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At least 775 records · Page 43Linked to original sources
PubMed2001

Limited-sampling strategy models for estimating the pharmacokinetic parameters of 4-methylaminoantipyrine, an active metabolite of dipyrone.

Bioanalytical data from a bioequivalence study were used to develop limited-sampling strategy (LSS) models for estimating the area under the plasma concentration versus time curve (AUC) and the peak plasma concentration (Cmax) of 4-methylaminoantipyrine (MAA), an active metabolite of dipyrone. Twelve healthy adult male volunteers received single 600 mg oral doses of dipyrone in two formulations at a 7-day interval in a randomized, crossover protocol. Plasma concentrations of MAA (N = 336), measured by HPLC, were used to develop LSS models. Linear regression analysis and a "jack-knife" validation procedure revealed that the AUC(0-infinity) and the Cmax of MAA can be accurately predicted (R2>0.95, bias <1.5%, precision between 3.1 and 8.3%) by LSS models based on two sampling times. Validation tests indicate that the most informative 2-point LSS models developed for one formulation provide good estimates (R2>0.85) of the AUC(0-infinity) or Cmax for the other formulation. LSS models based on three sampling points (1.5, 4 and 24 h), but using different coefficients for AUC(0-infinity) and Cmax, predicted the individual values of both parameters for the enrolled volunteers (R2>0.88, bias = -0.65 and -0.37%, precision = 4.3 and 7.4%) as well as for plasma concentration data sets generated by simulation (R2>0.88, bias = -1.9 and 8.5%, precision = 5.2 and 8.7%). Bioequivalence assessment of the dipyrone formulations based on the 90% confidence interval of log-transformed AUC(0-infinity) and Cmax provided similar results when either the best-estimated or the LSS-derived metrics were used.

Adult↗
PubMed1992

The lipoxygenase inhibitor nafazatrom inhibits stimulated prolactin secretion in cultured rat lactotrophs (GH4C1 cells).

Arachidonic acid metabolites are involved in the regulation of prolactin (PRL) secretion from rat lactotrophs (GH4C1 cells). Phospholipase A2 (PLA2) stimulated PRL secretion, while the PLA2 inhibitor quinacrine reduced both thyrotropin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP) stimulated PRL release. Hormonally stimulated PRL release was further increased in the presence of the cyclo-oxygenase inhibitor indomethacin. Nafazatrom, a lipoxygenase inhibitor, reduced stimulated PRL secretion regardless of the mechanism of stimulation [hormonally (VIP and TRH) or by increasing intracellular Ca2+ concentration by KCl or Bay-K and cAMP by forskolin]. None of the inhibitors used in this study had any effect either on the basal PRL secretion or on the production of cAMP. Lipoxygenase products seem to be involved in the regulation of PRL secretion, probably by affecting a late step in the signal transduction.

Animals↗
PubMed1993

Inhibitors of the arachidonic acid metabolism attenuate the thyroliberin (TRH) stimulated prolactin production without modifying the production of inositolphosphates in GH4C1 pituitary cells.

Some arachidonic acid metabolites might be among the intracellular signalling substances that regulate hormone release. We report that the phospholipase A2 and diacylglycerol lipase inhibitor quinacrine (1-10 mumol l-1) inhibited the thyroliberin stimulated prolactin (rPRL) production in a dose-dependent way in a rat pituitary tumour cell line (GH4Cl cells). The lipoxygenase inhibitor nafazatrom (5-50 mumol-1) also dose-dependently inhibited the thyroliberin stimulated rPRL production, while the cyclo-oxygenase inhibitor indomethacin had no such effect on rPRL production. The inhibitors of the arachidonic acid metabolism (quinacrine, ETYA and nafazatrom) had no effect on the accumulation of inositolpolyphosphates indicating that the arachidonic acid metabolites are not involved in the regulation of the phospholipase C activity.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1992

Plasma and urinary concentrations of methamphetamine after oral administration of famprofazone to man.

