3,4-Diaminopyridine and pyridostigmine are widely used to treat Lambert-Eaton myasthenic syndrome (LEMS), either alone or in combination. 3,4-Diaminopyridine enhances the release of acetylcholine at the neuromuscular synapse, and pyridostigmine inhibits the degradation of this neurotransmitter. Although this could lead to a synergistic effect on neuromuscular transmission, no studies have compared the effects of these drugs in patients with LEMS. Therefore, we performed a placebo-controlled, double-dummy, double-blind, randomized, crossover study in nine patients with LEMS.

The ability to rapidly identify active compounds in a complex mixture (e.g., natural products extract) is still one of the major problems in natural products screening programs. An elegant way to overcome this problem is to separate the complex mixture by gradient liquid chromatography followed by online biochemical detection parallel with chemical characterization, referred to as high-resolution screening (HRS). To find and identify phosphodiesterase (PDE) inhibitors in natural products extracts using the HRS technology, the authors developed a continuous-flow PDE enzymatic assay. The suitability of the continuous-flow PDE enzymatic assay for natural products screening was demonstrated. After optimization of the continuousflow PDE assay, the limit of detection for 3-isobutyl-1-methyl-xanthine (IBMX) was 1 µM, with a dynamic range from 1 to 100 µM IBMX. The applicability of the HRS technology for the detection of PDE inhibitors in natural products extracts was demonstrated by the analysis of a plant extract spiked with 2 naturally occurring PDE inhibitors. The plant extract was analyzed with 2 assay lines in parallel, enabling background fluorescence correction of the sample. The simultaneous quantification of the active compounds using evaporative light-scattering detection allowed the estimation of the IC 50 value of the active compounds directly in the crude extract. (Journal of Biomolecular Screening 2003:421-429)

The schedule in dosing of intravesical chemotherapy has thus far received little attention. Correlation of optimal contact time with bladder toxicity, as well as maximal chemotherapeutic effect for one of the drugs of first choice for intravesical instillation, i.e. mitomycin C (MMC), is a particularly important question. In a randomized study, we treated bladder cancer patients with intravesical MMC using 30-min and 60-min dwelling times. There were 28 evaluable patients in each of the 2 groups. The groups were comparable with respect to mean age, sex ratio and distribution of primary or recurrent and single or multiple tumors. Stages and grades of tumors were also comparable over both treatment groups. Pharmacokinetics of MMC and degradation/metabolism were monitored during the first 4 cycles and the last (8th) cycle using HPLC and mass spectrometry. Recurrence was significantly lower in the 60-min treatment group (35.7% vs. 14.3%, chi 2 test; 0.01 less than p less than 0.05). No recurrences were found in patients with Ta and T1 tumors when the 60-min dwelling time was used. Toxicity was mild and transient; the incidence was, surprisingly, lower in the 60-min group but the difference failed to reach the level of significance. Pharmacokinetics of systemic MMC and recovery in the urine was comparable over both groups and systemic absorption was calculated to be in the range of 1-5%.

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Cyclophosphamide was administered to 12 breast cancer patients in combination with methotrexate and fluorouracil. Doses prescribed were cyclophosphamide 75 mg/m2, methotrexate 30 mg/m2 and fluorouracil 500 mg/m2 (per square meter body surface). Cyclophosphamide was administered intravenously and orally in aqueous solutions and in tablets in a randomized cross-over trial. Methotrexate and fluorouracil were administered intravenously, methotrexate was given first and then fluorouracil. Assays of cyclophosphamide in blood plasma were performed by capillary gas chromatography. Data of mean bioavailability of cyclophosphamide administered by tablets were suggestive of sufficient absorption. In 2 patients, however, a lower bioavailability of cyclophosphamide was demonstrated. Intra-individual differences in the terminal slope of the plasma decay curves after intravenous and oral administration in some patients decreased the calculated bioavailability of cyclophosphamide, if these values were included in the calculation of cyclophosphamide bioavailability. Compared with the administration of the solutions peak times, lag-times and mean absorption times of cyclophosphamide given in tablets were markedly prolonged. It is concluded that interactions between cyclophosphamide and methotrexate and/or fluorouracil after oral dosing as tablets are different from interactions observed after intravenous administration of cyclosphosphamide.