The effects of anti-peptide antibodies against the second extracellular loop of human M2 muscarinic receptor on transmembrane potentials and currents in guinea pig single ventricular cells were analyzed using whole-cell patch clamp technique. These effects were compared with those of the muscarinic receptor agonists carbachol and acetylcholine. The antibodies shortened the action potential duration in a dose-dependent manner. By using a ramp or step rectangular pulse protocol, it was found that the antibodies increased the outward K+ current and decreased the inward basal ICa significantly. The reversal potential of both carbachol- and antibody-induced extra currents were close to -80 mV, being in proximity to the calculated Ek of -90 mV. A beta-adrenergic receptor agonist, isoprenaline, prolonged the action potential and increased the overshoot which could be inhibited by both antibody and carbachol. Isoprenaline increased inward ICa and outward Ik simultaneously. Both antibody and carbachol could significantly reduce the isoprenaline-stimulated ICa but not the isoprenaline-stimulated Ik. The antibody- or carbachol-induced outward K+ current and the depressant effects of antibody and carbachol on isoprenaline-stimulated ICa were partially antagonized by atropine. These results suggest that the anti-M2 muscarinic receptor antibodies display a stimulatory activity similar to muscarinic receptor agonist on the receptor-mediated electrophysiological events.

Acetylcholine↗

PubMedDate not supplied

Pharmacokinetics and bioavailability of sustained release and conventional formulation of acyclovir.

The pharmacokinetics and relative bioavailability of a new sustained release formulation (200mg) of acyclovir (ACV) in comparison with a 100mg reference was investigated. The studies were conducted in two-way crossover design, as single and multiple oral administration in twelve healthy volunteers. Serum samples were assayed for ACV using a high-performance liquid chromatography (HPLC) method with UV detection. The bioavailability of sustained release tablets relative to conventional tablets following single and multiple dosing was 105.9 +/- 12.0% and 95.2 +/- 8.4%, respectively. ANOVA and the two-sided t-test procedures showed significant difference in Cmax and tmax but no difference was found in AUC both in single and multiple dose studies. The results of this study indicated that the new sustained release tablets and the reference are bioequivalent.

Acyclovir↗

PubMedDate not supplied

Expression of proliferating cell nuclear antigen in premalignant lesions of the larynx.

PURPOSE: This study was performed to 1) evaluate the proliferative activity in premalignancies of the larynx by immunostaining for proliferating cell nuclear antigen (PCNA), 2) to examine the relationship between PCNA expression and histological diagnosis and 3) to evaluate clinical values of PCNA immunostaining. MATERIALS AND METHODS: The percentage of PCNA-positive nuclei (PCNA index) and their highest location (PCNA grade) were evaluated in 44 specimens of premalignant lesions, 7 premalignant lesions near carcinomas, 9 normal epithelium, and 12 early invasive carcinomas of the larynx. Follow-up was conducted. RESULTS: The mean of PCNA indices in premalignancies was significantly higher than in normal epithelium but lower than in early invasive carcinomas. PCNA index had no apparent correlation with the histological diagnosis, but in the same case, the higher degree of dysplasia showed higher PCNA index. PCNA grade showed significant correlation with the histological diagnosis. Cases with higher PCNA expression showed higher percentages of recurrence and cancerization. Premalignant lesions near carcinomas presented significantly high PCNA expression. CONCLUSIONS: The proliferative activity in premalignancies of the larynx is higher than in normal epithelium and lower than in carcinomas. It differs from case to case, but in the same case the higher degree of dysplasia possesses higher proliferative activity. Dysplasia is associated with abnormal proliferation pattern. Special attention should be paid to those with abnormal proliferation patterns as well as high proliferative activity. PCNA immunostaining is of some referential value in predicting clinical outcome and guiding to make an early diagnosis of malignancy.

Carcinoma↗

PubMedDate not supplied

Development of an integrated microanalytical system for analysis of lead in saliva and linkage to a physiologically based pharmacokinetic model describing lead saliva secretion.

There is a need to develop reliable portable analytical systems for biomonitoring lead (Pb) in noninvasively collected saliva samples. In addition, appropriate pharmacokinetic analyses are used to quantitate systemic dosimetry based on the saliva Pb concentrations. A portable microfluidics/electrochemical device was developed for the rapid analysis of Pb based on square wave anodic stripping voltammetry, in which a saliva sample flows over an electrode surface, Pb2+ is chemically reduced and accumulated, and the electric potential of the electrode scanned. The system demonstrates a good linear response over a broad Pb concentration range (1-2000 ppb). To evaluate the relationship between saliva and blood Pb, rats were treated with single oral doses ranging from 20 to 500 mg Pb/kg of body weight, and 24 hours later were administered pilocarpine, a muscarinic agonist to induce salivation. To correlate saliva levels with internal dose, blood and saliva were collected and quantitated for Pb by inductively coupled plasma-mass spectrometry (ICP-MS) and by the microanalytical system. The quantitation with the microanalytical system was slightly less (approximately 75-85%) than with ICP-MS; however, the response was linear, with concentration suggesting that it can be used for the quantitation of salivary Pb. To facilitate modeling, a physiologically based pharmacokinetic (PBPK) model for Pb was modified to incorporate a salivary gland compartment. The model was capable of predicting blood and saliva Pb concentration based on a limited data set. These results are encouraging, suggesting that once fully developed the microanalytical system coupled with PBPK modeling can be used as important tools for real-time biomonitoring of Pb for both occupational and environmental exposures.

Animals↗