Effect of fluconazole on fungicidal activity of flucytosine in murine cryptococcal meningitis.

Both animal and in vitro studies have demonstrated that combinations of flucytosine with amphotericin B and with fluconazole have significantly improved activity against cryptococcal meningitis compared with the activity of each drug used alone. However, very few dose levels of these agents have been tested in combination. This study evaluated the efficacy of fluconazole plus flucytosine in a murine model of cryptococcal meningitis over a broad range of dose combinations (fluconazole, 0 to 40 micrograms/g of body weight per day; flucytosine, 0 to 200 micrograms/g/day). Both drugs were dissolved in drinking water, with treatment on days 2 to 11. In this highly reproducible model, fluconazole had a dramatic effect on the fungicidal activity of flucytosine. Flucytosine at dose levels of as much as 200 micrograms/g/day alone or in combination with low doses of fluconazole had minimal fungicidal activity, whereas in combination with fluconazole at 24 to 40 micrograms/g/day, flucytosine showed fungicidal activity in the range of 45 to 65% of the animals treated at doses of 40 to 100 micrograms/g/day. This striking effect of fluconazole is consistent with the results of both in vitro and clinical studies. In the clinic, the use of flucytosine is often limited by severe toxicity, while toxicity is rarely observed with fluconazole. These results suggest that when flucytosine is given with higher doses of fluconazole, the maximum therapeutic effect of the former in the clinic may be observed at dose levels that are far less than the doses commonly employed (150 micrograms/g daily).     

Rosiglitazone improves exercise capacity in individuals with type 2 diabetes

OBJECTIVE: Although exercise is recommended as a cornerstone of treatment for type 2 diabetes, it is often poorly adopted by patients. We have noted that even in the absence of apparent cardiovascular disease, persons with type 2 diabetes have an impaired ability to carry out maximal exercise, and the impairment is correlated with insulin resistance and endothelial dysfunction. We hypothesized that administration of a thiazolidinedione (TZD) agent would improve exercise capacity in type 2 diabetes. RESEARCH DESIGN AND METHODS: Twenty participants with uncomplicated type 2 diabetes were randomly assigned in a double-blind study to receive either 4 mg/day of rosiglitazone or matching placebo after baseline measurements to assess endothelial function (brachial artery diameter by brachial ultrasound), maximal oxygen consumption (VO(2max)), oxygen uptake (VO(2)) kinetics, and insulin sensitivity by hyperinsulinemic-euglycemic clamp. Measurements were reassessed after 4 months of treatment. RESULTS: Participant groups did not differ at baseline in any measure. Rosiglitazone-treated participants (n = 10) had significantly improved VO(2max) (19.8 +/- 5.3 ml . kg(-1) . min(-1) before rosiglitazone vs. 21.2 +/- 5.1 ml . kg(-1) . min(-1) after rosiglitazone, P < 0.01), insulin sensitivity, and endothelial function. A change in VO(2max) correlated with improved insulin sensitivity measured by clamp (r = 0.68, P < 0.05) and with improved brachial artery diameter (r = 0.70, P < 0.05). Placebo-treated participants (n = 10) showed no changes in VO(2max) (19.4 +/- 5.2 ml . kg(-1) . min(-1) before rosiglitazone vs. 18.1 +/- 5.3 ml . kg(-1) . min(-1) after rosiglitazone, NS) or brachial artery diameter. CONCLUSIONS: This is the first known report showing that a TZD improved exercise function in type 2 diabetes. Whether this is due to the observed improvements in insulin sensitivity and/or endothelial function or to another action of the TZD class requires further exploration.     

Bradycardia and sinus arrest during percutaneous ethanol injection therapy for hepatocellular carcinoma

BACKGROUND: Percutaneous ethanol injection (PEI) is an established method in the treatment of hepatocellular carcinoma (HCC) and considered a safe procedure, with severe complications occurring rarely. Cardiac arrhythmias have not been reported to date. Aim of the study was to investigate the occurrence of dysrhythmias during PEI. PATIENTS AND METHODS: Twenty-six consecutive patients with inoperable HCC were included. During ultrasound-guided PEI with 95% ethanol, electrocardiogram (ECG) monitoring was performed before starting and continuously during PEI. RESULTS: During PEI a significant reduction in mean heart rate (> 20%) was seen in 15 of 26 (58%) patients. In 11 of 26 patients (42%) occurrence of sinuatrial block (SAB) or atrioventricular block (AVB) was observed after a median time of 9 s (range 4-50) from the start of PEI with a median length of 24 s (range 12-480). Clinical symptoms were seen in two patients, including episodes of unconsciousness, seizure-like symptoms in both and a respiratory arrest during PEI in one patient, requiring mechanical ventilation. In four of 12 patients with repeat interventions, dysrhythmias were reproducible during monthly performed procedures. There was a significant association between the occurrence of SAB or AVB and the amount of instilled alcohol (P = 0.03) and post-PEI serum ethanol levels (P = 0.03). CONCLUSIONS: Bradycardia and block formation occur frequently during PEI. These symptoms could be explained by a vasovagal reaction and/or the direct effect of ethanol on the sinus node or the right atrial conduction system. Ethanol dose is an important factor for the occurrence of SAB/AVB. ECG-monitoring seems mandatory during PEI. Prophylactic use of intravenously administered Atropine might be useful.     