1. To obtain further evidence for the metabolic formation of methamphetamine from famprofazone in man, concentrations of methamphetamine in plasma, as well as in urine, were measured by g.l.c. In addition, intact famprofazone and famprofazone N-oxide were analysed in the urine. 2. Methamphetamine appeared in plasma 1 h after a single 100 mg dose of the drug to two male subjects, and the concentration maintained between 24 and 44 ng/ml over 2-12 h, declining to 10 ng/ml and an undetectable level respectively after 24 h. 3. Total urinary excretion of methamphetamine over 72 h was 1.9 mg for a 25 mg dose and 2.2 mg for a 50 mg dose. After a 100 mg dose, 4.6 mg of methamphetamine was excreted over 36 h. Neither intact famprofazone nor famprofazone N-oxide were detected when the urine samples after the 100 mg dose were examined. 4. The results provide further evidence that methamphetamine is a bona fide human metabolite of famprofazone and suggest that at least 20% dose may be broken down via the pathways leading to the formation of methamphetamine. This could have significant clinical implications as the result of pharmacological activity of this metabolite.

Administration, Oral↗
PubMed1993

Reaction kinetics of alpha-tocopheroxyl radical with biologically and pharmacologically active substances.

The alpha-tocopheroxyl radical (alpha TR.)generated in the reaction with 1,1-diphenyl-2-picrylhydrazyl in n-butanol decayed according to second-order kinetics with a rate constant k alpha = 3 x 10(3) M-1s-1 as determined by EPR spectroscopy. Various biologically and pharmacologically active substances like isoprenaline (ISO), epinephrine (EPI), histamine (HIS), stobadine (STO), nafazatrom (NAF) and Kampo C medicine (KMC) accelerated the decay rate of alpha TR(.). The whole process is formally a third-order reaction with the rate constants (in 10(9) M-2s-1): ks(ISO) = 1.28, ks(NAF) = 1.25, ks(EPI) = 0.6, ks(HIS) = 0.4, and ks(STO) = 0.1. In the kinetics of the reaction mechanism, bimolecular intermediates are assumed and the rate constants of their formation were determined.

Antioxidants↗
PubMed1996

Validation of cleaning procedures for highly potent drugs. I. Losoxantrone.

The validation of a procedure designed to clean glass and stainless steel surfaces after exposure to the experimental anticancer drug losoxantrone is described. The cleaning procedure, using water and hypochlorite bleach, was validated using a wipe test and a high-performance liquid chromatography (HPLC) method developed to quantitate low levels of losoxantrone. The HPLC method is shown to be linear and reproducible (relative standard deviation (RSD): 7.1% or less), with a detection limit of 2 ng/ml. Recoveries of 71.0%, 50.1%, and 57.6% were reproducibly obtained from the wipe pads, glass plates, and stainless steel plates, respectively, at levels of 70-140 ng per 100 cm2. The cleaning procedure is shown to clean glass and stainless steel plates to less than 20 ng and 17 ng losoxantrone per 100 cm2, respectively. These results demonstrate the need to fully characterize the recovery of drugs from surfaces and swabs in order to properly validate cleaning procedures.

Anthraquinones↗
PubMed2002

Bioavailability of two metamizole (dipyrone) solutions as single doses of 2 g versus metamizole capsules.

OBJECTIVE: The aim of this study was to investigate the extent and the rate of absorption of metamizole, appearing in blood as methylaminoantipyrine (MAA), from a new oral solution and a parenteral solution administered by the oral route relative to capsules. METHODS: An open, randomized, 3 single-dose (2 g metamizole), crossover study with intervals of 7 days between periods was performed in 19 male and female healthy volunteers (age 22 - 45 years, body weight 49 - 88 kg, body height 156 - 189 cm). Metamizole metabolites were measured with an HPLC technique. The test formulations were considered bioequivalent with the reference formulation if the 90% confidence limits of the AUC0-->infinity and Cmax ratios and the tmax differences were within the range of 80 - 125%. RESULTS: The 90% confidence limits of the comparisons between capsules (reference) and oral solution, capsules (reference) and ampoules, and ampoules (reference) and oral solution were 98.5 - 117.8, 99.5 - 132.6 and 81.3 - 105.8 for AUC0-->infinity 98.7 - 119, 101.7 to 129.2, and 82.1 - 104.8 for Cmax, and 84.4 to 115.6, 100 - 105.6 and 70.3 - 100 for tmax, respectively. CONCLUSION: The oral solution was bioequivalent to capsules with regard both to the extent and the rate of MAA absorption. Metamizole as oral solution was bioequivalent to reference ampoules in the extent of MAA absorption, but absorption rate was faster. Ampoules showed a higher MAA bioavailability than capsules.

