No abstract

Background-Antiretroviral drugs (ARV), specifically nucleoside analogs, are toxic to mitochondrial oxidative phosphorylation (OXPHOS). Other metabolic pathways, such as fatty acid oxidation, organic acid metabolism and amino acid metabolism, are dependent on normal OXPHOS but remain unexamined as potential points of ARV toxicity.

No abstract

Background: Measurement of porphobilinogen (PBG) is useful in the diagnosis of the acute neurologic porphyrias. Currently used colorimetric assays lack analytical and clinical sensitivity and specificity. Methods: We developed a liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS) method for the measurement of PBG in 1 mL of urine, using 5-(aminoethyl)-4-(carboxymethyl) 1H-2,4-[13C]pyrolle-3-propanoic acid ([2,4-13C]PBG; 2.75 μg) as internal standard. After solid-phase extraction, LC-MS/MS analysis was performed in the selected-reaction monitoring (SRM) mode. PBG and [2,4-13C]PBG were monitored through their own precursor and product ion settings (m/z 227 to 210 and m/z 229 to 212, respectively). The retention time of PBG and [2,4-13C]PBG was 1.0 min in a 2.3-min analysis. Results: Daily calibrations (n = 6) between 0.1 and 2.0 mg/L were linear and reproducible. Inter- and intraassay CVs were 3.2–3.5% and 2.6–3.1%, respectively, at mean concentrations of 0.24, 1.18, and 2.15 mg/L. The regression equation for the comparison between an anion-exchange column method (y) and the LC-MS/MS method (x) was: y = 0.84x + 0.74 (Sy|x = 5.8 mg/24 h; r = 0.85; n = 100). In 47 volunteers, PBG excretion was 0.02–0.42 mg/24 h, lower than reported reference intervals (up to 2.0 mg/24 h) based on colorimetric methods. In 85 samples with PBG ≤0.5 by LC-MS/MS, 8 (9.4%) had values ≥2.0 mg/24 h by the anion-exchange method (mean ± SD, 4.3 ± 1.8 mg/24 h). In 11 patients with confirmed diagnoses of acute porphyria and increased PBG by LC-MS/MS, 2 had values within the reported reference intervals by a quantitative anion-exchange method. Conclusions: The quantitative LC-MS/MS method for PBG measurement exhibits greater analytical specificity and improved clinical sensitivity and specificity than currently available methods.

Background: Treatment results in advanced colorectal cancer (CC) remain unsatis-factory and palliative, with 5-fluorouracil with or without calcium folinate being the only drug able to induce clinically acceptable response rates.Patients and Methods: A clinical phase II study is presented with an oral formulationof the phospholipid derivative miltefosine (MIL) in patients with advanced colorec-tal cancer. Patients were stratified according to pretreatment. Only non-pretreatedor pretreated patients who had received 5-fluorouracil with or without calcium folinate were accepted. MIL was given as capsule twice daily at a single dose of 50 mg for the 1st week with dose escalation to 150 mg (50 mg × 3) in the 2nd week and subsequently in case of good tolerability. Nine weeks were considered the minimal duration of treatment.Results: 54 patients were evaluable for toxicity and 44 were evaluable for response. A short-lived partial response was observed in one pretreated female patient with multiple lung lesions, a ‘no change’ status in 14 patients, including 8 nonpretreated patients (42%) and 6 pretreated patients (24%). Side effects were distinct, with loss of appetite, nausea and vomiting up to grade 4 WHO and weight loss of more than 5 kg in 3 months in a considerable number of patients. Furthermore, an increase of leukocyte and platelet counts was observed during the first 2 months of treatment. Conclusion: Oral MIL is considerably toxic and has only marginal therapeutic activity in patients with colorectal cancer.