A nonprimate animal model applicable to zidovudine pharmacokinetics in humans: inhibition of glucuronidation and renal excretion of zidovudine by probenecid in rats.

The monkey is considered the best animal model to study the pharmacokinetics of zidovudine (azidothymidine, AZT) because humans and monkeys eliminate 60 to 75% of AZT by metabolism to the 5'-O-glucuronide (GAZT), in contrast to other experimental animals, which excrete most of the drug unchanged in the urine. It has become increasingly difficult and costly to use monkeys in research. Therefore, we undertook studies to determine the suitability of the rat as an alternative animal model to study the pharmacokinetics of AZT. In the initial experiments, [3H]AZT was administered i.v. at doses of 19, 60 and 187 mumol/kg to male Sprague-Dawley rats with intact bile ducts. The respective values (mean +/- S.D.) for total clearance of AZT were 2.4 +/- 0.2, 2.3 +/- 0.3 and 1.8 +/- 0.4 l/hr/kg and for renal clearance were 1.7 +/- 0.2, 1.8 +/- 0.4 and 1.5 +/- 0.4 l/hr/kg. The renal clearance of AZT was approximately equal to renal plasma flow of rats (1.5 l/hr/kg), suggesting that in addition to filtration, AZT is also efficiently secreted in the kidney of the rat. The respective values for volume of distribution at steady state were 1.3 +/- 0.2, 1.0 +/- 0.2 and 0.84 +/- 0.19 l/kg (P less than .05) and elimination half-life were (harmonic mean) 0.55, 0.44 and 0.46 hr. Urinary excretion of AZT as unchanged drug in intact rats accounted for 70 +/- 6, 79 +/- 6, and 83 +/- 12% of the dose, whereas only 0.7 to 0.8% of the dose was recovered in the urine as GAZT. Rats with exteriorized bile ducts, the proposed alternative animal model, were given an i.v. dose of 60 mumol/kg of [3H]AZT. To test the effect of a concurrently administered drug on the elimination of AZT in the model, some rats with bile duct cannulas were pretreated with probenecid, a known inhibitor of AZT elimination in humans. Urine and bile were collected to quantify the formation of GAZT. GAZT was identified by fast atom bombardment mass spectrometry as the major metabolite of AZT in the rat. GAZT excretion in the bile and urine accounted for 11 +/- 3% of the dose in saline-treated rats, compared to only 1.4 +/- 0.3% in rats treated with probenecid (P less than .001).(ABSTRACT TRUNCATED AT 400 WORDS)     

Stimulated acoustic emission to image a late liver and spleen-specific phase of Levovist in normal volunteers and patients with and without liver disease

Quantitative studies were performed to investigate liver- specific uptake of the microbubble Levovist®, using stimulated acoustic emission (SAE), which can detect microbubbles even when stationary or slow-moving. These comprised studies of biodistribution comparing the liver and kidney in five normal volunteers, reproducibility in 34 patients, comparison between cirrhotics and controls (n = 9 each) and maximal depth of effect at different frequencies (180 measurements in 31 patients). Stimulated acoustic emission lasted beyond 30 min, with strongly liver-specific properties in each volunteer and was highly reproducible. No difference in the amount of SAE in the superficial liver was seen between cirrhotic and normal livers, but attenuation was higher in cirrhotics. This demonstrates a frequency-dependent effect on liver SAE penetration. We conclude that the liver uptake of Levovist® lasts over 30 min, is reproducible, occurs even where diffuse liver disease is present and can be used to assess tissue attenuation in a novel fashion.     

