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A sensitive LC-MS-MS assay for the quantitative determination of bromocriptine has been developed and validated and is described in this work. The assay involved the extraction of the analyte from 1 ml of human plasma using a solid phase extraction on Oasis MCX cartridges. Chromatography was performed on a Symmetry C18 (2.1 mm x 100 mm, 3.5 microm) column using a mobile phase consisting of 25:75:01 acetonitrile-water-formic acid with a flow rate of 250 microl/min. The linearity was within the concentration range of 2-500 pg/ml. The lower limit of quantification was 2 pg/ml. This method has been demonstrated to be an improvement over existing methods due to its greater sensitivity and specificity.

The objective of the present study was to evaluate the pharmacokinetic parameters for both S- and R-ibuprofen enantiomers in very premature neonates (gestational age strictly inferior to 28 weeks) and possible relationships between the pharmacokinetic parameters and various covariates. Newborns were randomized to receive ibuprofen or placebo for the prophylactic treatment of patent ductus arteriosus (PDA) at an initial dose of 10 mg/kg ibuprofen within 6 hours after birth, followed by two 5-mg/kg doses at 24-hour intervals (n = 52). If a PDA was still present afterwards, a curative course of ibuprofen using the same dosage regimen was administered (n = 10). A sparse sampling strategy was used because only 2 samples were collected after the third prophylactic injection and 1 after the third curative injection. A model including the chiral transformation of R- to S-ibuprofen was fitted to the concentration-time data using a population approach (NONMEM). R- and S-ibuprofen t(1/2) were about 10 hours and 25.5 hours, respectively. After prophylactic treatment, the mean clearance of R-ibuprofen (CLR = 12.7 mL/h) was about 2.5-fold higher than for S-ibuprofen (CLS = 5.0 mL/h). In addition, clearance of R- and S-ibuprofen increased significantly with gestational age. The mean estimation of R-ibuprofen clearance was found to be higher than for S-ibuprofen, and the clearance of both enantiomers increased with gestational age. This should be considered to assess pharmacokinetic-pharmacodynamic relationships of ibuprofen in premature neonates and subsequently to understand and refine the use of ibuprofen in managing PDA either as a prophylactic or curative treatment., (Copyright 2004 American College of Clinical Pharmacology)

Objective: Two oral enteric-coated pellet formulations of omeprazole, Pepticum((R)) (test formulation) and Mopral((R)) (reference), were administered to 24 healthy volunteers for 5 days at a daily dose of 20mg omeprazole in order to investigate the comparative bioavailability of the two formulations., Results: The data obtained in this study demonstrated the bioequivalence of the two formulations. No statistical differences were observed for the area under the plasma concentration-time curve (AUC(0-t)), the parameter to which the inhibition of acid secretion induced by omeprazole is directly related. Differences observed in maximum plasma drug concentration (C(max)) at day 1 for both formulations were not statistically significant. At steady-state, the differences found in C(max) were associated with a p-value <0.05 with the 90% confidence interval lying between the acceptance range (70 to 140%). Regarding time to reach C(max) (t(max)), p < 0.01 was found both after single and repeated doses. In both cases, Pepticum((R)) showed a delay in reaching C(max) compared with Mopral((R)): 2.15 +/- 1.11 vs 1.48 +/- 0.52h (day 1) and 1.94 +/- 0.66 vs 1.31 +/- 0.75h (day 5)., Conclusion: This study confirmed the reported increases in AUC and C(max) after repeated administrations, the important intersubject variability and the excellent biological and clinical tolerability of both formulations.

A reversed-phase isocratic HPLC method is described for the determination of baclofen in human plasma. Solid-phase extraction using a SCX Bond Elut column is used followed by derivatization with o-phthalaldehyde-tert.-butanethiol and electrochemical detection. Both the within- and between-day R.S.D. and inaccuracy are less than 10% and 7%, respectively, even at the limit of quantification of the method, i.e., 10 ng/ml. The method was shown to give optimum performance in terms of sensitivity, precision and accuracy for the pharmacokinetic study of baclofen after a single oral administration to volunteers.

