Biomedical subjects

M Bauer

Publications and source records attributed to M Bauer.

At least 73 records · Page 4Linked to original sources

PubMed1998

[Anesthesia and perioperative immune function].

Innate and acquired immunity plays a pivotal role in the host defense response. Pain, stress, necrotic tissue and invading microorganisms are known modulators of the complex immune response of patients undergoing major surgery. Anaesthesia itself or perioperative interventions of the anaesthesiologist may substantially alter the immune function with potential impact on the postoperative course. For instance, transfusion of allogenic blood and administration of dopamine or metoclopramide may interfere with immunity. Stress and pain are associated with immune tolerance, increased susceptibility to infection and tumor spreading in animal models. Thus, anaesthesia may--through modulation of the neurohumoral stress response--indirectly affect immunity of the surgical patient. In particular epidural anaesthesia and/or administration of epidural or spinal opioids seem to attenuate the stress response with beneficial effects on cellular and humoral immunity. In addition, anaesthetics, such as etomidate, propofol, or thiopentone and opioid analgesics may directly affect function of immune competent cells. However, these actions may only be apparent with high or supraclinical concentrations and/or long-term exposure. Regarding the latter, evidence suggests that long-term sedation using thiopentone in neurosurgical patients is paralleled by infectious complications in a dose-dependent manner. At present, no data are available regarding the significance of the observed alterations associated with various anaesthetic procedures of the incidence of postoperative complications associated with impaired immunity, such as infection or metastatic spreading in oncological surgery.

Anesthesia↗

PubMed1998

[The effect of gamma-hydroxybutyrate (GHB) on proinflammatory cytokine gene expression in coronary surgical procedures].

OBJECTIVE: To determine the influence of gamma-hydroxy-butyrate (GHB) on spontaneous and lipopolysaccharide (LPS)-stimulated release of tumour necrosis factor-alpha (TNF), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and interleukin-10 (IL-10) in whole blood from patients undergoing coronary artery bypass grafting (CABG) with extracorporeal circulation (ECC). In addition, the pharmacological modulation on lipopolysaccharide (LPS)-stimulated cytokine release by GHB (GHB-Na and GHB-ethanolamide) was characterized in a separate in vitro-assay. METHODS: In a prospective, randomized, double-blinded study, 12 patients undergoing elective CABG were assigned to receive either saline (control) or GHB-Na (25 mg/kg as loading dose followed by 25 mg/kg/h) intraoperatively. Blood samples were obtained (A) preoperatively, (B) 20 min after ECC and (C) 24 h after ECC. Plasma levels (spontaneous release) as well as LPS-stimulated cytokine secretion were measured in a whole blood culture system ex vivo and correlated with mRNA-expression in peripheral blood mononuclear cells (PBMC). In addition, the dose-response characteristics of modulation of the cytokine response by GHB was studied in vitro in the same assay. RESULTS: Plasma IL-6 and IL-10 levels were significantly elevated after CABG, while TNF and IL-1 beta were detectable only occasionally in both groups. Expression of all cytokines studied was significantly reduced upon ex vivo LPS-stimulation at time point B. Despite maintained expression of TNF and IL-1 beta mRNA-transcripts upon ex vivo LPS-stimulation in patients treated with GHB, release of the cytokines in the supernatant was decreased to a similar degree as in the control group. Cytokine response upon LPS-stimulation was restored 24 h after CABG for the group mean, however, with substantial individual heterogeneity. In vitro, pharmacological doses of GHB-Na (2 mg/ml) attenuated LPS-induced IL-1 beta release. However, application of the GHB-receptor antagonist NCS-382 caused a nearly complete cessation of IL-1 beta release in vitro (to 2.5% of control). GHB-ethanolamide (LK 544) did not influence the LPS-stimulated release of the cytokines studied. CONCLUSION: The results suggest a biphasic response of stimulated PBMC cytokine gene expression during CABG with an initial tolerance to LPS-stimulation shortly after termination of ECC. However, whether or not PBMC express functional GHB receptors remains unclear in light of contradictory effects of the different ligands. In spite of the ex vivo and in vitro results, application of GHB-Na in doses which are primarily based on its use as an anesthetic agent do not seem to modulate the release of the cytokines studied.

Adult↗

PubMed1998

[Thyroid gland function in lithium treatment].