Reversal of cisplatin resistance with a BH3 mimetic, (-)-gossypol, in head and neck cancer cells: role of wild-type p53 and Bcl-xL

Organ preservation protocols in head and neck squamous cell carcinoma (HNSCC) are limited by tumors that fail to respond. We observed that larynx preservation and response to chemotherapy is significantly associated with p53 overexpression, and that most HNSCC cell lines with mutant p53 are more sensitive to cisplatin than those with wild-type p53. To investigate cisplatin resistance, we studied two HNSCC cell lines, UM-SCC-5 and UM-SCC-10B, and two resistant sublines developed by cultivation in gradually increasing concentrations of cisplatin. The cisplatin-selected cell lines, UM-SCC-5PT and UM-SCC-10BPT, are 8 and 1.5 times more resistant to cisplatin than the respective parental cell lines, respectively. The parental lines overexpress p53 and contain p53 mutations but the cisplatin-resistant cell lines do not, indicating that cells containing mutant p53 were eliminated during selection. Bcl-x(L) expression increased in the cisplatin-resistant lines relative to the parental lines, whereas Bcl-2 expression was high in the parental lines and decreased in the cisplatin-resistant lines. Thus, cisplatin selected for wild-type p53 and high Bcl-x(L) expression in these cells. We tested a small-molecule BH3 mimetic, (-)-gossypol, which binds to the BH3 domain of Bcl-2 and Bcl-x(L), for activity against the parental and cisplatin-resistant cell lines. At physiologically attainable levels, (-)-gossypol induces apoptosis in 70% to 80% of the cisplatin-resistant cells but only in 25% to 40% of the parental cells. Thus, cisplatin-resistant cells seem to depend on wild-type p53 and Bcl-x(L) for survival and BH3 mimetic agents, such as (-)-gossypol, may be useful adjuncts to overcome cisplatin resistance in HNSCC.     

A comparative study of clarithromycin modified release and amoxicillin/clavulanic acid in the treatment of acute exacerbation of chronic bronchitis

This phase III, investigator-blind, randomized, parallel-group study compared the efficacy and tolerability of clarithromycin modified release (MR) with those of amoxicillin/clavulanic acid in 250 adult outpatients with acute exacerbation of chronic bronchitis (AECB). Patients received either clarithromycin MR 500 mg once daily or amoxicillin/clavulanic acid 500 mg/125 mg three times daily for 7 days. Primary endpoints were sponsor-defined clinical response and pathogen outcome at the end of treatment. Secondary endpoints were sponsor-defined clinical response and pathogen outcome at study end, investigator-defined clinical response at end of treatment and end of study, resolution or improvement of signs and symptoms, eradication of baseline pathogens, serologic outcome for atypical pathogens, and occurrence of reinfection and superinfection. Adverse events and compliance were also evaluated. Clinical and bacteriologic outcomes with both treatments for all endpoints were statistically equivalent, as were total adverse events, although the incidences of digestive disturbances (13% vs 4%) and discontinuations due to adverse events (8 vs 2 patients; P≤.05) were significantly higher with amoxicillin/clavulanic acid. Ninety-five percent of patients receiving clarithromycin MR and 80% receiving amoxicillin/clavulanic acid were 100% compliant with medication (P≤.05). Clarithromycin MR and amoxicillin/clavulanic acid are both well tolerated and effective as therapy for AECB; however, clarithromycin produced fewer side effects and discontinuations and higher compliance rates.     

Can noncontact mapping distinguish between endo- and epicardial foci?

Objectives  Noncontact mapping has been demonstrated to facilitate RF ablation of ventricular arrhythmias, but the reproducibility in the localization of endocardial exit sites during focal ventricular tachycardia (“VT”) originating from defined myocardial layers has not been systematically studied. Furthermore, it remains unclear whether noncontact mapping can distinguish between endo- and epicardial foci. Methods  In six dogs, constant pacing was applied through octopolar needle electrodes in the left ventricle to mimic VT of subendocardial, midmyocardial (mid1; mid2) or subepicardial origin. Using noncontact mapping, the site of origin was determined for each of 50 consecutive beats of all “VTs” and the variation between respective exit sites was measured. Exit sites were reconstructed for 50 consecutive beats of each “VT” and the time span between site of origin and exit site was measured as a parameter of intramural conduction. Results  While subendocardial and midmyocardial (mid1, mid2) foci were pinpointed with a variation of ≤2 mm, a variation of 4 mm was encountered for subepicardial foci. A gradual increase in intramural conduction was evident from endocardial towards epicardial foci, with significant differences between subendocardial (4.8 ± 0.9 ms), midmyocardial (mid1 = 11.1 ± 4.6 ms; mid2 = 11.8 ± 3.5 ms) and subepicardial (16.8 ± 3.6 ms) foci (P < 0.005). Systematic differences in the morphology of virtual waveforms depending on the site of origin could not be detected. Conclusions  Except for subepicardial foci, noncontact mapping localized focal activity in the LV with high reproducibility. In contrast to morphological parameters, the determination of intramural conduction provides a fair estimate of the depth of foci and is proposed as a novel parameter to identify a subepicardial origin. Dr. Frederik Voss and Dr. Alexander Bauer contributed equally to this work.