The pharmacokinetics of terbinafine and its inactive metabolites SDZ 86-621 (the N-demethyl form), SDZ 280-027 (the carboxybutyl form), and SDZ 280-047 (N-demethyl- carboxybutyl form) in plasma were characterized for 10 healthy male subjects receiving 250 mg of terbinafine orally once a day for 4 weeks and in the subsequent 8-week washout phase. Terbinafine concentrations were also measured in sebum, hair, nail, and stratum corneum samples. Concentrations of the parent compound and metabolites were determined by validated high-performance liquid chromatography methods. Terbinafine was rapidly absorbed, with peak concentrations in plasma of 1.70 +/- 0.77 micrograms/ml occurring 1.2 +/- 0.3 h postdose. Concentrations subsequently exhibited a triphasic decline, with a terminal deposition half-life of 16.5 +/- 2.8 days. Terbinafine accumulated approximately twofold over the 4-week dosing phase. The predominant metabolite in plasma samples was SDZ 280-027; specifically, the ratios of metabolite area under the curve to terbinafine area under the curve following the last dose were 1.25, 1.38, and 1.08 for metabolites SDZ 86-621, SDZ 280-027, and SDZ 280-047. Measurable concentrations of terbinafine were achieved in sebum and hair samples within the first week of administration and by week 3 in stratum corneum and nail samples. Fungicidal concentrations persisted in plasma and peripheral tissue samples for prolonged periods (weeks to months) after administration of the last dose. These pharmacokinetic properties are likely an underlying factor in the shorter treatment times and good clinical cure rates which have been reported for terbinafine in the therapy of onychomycoses and dermatomycoses.

An HPLC method was developed and validated for the determination of ceftiofur-related metabolites that have the potential to be microbiologically active in swine muscle, kidney, liver and fat. Its performance was evaluated against incurred-residue swine tissues. This method is based on the cleavage of the disulfide and/or thioester bonds between the metabolites and their conjugate sulfur containing moiety using dithioerythritol to yield desfuroylceftiofur, and further stabilization to desfuroylceftiofur acetamide. The limit of quantitation was 0.1 micrograms ceftiofur equivalents/g tissue. The assay is specific for ceftiofur-related metabolites when evaluated against commercially available antibiotics for swine.

In earlier skin pharmacokinetic studies we have shown that terbinafine is rapidly delivered to the stratum corneum, nails and hair both through sebum and by direct diffusion through dermis-epidermis. In the present study the skin pharmacokinetic profile of terbinafine was studied in two groups of eight human male volunteers during and after 250 mg orally once daily for 7 and 14 days. In the 7-day study high terbinafine levels were found in sebum (19.0 micrograms/g) and stratum corneum (2.5 micrograms/g), and a concentration in stratum corneum above the minimal inhibitory concentration for most dermatophytes was still found 48 days after the last day of medication. Terbinafine was found in peripheral nail clippings after 7 days of medication and the concentration was, in the 7-day study, 0.5 microgram/g 1 day after stopping medication; it was still 0.2 microgram/g 90 days after stopping treatment. The results in the 14-day study were in parallel with, but higher than, in the 7-day study. The elimination of terbinafine from several compartments is biphasic, with a faster initial elimination followed by a slower secondary elimination. For nails, the elimination is slower compared with the other compartments. The results indicate that terbinafine may be effective in short-term treatment of several dermatophytoses. The concentration of 0.2 microgram/g of terbinafine found in nails 90 days after stopping medication, following 7 days of treatment, indicates that the duration of therapy, even in tinea ungium, may be shorter than is currently the case.

The distribution of terbinafine in stratum corneum dermis-epidermis (without stratum corneum), sebum, hair, nails and plasma was studied in human male volunteers during and after 250 mg orally once daily for 28 days. The highest concentration was seen in sebum, 56.07 micrograms/g, after 14 days of therapy. The concentration was still 1.0 microgram/g 44 days after stop of medication. In stratum corneum the highest concentration, 14.4 micrograms/g, was seen 1 day after the last day of therapy, and it was 2.1 micrograms/g 44 days after stop of medication. The concentrations in hair and nails were lower with a maximum of 2.36 and 0.39 micrograms/g respectively, 1 day after stop of therapy, and still 0.21 microgram/g in hair and 0.09 microgram/g in nails 55 days after the last day of medication. With the exception of nails, all other tissue levels were at all times above the plasma concentrations. For nails, tissue levels exceeded that of plasma as early as 1 day after stop of medication, and this difference continued to increase until the last day of tissue sampling, 55 days after the last tablet. These results indicate that terbinafine is delivered to the stratum corneum through sebum and to a minor extent by direct diffusion through dermis-epidermis. Probably short-term therapy with terbinafine may be effective in the treatment of several dermatomycoses, due to the strong binding of terbinafine to stratum corneum for a long time after stop of medication.(ABSTRACT TRUNCATED AT 250 WORDS)