Lithium is widely used in the acute and prophylactic treatment of affective disorders. Lithium affects thyroid hormone metabolism via different mechanisms. In patients this leads to a compensatory increase in pituitary thyroid stimulating hormone (TSH) which usually maintains the euthyroid status. This is probably the reason for the relatively high prevalence of goitre in lithium-treated patients; however, the enlargement of the gland is only moderate in most cases. Due to its immunostimulating effects lithium may support the appearance of thyroid auto-antibodies and the development of thyroiditis, which may be the reason for a higher prevalence of hypothyroidism in patients receiving lithium. However, also cases of hyperthyroidism in such patients have been reported repeatedly. Therapeutic recommendations for the treatment of disturbances of thyroid function during lithium treatment are given.

Affective Disorders, Psychotic↗

PubMed1998

[High dosage thyroxine treatment in therapy and prevention refractory patients with affective psychoses].

The following review summarizes current knowledge on the treatment of therapy-resistant patients with affective disorders with supraphysiological doses of thyroxine (T4). Several groups have reported independently of each other that administration of 200-500 micrograms T4/day has excellent effects in 50-65% of patients a) with bipolar disorder, with or without, "rapid cycling" course, who were previously resistant to all prophylactic drugs and b) in the treatment of therapy-resistant depression. T4 is effective only in combination with an antidepressant or a prophylactic drug. Side effects are minimal, even when T4 is administered over several years. These results now justify to recommend high dose T4-augmentation as "last-resort" treatment also beyond research purposes, i.e. in psychiatric wards and in private practice. Recommendations for clinical applications are given and hypotheses on possible mechanisms underlying the efficacy of T4 treatment are discussed.

Bipolar Disorder↗

PubMed1998

Statistical pattern detection in univariate time series of intensive care on-line monitoring data.

OBJECTIVES: To determine how different mathematical time series approaches can be implemented for the detection of qualitative patterns in physiologic monitoring data, and which of these approaches could be suitable as a basis for future bedside time series analysis. DESIGN: Off-line time series analysis. SETTING: Surgical intensive care unit of a teaching hospital. PATIENTS: 19 patients requiring hemodynamic monitoring with a pulmonary artery catheter. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Hemodynamic data were acquired in 1-min intervals from a clinical information system and exported into statistical software for further analysis. Altogether, 134 time series for heart rate, mean arterial pressure, and mean pulmonary artery pressure were visually classified by a senior intensivist into five patterns: no change, outlier, temporary level change, permanent level change, and trend. The same series were analyzed with low-order autoregressive (AR) models and with phase space (PS) models. The resulting classifications from both models were compared to the initial classification. Outliers and level changes were detected in most instances with both methods. Trend detection could only be done indirectly. Both methods were more sensitive to pattern changes than they were clinically relevant. Especially with outlier detection, 95% confidence intervals were too close. AR models require direct user interaction, whereas PS models offer opportunities for fully automated time series analysis in this context. CONCLUSION: Statistical patterns in univariate intensive care time series can reliably be detected with AR models and with PS models. For most bedside problems both methods are too sensitive. AR models are highly interactive, and both methods require that users have an explicit knowledge of statistics. While AR models and PS models can be extremely useful in the scientific off-line analysis, routine bedside clinical use cannot yet be recommended.

Aged↗

PubMed1998

Acute pancreatitis due to pyritinol: an immune-mediated phenomenon.

A 23-year-old man experiencing three episodes of acute pancreatitis of undetermined etiology is described. Repeated questioning revealed that all three events had occurred after intake of the drug pyritinol. Controlled rechallenge with a single dose of the drug led to a fourth episode of acute pancreatitis. Skin testing was negative, but lymphocyte stimulation tests and double fluorescence analysis detected pyritinol-activated CD4 and CD8 lymphocytes. Together with the clinical observation that the intervals between drug intake and start of symptoms of acute pancreatitis became shorter with repeated exposure, the data are consistent with an immune-mediated origin of the pancreatitis. Pyritinol has to be added to the list of drugs capable of inducing acute pancreatitis.

Acute Disease↗

PubMed1998

Differential regulation of hepatic arterial and portal venous vascular resistance by nitric oxide and carbon monoxide in rats.