Administration, Oral↗
PubMed1999

A phase I and pharmacokinetic study of losoxantrone and paclitaxel in patients with advanced solid tumors.

A Phase I and pharmacological study was performed to evaluate the feasibility, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics of the anthrapyrazole losoxantrone in combination with paclitaxel in adult patients with advanced solid malignancies. Losoxantrone was administered as a 10-min infusion in combination with paclitaxel on either a 24- or 3-h schedule. The starting dose level was 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel (as a 24- or 3-h i.v. infusion) without granulocyte colony-stimulating factor (G-CSF). Administration of these agents at the starting dose level and dose escalation was feasible only with G-CSF support. The following dose levels (losoxantrone/paclitaxel, in mg/m2) of losoxantrone and paclitaxel as a 3-h infusion were also evaluated: 50/135, 50/175, 50/200, 50/225, and 60/225. The sequence-dependent toxicological and pharmacological effects of losoxantrone and paclitaxel on the 24- and 3-h schedules of paclitaxel were also assessed. The MTD was defined as the dose at which >50% of the patients experienced DLT during the first two courses of therapy. DLTs, mainly myelosuppression, occurring during the first course of therapy were noted in four of six and five of eight patients treated with 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel over 24 and 3 h, respectively, without G-CSF. DLTs during the first two courses of therapy were observed in one of six patients at the 50/175 (losoxantrone/paclitaxel) mg/m2 dose level, two of four patients at the 50/200 mg/m2 dose level, one of four patients at the 50/225 mg/m2 dose level, and two of five patients at the 60/225 mg/m2 dose level. The degree of thrombocytopenia was worse, albeit not statistically significant, when 24-h paclitaxel preceded losoxantrone, with a mean percentage decrement in platelet count during course 1 of 80.7%, compared to 43.8% with the reverse sequence (P = 0.19). Losoxantrone clearance was not significantly altered by the sequence or schedule of paclitaxel. Cardiac toxicity was observed; however, it was not related to total cumulative dose of losoxantrone. An unacceptably high rate of DLTs at the first dose level of 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel administered as either a 24- or 3-h i.v. infusion precluded dose escalation without G-CSF support. The addition of G-CSF to the regimen permitted further dose escalation without reaching the MTD. Losoxantrone at 50 mg/m2 followed by paclitaxel (3-h i.v. infusion) at 175 mg/m2 with G-CSF support is recommended for further clinical trials.

Adult↗
PubMed1999

Paclitaxel and anthracycline combination chemotherapy for metastatic breast cancer.

Numerous clinical trials have demonstrated that the combination of paclitaxel and doxorubicin is extremely active in metastatic breast cancer. Overall response rates of 42% to 94% and complete response rates of 4% to 41% have been reported. However, several trials with the highest response rates were associated with the development of congestive heart failure (CHF) in approximately 20% of patients. These early findings resulted in reducing the maximum permitted cumulative dosages of doxorubicin in subsequent trials, with a corresponding decrease in cardiac toxicity being noted. Several subsequent series suggest that with cumulative dosing of 360 mg/m2 doxorubicin, the rate of CHF can be reduced to approximately 5%. A recently completed Eastern Cooperative Oncology Group phase III randomized trial comparing paclitaxel versus doxorubicin versus combination therapy with paclitaxel and doxorubicin noted an overall response rate of 33% and 34% in each single-agent arm, respectively, and a response rate of 46% with the combination therapy. There was an acceptable incidence of CHF. However, no difference in overall survival was noted with the combination therapy compared with the single-agent treatment. Losoxantrone, an anthrapyrazole in clinical development, has shown promising single-agent activity in metastatic breast cancer. An initial phase III randomized clinical trial comparing treatment with either paclitaxel alone versus losoxantrone and paclitaxel was recently completed. With no maximal cumulative dosage of losoxantrone incorporated into this trial design, an overall incidence of CHF of 4.9% was noted with combination therapy. Other hematologic and nonhematologic toxicities were overall acceptable with this new regimen as well. Additionally, preliminary analyses of clinical efficacy suggest that this new combination is promising therapy for the treatment of patients with metastatic breast cancer.