A spleen-derived immunosuppressive peptide (SDIP) has been purified to homogeneity. Its physicochemical properties (electrophoretic mobility, u.v. spectra, absence of dansyl derivative) and its enzymatic susceptibilities (proteolytic enzymes, RNase, and DNase) were similar to those of the thymic hormone 'FTS'. SDIP and FTS were eluted with identical retention times in high performance liquid chromatography analysis in three different systems. When tested in sheep cell rosettes, and in the FTS radioimmunoassay in J.F. Bach's laboratory, SDIP presented an activity similar to FTS. In order to compare the thymic hormone to SDIP the biological activity of FTS was determined in in vivo and in in vitro humoral immunity reactions to a T-dependent antigen. As SDIP, FTS inhibited in vivo and in vitro the 19S-bearing cell formation during the last step of the differentiation of the lymphocytes, in the same range of concentration. The two factors appeared to stimulate the incorporation of [3H]-thymidine into the DNA of short-term cultures of thymocytes. The similarity of biological properties of SDIP and FTS together with the similarity observed in the physico-chemical and biochemical properties led to the conclusion that bovine spleen contains a factor similar to FTS.

Some biological properties of a highly-purified non-cytotoxic spleen-derived immunosuppressive peptide (SDIP) have been investigated. SDIP was shown to inhibit the primary anti-sheep red blood cell (SRBC) response at the last step of differentiation of the lymphocyte. In the present study we demonstrated that this response seemed to be T- and adherent spleen-cell dependent as no inhibition was noticed either in the response to TNP-LPS, a T-independent antigen, or in the response to SRBC in adherent spleen cell-depleted cultures. SDIP activity did not occur through an inhibition of splenocytes DNA synthesis since [3H]-thymidine ([3H]-TdR) incorporation was not modified in mitogen or allogenic stimulated cultures. Conversely, SDIP could act through a stimulation of a T-cell subset as a low specific increase of [3H]-TdR was noticed in cultured thymocytes.

Looking for a "lymphocytic chalone" in Bovine spleen extracts, we isolated an immunosuppressive peptide, whose biochemical and biological properties are identical to those of the serum thymic factor FTS. This factor appeared to be a regulator of the humoral immune response.

The presence of immunological stimulatory and inhibitory activities has been detected in a bovine spleen extract F prepared by acetic extraction of an acetonic powder. F was fractioned after water dilution, by ultrafiltration on an Amicon PM-10 membrane. Two successive ultrafiltrates (mol. wt. less than 10,000) are obtained: U1 which contained the largest pool of the low molecular weight substances, and U2 which was shown previously to be enriched in an immunosuppressive peptide. The biological activities of U1 have been studied compared to those of U2: 1. Added to mouse spleen cells culture, U1, at low dose, stimulated 3H-thymidine incorporation into the DNA of the cells, but inhibited it when large dose was added. In this test, U2 was devoid of stimulatory action. 2. When injected into mice sensitized with sheep red blood cells, three distinct activities were detected: U1 was inhibitory at the sensitization period; at the last step of differentiation of the lymphocyte, U1 was stimulatory at low dose and inhibitory at large dose. As assessed by Biogel P-2 chromatography, this last activity was attributed to the presence in fraction U1 of the immunosuppressive peptide previously characterized in U2.

Immunosuppressive activities have been detected in bovine spleen extracts and attributed to the presence of a 'lymphocytic chalone'. Following the immunosuppression of a T cell-dependent humoral response in mice as assay, we purified a peptide to homogeneity present at a concentration of 10-50 ng/kg of spleen whose properties were identical to those of the serum thymic factor. This factor appeared to be a regulator of the humoral immune response in the splenic extract and as such might be responsible for part of the immunosuppressive activities detected in the splenic 'chalone' fraction.

We studied the pharmacokinetics of cefotiam, a parenteral cephalosporin, at intravenous doses of 0.5, 1, and 2 g and intramuscular doses of 0.5 and 1 g in two groups of eight healthy adult volunteers. The concentrations of cefotiam in plasma were determined over a period of 5 or 6 h and in urine over 24 h, using high-pressure liquid chromatographic procedures. Plasma concentration-time data were fitted to a three-exponential equation for the intravenous administration, and after intramuscular administration, the data were analyzed by a two-compartment or a one-compartment open model. Over the above dosing range and routes of administration, cefotiam pharmacokinetics were essentially linear, with plasma clearances varying from 19.6 to 22.5 liters/h. No significant differences were observed with respect to the terminal half-life (1 h) and the area under the curve versus the dose. Intramuscularly injected cefotiam was 63 to 74% available. The fraction of dose excreted unchanged in urine (0.50 to 0.67) indicated a substantial nonrenal mechanism of elimination. The apparent volume of distribution (about 30 liters) was higher than those of other parenteral cephalosporins.