Nitric oxide (NO), a gaseous mediator that accounts for the biological activity of endothelium-derived relaxing factor, has been shown to play an important role in the reduction of basal vascular tone in multiple vascular beds, including the hepatic circulation. On the other hand, recent studies have provided first evidence that endogenously generated carbon monoxide (CO) may exert vasodilatory effects in the hepatic portal vein and within sinusoids. Thus, we defined the differential role of NO and CO in the regulation of vascular resistance in the two inflows to the liver in the normal rat in vivo. Male Sprague-Dawley rats were anesthetized with pentobarbital sodium and surgically instrumented in order to study the change in hepatic arterial (Rha) and portal venous vascular resistance (Rpv) in response to intravenous bolus administration of either the NO-synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) (1 mg/kg; n = 7 animals) or of tin protoporphyrin-IX (SnPP-IX) (50 micromol/kg), a specific inhibitor of the CO-generating enzyme heme oxygenase (n = 8 animals). While L-NAME caused a substantial increase in Rha, Rpv increased only slightly under these conditions. In sharp contrast, SnPP-IX did not affect Rha, but caused a profound increase in Rpv. In conclusion, Rha and Rpv are differentially regulated by NO and CO in the normal rat liver in vivo, i.e., NO serves as a potent vasodilator in the hepatic arterial circulation, but exerts only a minor vasodilatory effect in the portal venous vascular bed. In contrast, while there is no intrinsic CO-mediated vasodilation in the hepatic artery, CO acts to maintain portal venous vascular tone in a relaxed state.

Animals↗

PubMed1998

Reproducibility of 1H-NMR integrals: a collaborative study.

The quantitative use of NMR spectroscopy was investigated by a reproducibility study of 1H-NMR integrals involving five laboratories. A significant laboratory effect was found confirming the difficulty to obtain very precise data by integration of complex signals. The reproducibility of any NMR assay measurement, which requires a high precision should be validated by an interlaboratory study.

Evaluation Studies as Topic↗

PubMed1998

An evaluation of fit factors and dissolution efficiency for the comparison of in vitro dissolution profiles.

Dissolution efficiency (D.E.), the area under a dissolution curve between defined time points, and the fit factors (f1 and f2) have been compared for the characterisation of dissolution profiles, using data from three batches of a product in nine different packs stored under two conditions. The factors f1 and f2 offer ease of calculation and a simple measure of similarity between pairs of dissolution profiles. This is well suited to the qualitative determination of 'similarity' as required by the FDA's SUPAC Guide. However, they do not provide information on individual batches, including their consistency. In contrast, D.E. does provide such information is well-suited to making quantitative comparisons amongst batches. Because D.E. has a simple physical meaning, it is easier to interpret D.E. data then corresponding f1 and f2 results. The confidence limits in D.E. values provide a useful measure of the variability in batch dissolution and allow the statistical significance of difference in D.E. between pairs of batches to be determined. Both of the above measures lead to the same conclusions regarding the similarity in protective power amongst the nine packs under test and to the value of added desiccant in maintaining the dissolution profile of the product when stored under high humidity conditions. It is concluded that D.E. offers a suitable alternative to the single point dissolution measurement for QC of immediate release products.

Models, Chemical↗

PubMed1998

Treatment of refractory depression with high-dose thyroxine.

In an open clinical trial we investigated whether addition of supraphysiological doses of thyroxine (T4) to conventional antidepressant drugs has an antidepressant effect in therapy-resistant depressed patients. Seventeen severely ill, therapy-resistant, euthyroid patients with major depression (12 bipolar, five unipolar) were studied. The patients had been depressed for a mean of 11.5 +/- 13.8 months, despite treatment with antidepressants and, in most cases, augmentation with lithium, carbamazepine, and neuroleptics. Thyroxine was added to their antidepressant medication, and the doses were increased to a mean of 482 +/- 72 micrograms/day. The patients' scores on the Hamilton rating Scale for Depression (HRSD) declined from 26.6 +/- 4.7 prior to the addition of T4 to 11.6 +/- 6.8 at the end of week 8. Eight patients fulfilled the criteria for full remission (a 50% reduction in HRSD score and a final score of < or = 9) within 8 weeks and two others fully remitted within 12 weeks. Seven patients did not remit. The 10 remitted patients were maintained on high-dose T4 and followed up for a mean of 27.2 +/- 22.0 months. Seven of these 10 remitted patients had an excellent outcome, two had milder and shorter episodes during T4 augmentation treatment, and one failed to profit from T4 treatment during the follow-up period. Side effects were surprisingly mild, and no complications were observed at all. In conclusion, augmentation of conventional antidepressants with high-dose T4 proved to have excellent antidepressant effects in approximately 50% of severely therapy-resistant depressed patients.