Anthraquinones↗
PubMed2000

A multicenter phase II trial of losoxantrone (DuP-941) in hormone-refractory metastatic prostate cancer.

Our purpose in this study was to determine the efficacy and toxicity of losoxantrone (DuP-941), an anthrapyrazole, in patients with metastatic hormone-refractory prostate cancer. Patients with metastatic prostate cancer progressing on androgen ablation therapy without demonstrable antiandrogen withdrawal response were treated with losoxantrone 50 mg/m2 i.v. bolus every 21 days. All of the patients had elevated serum prostate-specific antigen (PSA) before study entry and had no prior chemotherapy. Forty-three assessable patients were entered. The median age was 70.6 years (range, 53.9-85.9), median Karnofsky performance scale (KPS), 70% (50-90%), and the median serum PSA, 173 microg/liter (12.5-11,140). The median number of courses was 4 (1-9). Five patients (25%) had a partial response as defined by >50% decline in the serum PSA. Two of nine patients with measurable disease had partial responses and three had minor responses. Thirty percent of patients had improvement in KPS and 37% had an improvement in symptoms with decrease in pain and/or decrease in analgesic requirement. Nonhematological grade 3 and 4 toxicities were one each of grade 3 headache, grade 4 hypocalcemia, grade 3 hyperbilirubinemia, and grade 3 dyspnea. Twenty-six patients (60%) had grade 3 or 4 absolute neutropenia. In conclusion, losoxantrone demonstrated a partial biochemical response rate of 25%, response in measurable disease sites in 22%, and improvement in clinical symptoms in one-third of patients. In this study, PSA increase was not necessarily associated with lack of palliative response.

Aged↗
PubMed2001

Elimination pathways of [14C]losoxantrone in four cancer patients.

Losoxantrone is an anthrapyrazole derivative in Phase III development in the U.S. for solid tumors, notably breast cancer. To obtain information on the routes of elimination of the drug, a study was conducted in four patients with advanced solid tumors, which involved intravenous administration of 100 microCi of [14C]losoxantrone for a total dose of 50 mg/m(2) during the first course of losoxantrone therapy. Blood, urine, and feces were collected for up to 2 weeks and were analyzed for total radioactivity and parent drug. In addition, feces were profiled for the presence of metabolites. Plasma concentrations of total radioactivity exhibited a temporal pattern similar to the parent drug. Combined recovery of administered total radioactivity from urine and feces was 70% with the majority (87%) of this radioactivity excreted in the feces, presumably via biliary excretion. Feces extracts were profiled for metabolites using a high-performance liquid chromatography method developed to separate synthetic standards of previously identified human urinary metabolites. Only intact losoxantrone was found in the feces. About 9% of the dose was excreted in the urine, primarily during the first 24 h and mostly in the form of parent compound. Collectively, these data indicate that fecal excretion of unmetabolized drug via biliary and/or intestinal excretion is the primary pathway of intravenously administered losoxantrone elimination in cancer patients with refractory solid tumors.

Anthraquinones↗
PubMed1997

[Studies on HPLC method for determination of 4-methylaminoantipyrine and relative bioavailabilities of analgin nasal drops in human volunteers].

