective elimination half-lives on days 1 and 15 were 15 and 34 h (regimen A), 20.7, and 36.5 h (regimen B), and 25 and 41.7 h (regimen C), respectively. The areas under the plasma concentration versus time curves (0 to infinity) on day 1 were 1,320 (regimen A), 4,160 (regimen B), and 12,600 ng.h/ml (regimen C). With the exception of one patient on day 15 of regimen C, itraconazole was not detected in the urine. All data support dose-dependent pharmacokinetic behavior for itraconazole.

Administration, Oral↗
PubMed1986

Rapid replacement of serum albumin in patients receiving total parenteral nutrition.

The albumin deficit (AD) of 13 malnourished patients with serum albumin concentrations (SAC) of less than 3.0 grams per deciliter was estimated using a simple equation. The AD was replaced over a period of 24 to 72 hours as a component of the formulation of total parenteral nutrition (TPN). AD was estimated assuming a volume of distribution of 3 deciliters per kilogram of actual body weight and a minimum acceptable SAC of 3.5 grams per deciliter. The mean AD was 200 +/- 94 grams (mean +/- standard deviation), the average dose administered was 206 +/- 97 grams. TPN regimens provided 42.0 +/- 8.5 nonprotein kilocalories per kilogram with a nonprotein calorie to nitrogen ratio of 125 to 150:1. The SAC increased from 2.36 +/- 0.38 grams per deciliter to 3.46 +/- 0.26 grams per deciliter immediately after replacement. At follow-up study, the SAC at 6.4 +/- 1.5 days yielded a SAC value of 3.35 +/- 0.30 grams per deciliter, indicating no significant decrease from immediate replacement values. AD can be easily estimated, rapidly replaced and maintained with adequate nutritional support.

Adult↗