Aged↗

PubMed1998

Purity as an issue in pharmaceutical research and development.

In the third EUFEPS Nuremberg Conference, three important aspects in the purity area were extensively covered. The first one dealt with the setting up of practical strategies to establish specifications during the complete R&D process. An industrial strategy on how this goal could be reached was presented. A safety evaluation aspect reflecting the discussion between ten pharmaceutical companies was given and the regulatory point of view was presented. The second one focused on the physical aspect of the purity issue (polymorphism, crystallinity...). The scientific background of this problem was presented and the necessity to cover this problem during the early phases of an industrial R&D project was outlined. Regulatory aspects were covered and the necessity to perform in certain cases bioequivalence studies was pointed out. The last session raised the particularity of biotechnological products. The contributors stressed that the impurity limits should be based on safety evaluation as well as the necessity to review carefully the production methods. Finally, a review was done on the current progress of the ICH guidelines establishment.

Biotechnology↗

PubMed1998

Successful surgical treatment of a giant aneurysm of the right coronary artery.

We describe the case of a 46-year-old female patient, who was referred to us under the suspicion of an acute type-A aortic dissection. After perusal of the computer tomogram and subsequent transesophageal echocardiography, we decided to operate, albeit under the assumption of the existence of a pericardial cyst. Intraoperatively a strikingly large aneurysm of the right coronary artery presented itself, which was successfully treated through resection and end-to-end anastomosis.

Anastomosis, Surgical↗

PubMed1998

[Economic aspects of anesthesia. I. Health care reform in the German Republic].

Implications for Hospitals and Departments of Anaesthesiology. This article outlines the new German health care laws and their impact on the statutory health care system, hospitals and anaesthesia departments. The German health care system provides coverage for all citizens, although financial support from the public sector is on the downgrade. Hence, pressure to reduce public sector health care spending is likely to continue in the near future. Hospital costs account for one-third of total health care spending in Germany, and hospitals are facing increasing economic constraints: the volume and the charges for specific medical treatments are negotiated between the hospitals and the insurance agencies (or sickness funds) in advance. Only part of hospital care is still reimbursed on the basis of a per diem rate, and an increasing number of services are based on fixed payments per case or treatment. Reducing the costs for this treatment is therefore of utmost importance for hospitals and hospital departments. The prospective payment system and the pressure to contain costs demand a controlling system that allows for cost accounting per case. However, an economic evaluation must include comparative analysis of alternative therapeutic options in terms of both costs and outcome. Economic aspects challenge the traditional relationship between physicians and patients: doctors are still the advocates of their patients, but also act as agents for their institutions. Nevertheless, not only economic issues, but also ethical priorities and the value of an anaesthetic practice must be considered in the era of cost containment. Anaesthetists must be actively involved in providing high-quality care with its obvious benefits for the patient and be able to resist efforts to cut out expensive treatment modalities regardless of their benefits.

Anesthesia↗

PubMed1998

[Lithium in the treatment of acute depression].

In contrast to its widespread use in the prophylaxis of affective illness and in the acute treatment of mania lithium has not well been established in the treatment of acute depressive disorders. However, recent results from placebo controlled trials on lithium augmentation have shown its efficacy in the treatment of depressive disorders. Three different modes of application of lithium have been investigated since the 1960s and are reviewed in this article: 1. Although not a first line antidepressant lithium can be applied in monotherapy in the treatment of mild depressive episodes particularly in bipolar patients. 2. The successful additional use of lithium in patients not responding to conventional antidepressive treatment (lithium augmentation) has repeatedly been shown in controlled clinical trials since the 1980s. Therefore, lithium augmentation therapy has been established as treatment option of first choice in refractory depression. 3. Up to now there is little data concerning the initial combination of lithium with a conventional antidepressive drug: this indication of lithium seems to be useful in the treatment of depressive episodes in bipolar patients with a history of switching into mania during administration of tricyclics and leading to faster symptom relief.