A new HPLC method for the determination of a metabolite of analgin, MAA (4-methylaminoantipyrine), in plasma and its application to determine the bioavailabilities of analgin nasal drops in human volunteers is reported in this paper. A Waters Model 481 instrument was used throughout the experiment. IAA (isopropylaminoantipyrine) was shown to be the most suitable internal standard at absorption wavelength of 254 nm. A mixture of phosphate buffer (pH 5.5) and methanol (68:32) was used as the mobile phase with a flow rate of 2 ml.min-1, and YWG-C18H37 as stationary phase. Calibration curve was linear (gamma = 0.9998) in the concentration range of 0.1-5 micrograms.ml-1. The within day and day-to-day precision (RSD) of this method were 2.35% and 2.61%, respectively, with average recoveries of 99.3%-103.9%. No interference was found in the body fluid. The plasma samples of healthy volunteers were treated with acid and extracted with ether. The system of mobile phase and the process of blood sample treatment were simpler than those reported in literature. So, the method is suitable for the study of pharmacokinetics and clinical determination of blood level of analgin. The studies on bioavailabilities of analgin nasal drops were carried out in 8 men relative to intramuscular injection and 6 men relative to oral tablets, respectively, at the dose of 250 mg analgin in different preparations administered by cross-over method. The main pharmacokinetic parameters were shown in Table 3. The results indicate that analgin nasal drops exhibited a higher bioavailability (relative to injection) and faster absorption (relative to tablet). So, analgin is suitable to be developed as a nasal preparation.

Administration, Intranasal↗
PubMed2002

[Clinical response to combined treatment with reaferon and iodantipirin in patients with chronic HCV- and HBV-infection].

The treatment was given to 100 patients with chronic virus hepatitis of moderate activity and chronicity stage I. Of them, 50 patients received reaferon (3 IU 3 times a week) in combination with antiviral and immunomodulating drug iodantipirin (100 mg/d) given on the days of reaferon injections for 6 months. The other 50 patients received reaferon alone in the same doses and duration of the treatment course. Efficiency was assessed by the level of ALT, findings at polymerase chain reaction, index of histological activity of hepatic biopsy. The combined scheme demonstrated higher efficiency and tolerance.

Adjuvants, Immunologic↗
PubMed1976

Spectrophotometric analysis of alkaloids with picrolonic acid.

The spectroscopic characteristics of the interaction of alkaloids with picrolonic acid were studied. In solvents of low and intermediate polarity, the presence of alkaloids caused a red shift of the 322 nm band of nonionized picrolonic acid to 355 nm, corresponding to the anionic resonance band. There was also a considerable increase in absorptivity, which was dependent on both the basicity (pKa) and molar concentration of the alkaloid present. Arylamines, aromatic N-heterocycles, and alkaloids lacking an aliphatic amine moiety did not show observable shifts. The interaction was developed into a spectrophotometric assay for the following alkaloids in pharmaceutical preparations: atropine, ephedrine, codeine, emetine, quinine, and strychnine. The method is sensitive to 2 mug alkaloid/ml, with an accuracy of not equal to 1.5% and a standard deviation of not equal to 1.05 - 1.31%.

Alkaloids↗
PubMed2002

[Synthesis and spectral characterization of U(VI) and Th(IV) complexes of thenoylpyrazolone-ethylenediamine].

Two novel bis-schiff base complexes [UO2 (PMTHP)2en] and [Th(PMTHP)2en(NO3)2] have been synthesized, where (PMTHP)2en = N,N'-bis[(1-phenyl-3-methyl-5-oxo-5-pyrazolinyl)- 2-thenoylmethylidyne] ethylenediamine, and characterized by elemental analysis, IR, UV-Vis, 1H NMR, 13C NMR and molar conductance measurements. The results show that the bis-schiff base is a quadridentate ligand and the nitrate a bidentate ligand, and the uranyl and thorium ions exhibit coordination of six and eight in the complexes, respectively.

Chelating Agents↗
PubMed1992

[Study of the relationship between structure and anticonvulsant activities of 5-substituted-1-butry-3-pyrazolidinones and their synthesis].

According to the quantitative structure-activity relationship studies of 3-pyrazolidinones with different substituent on positions 1 and 5 reported previously, the anticonvulsant activity is parabolically related with the total fragment constent (Fr hydrophobic parameter) of the 1 and 5 substituents of 3-pyrazolidion. The optimum Fr was about 5.6. Therefore, eleven new 5-substituted-3-pyrazolidinones have been synthesized. Pharmacological test showed that they are all potent anticonvulsant agents. Among them 1-n-butyl-5-(p-chlorophenyl)-3-pyrazolidinone was shown to be the most potent so far synthesized.

Anticonvulsants↗