Acute Disease↗

PubMed1998

Comparison of the mutagenic potency of 1,3-butadiene at the hprt locus of T-lymphocytes following inhalation exposure of female B6C3F1 mice and F344 rats.

1,3-Butadiene (BD) is an indirect alkylating agent that has greater cancer potency in the mouse than in the rat. The purpose of the present study was to compare the mutagenic potency of BD at the hprt locus of T-lymphocytes of exposed mice and rats and to determine whether mutations induced in this marker gene can be used as a quantitative indicator for species differences in susceptibility to cancer. To this end, experiments were conducted to define the effects of exposure duration and the time elapsed after exposures on the frequency of hprt mutations (Mf) in T-cells from female B6C3F1 mice and F344 rats of similar age (4-5 weeks) when exposed to BD by inhalation. The accumulation of hprt mutations in T-cells from thymus was assessed in animals necropsied 2 weeks after exposure to 0 or 1250 ppm BD for 1 or 2 weeks, while the time course for the appearance of hprt mutant T-cells (i.e., the phenotypic expression and cell migration) in thymus and spleen was evaluated in animals necropsied at weekly/biweekly intervals up to 10 weeks after exposure for 2 weeks. At necropsy, T-cells were isolated from thymus and spleen and cultured in the presence of IL-2, concanavalin A, and 6-thioguanine (Walker and Skopek, Mutat. Res., 288, 151-162, 1993). BD exposures of 1 and 2 weeks led to mutagenic effects in mouse thymus, with the average Mfs being 3- and 5-fold greater than background values, respectively. In rat thymus, there was only a 1.7-fold increase in Mfs after 2 weeks of BD exposure. In the mutant expression experiment, hprt Mfs in thymus and spleen of both species increased for several weeks post-exposure and then declined. Hprt Mfs in thymus reached maximum levels at 2 weeks post-exposure in mice (Mfs = 11.3 +/- 2.4 x 10(-6)) and at 3 weeks post-exposure in rats (4.9 +/- 1.2 x 10(-6)), while hprt Mfs in spleen reached peak levels at 5 weeks post-exposure in mice (19.7 +/- 1.9 x 10(-6)) and 4 weeks post-exposure in rats (10.1 +/- 1.8 x 10(-6)). Background Mfs for mouse and rat thymus and spleen ranged from 1.6 +/- 0.3 x 10(-6) to 3.0 +/- 1.1 x 10(-6). Statistical analyses of the hprt Mf data for spleen demonstrated that, under these exposure conditions, the mutagenic potency of BD (represented by the difference in the areas under the phenotypic expression curves of treated versus control animals) was 5-fold greater in mice than in rats. The magnitude of the species differences in mutagenic potency, observed after 2 weeks of BD exposure, resembles the species differences in metabolism more closely than the species differences in cancer potency.

Animals↗

PubMed1998

Effect of intravenous anesthetics on spontaneous and endotoxin-stimulated cytokine response in cultured human whole blood.

BACKGROUND: Various anesthetics have been suggested to interfere with the immune system. The ability of leukocytes to express surface receptors and mediators is fundamental to a successful host defense. Therefore, the effects of intravenous anesthetics on cytokine release by leukocytes and expression of surface molecules known to modulate this response were determined. METHODS: Concentration-dependent effects of thiopentone, etomidate, propofol, ketamine, midazolam, and fentanyl on spontaneous and endotoxin (lipopolysaccharide; 1 microg/ml)-stimulated cytokine release were studied in whole blood from volunteers (n = 6) cultured for 25 h. In addition, expression of the lipopolysaccharide-recognition molecule CD14 and the major histocompatibility complex class II molecule human leukocyte locus A system-DR (HLA-DR) on monocytes were assessed using flow cytometry. RESULTS: All anesthetics studied elicited only minor effects on spontaneous cytokine release even at pharmacologic concentrations. However, expression density of CD14 was reduced in the presence of thiopentone, etomidate, and propofol, whereas HLA-DR was unaffected. Lipopolysaccharide-stimulated tumor necrosis factor response was inhibited by thiopentone (12.8% [median]; 7.6-18.8 [25-75 percentile]) of control, and ketamine (46.4% [median]; 44.4-56.4 [25-75 percentile]), at pharmacologic concentrations, whereas it was augmented even in the presence of low concentrations of propofol (172.3% [median]; 120.5-200.7 [25-75 percentile]). Ketamine additionally decreased the concentration of interleukin (IL)-1beta (14.8% [median]; 12.0-18.0 [25-75 percentile]). Release of IL-1 receptor antagonist (IL-1ra) was inhibited by thiopentone, etomidate, and propofol, whereas the same anesthetics increased IL-10 concentration simultaneously. Midazolam and fentanyl did not alter the concentrations of any cytokine. CONCLUSIONS: These results suggest a complex modulation of the cytokine response by the studied anesthetics in cultured whole blood. Although effects on spontaneous cytokine release by leukocytes were negligible, some anesthetics affected their ability to respond to lipopolysaccharide.

Anesthetics, Intravenous↗

PubMed1998

Proinflammatory cytokine gene expression in whole blood from patients undergoing coronary artery bypass surgery and its modulation by pentoxifylline.

The influence of coronary artery bypass grafting (CABG) on spontaneous and lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10 as well as its modulation by pentoxifylline (PTF) were studied in a prospective, randomized, double-blinded study. 12 patients undergoing elective CABG were randomly assigned to receive either saline or PTF (1 mg/kg as a loading dose followed by 1 mg/kg/h) intraoperatively. Blood samples were obtained (A) preoperatively, (B) 20 min after CABG, and (C) 24 h after CABG. Cytokine plasma levels as well as LPS-stimulated cytokine secretion were measured in a whole blood culture system ex vivo and correlated with mRNA expression in peripheral blood mononuclear cells. In addition, the dose-response characteristics of modulation of the cytokine response by PTF were studied in cultured whole blood in vitro. Plasma IL-6 and IL-10-levels were significantly elevated after CABG, whereas neither TNF-alpha nor IL-1beta were detectable. In contrast to the spontaneous release of IL-6 and IL-10, the expression of all cytokines studied was significantly reduced upon ex vivo LPS stimulation early after CABG. Proinflammatory cytokine response upon LPS stimulation was restored 24 h after CABG for the group mean, however, with substantial interindividual heterogeneity. Therapeutic doses of PTF in vitro attenuated LPS-induced TNF-alpha (-50.5%) and most notably IL-10 (-83.9%) release, whereas IL-1beta was even increased (+45.7%). However, application of PTF during CABG neither inhibited the spontaneous production of IL-10 nor modulated cytokine production ex vivo. These results suggest a biphasic response of stimulated peripheral blood mononuclear cell cytokine gene expression during CABG with an initial tolerance to LPS stimulation. The application of PTF during CABG in doses that are primarily based on its use in occlusive arterial disease do not seem to modulate the release of the cytokines studied.

Adult↗

PubMed1998

Amphotericin B colloidal dispersion combined with flucytosine with or without fluconazole for treatment of murine cryptococcal meningitis.

Studies with animals and in vitro studies have demonstrated that flucytosine plus amphotericin B or fluconazole has significantly improved mycologic activity against meningitis caused by Cryptococcus neoformans compared to the activity of amphotericin B or fluconazole used alone. However, few doses have been tested in combination. This study evaluated the antifungal efficacy of amphotericin B colloidal dispersion (ABCD) combined with flucytosine with and without fluconazole in a murine model of cryptococcal meningitis. The following dosages were tested: ABCD at 0 to 12.5 mg/kg of body weight given intravenously 3 days/week, flucytosine at 0 to 110 mg/kg/day, and fluconazole at 0 to 50 mg/kg/day. Meningitis was established in male BALB/c mice by intracerebral injection of C. neoformans. Treatment with flucytosine with or without fluconazole dissolved in the sole source of drinking water was started on day 2; animals were sacrificed at 16 days, and the numbers of fungal colonies in the brain were quantified. A survival rate of 100% was achieved with ABCD plus flucytosine without fluconazole; however, the addition of fluconazole was required to prevent weight loss (P < 0.00001) and to achieve the maximum antifungal effect (P < 0.00001). The only region of dose combinations for which the 99% confidence intervals were less than 100 CFU/g of brain was defined by ABCD at 5.0 to 7.5 mg/kg combined with flucytosine at 20 to 60 mg/kg/day and fluconazole at 30 to 40 mg/kg/day. The triple combination of ABCD plus flucytosine and fluconazole was necessary to achieve the greatest antifungal activity.

Amphotericin B↗