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At least 1,621 records · Page 90Linked to original sources
PubMed2006

Determination of tipranavir in human plasma by reverse phase liquid chromatography with UV detection using photodiode array.

Tipranavir has recently received accelerated approval from the FDA. The initial clinical use of tipranavir will be for patients with prior virologic failure with the presence of key HIV-1 protease inhibitor mutations. In Phase III trials patients with greater virologic response also had higher trough tipranavir concentrations (BI product information 2005). In addition, hepatotoxicity was concentration-related with a higher incidence in those patients exceeding a trough plasma concentration of 48.2 microg/mL (80 microM). Therefore, tipranavir may be an HIV-1 protease inhibitor for which therapeutic drug monitoring (TDM) may be helpful in optimizing outcomes. To quantitate tipranavir concentrations in human plasma, a method using reversed phase high performance liquid chromatography (RP-HPLC) was validated. Detection was effected using a photodiode-array detector, scanning at a wavelength of 254 nm. This method allows for detection of tipranavir to a lower limit of quantitation of 0.390 microg/mL with an interday variation in control value ranging from 2.9 to 4.6%. The method is being used in a clinical therapeutic drug monitoring program that is ongoing in our laboratory.

Calibration↗
PubMed1991

Discodermolide--a new, marine-derived immunosuppressive compound. I. In vitro studies.

The in vitro immunosuppressive properties of a novel, marine-derived compound, discodermolide, are reported here. Discodermolide suppressed the proliferative responses of splenocytes in the murine two-way mixed lymphocyte reaction (MLR) and concanavalin A stimulated cultures, with IC50 values of 0.24 microM and 0.19 microM, respectively. There was no evidence of cytotoxicity for murine splenocytes at concentrations of discodermolide as high as 1.26 microM. Similarly, discodermolide suppressed the proliferative responses of human peripheral blood leukocytes (PBL) in the two-way MLR, and Con A and phytohemagglutinin mitogenesis. The IC50 values were 5.65 microM, 28.02 microM, and 30.12 microM for the MLR, Con A, and PHA mitogenic responses, respectively. There was no evidence of cytotoxicity toward human PBL at discodermolide concentrations as high as 80.64 microM. Discodermolide was equally effective, compared with cyclosporine, in suppressing the PMA-ionomycin induced proliferation of purified, murine T cells, with IC50 values of 9.0 nM and 14.0 nM for discodermolide and CsA, respectively. The production of IL-2 by PMA-ionomycin stimulated T cells was not inhibited by discodermolide; however, the percentage of IL-2 receptor-bearing cells as measured by immunofluorescence with 7D4 antibody, specific for the 55-kDa chain (p55) comprising the murine IL-2 receptor, was reduced. The expression of a similar chain comprising the human IL-2 receptor (Tac antigen, p55) by PHA or Con-A-stimulated PBL was similarly suppressed by discodermolide. The precise mechanism of action of discodermolide remains to be elucidated.

Alkanes↗
PubMed1991

Discodermolide--a new, marine-derived immunosuppressive compound. II. In vivo studies.

The in vivo immunosuppressive properties of a novel, marine-derived compound, discodermolide, are reported here. Discodermolide was effective in suppressing the graft-versus-host splenomegaly response of BALB/c----CB6F1 (BALB/c X C57BL/6J)F1 grafted mice at 5.0, 2.5, and 1.25 mg/kg, when administered as daily, i.p. injections, for 7 days. Mice treated with 5.0 and 2.5 mg/kg demonstrated a high degree of suppression (219 and 150%, respectively); however, these dosages were associated with some degree of morbidity (2/5 and 4/5 survivors for 5.0 and 2.5 mg/kg, respectively). Mice that were treated with 1.25, 0.625, and 0.313 mg/kg remained healthy after a 7-day regimen, and continued to demonstrate suppression of splenomegaly (106%, 72%, and 76% suppression, respectively). Splenocytes obtained from discodermolide-treated, allogeneic grafted mice were suppressed in their ability to respond in vitro to optimal mitogenic concentrations of concanavalin A, and natural-killer-cell activity directed against YAC-1 tumor cells, compared with vehicle-treated, allogeneic grafted control mice. Lower dosages (2.5 and 1.25 mg/kg) of discodermolide, however, did not affect the subsequent ability of splenocytes obtained from these mice to produce IL-2 following in vitro stimulation with Con A. This was observed to be in contrast to the immunosuppressive activity observed with cyclosporine treatment of mice (150 mg/kg) for the ex vivo suppression of splenocyte production of IL-2. Treatment of normal, nongrafted mice with similar high dosages of discodermolide (5.0 mg/kg) for 4 days did not affect the primary antibody response of mice immunized with sheep red blood cells as measured by hemagglutination activity of their serum. These results suggest that discodermolide's in vivo immunosuppressive action appears not to be that of a generalized immunosuppressive agent and that its specific in vivo mechanism of action warrants further preclinical evaluation.

Alkanes↗
PubMedDate not supplied

The Michigan Local Public Health Accreditation Program: many partners--one vision.

The Michigan Local Public Health Accreditation Program ensures the quality of local public health in Michigan by identifying and promoting the implementation of public health standards and evaluating and accrediting local departments' ability to meet them. The program is a collaborative effort between the Michigan Public Health Institute and the Michigan Departments of Agriculture, Community Health, and Environmental Quality. This article presents a case study. From the conceptual stage of designing a mode of collaboration to examining each step in the process, the goal is to provide a basic understanding of objectives of the accreditation program. The article concludes with the early results, providing a platform for future study.

Accreditation↗
PubMed2003

Tipranavir: a protease inhibitor from a new class with distinct antiviral activity.

Tipranavir (TPV) is the first of a new class of non-peptidic protease inhibitors (NPPIs). It is a sulphonamide-containing dihydropyrone, which is highly selective for the HIV protease enzyme and demonstrates potent in vitro activity against wild-type HIV-1 and HIV-2. The IC90 for TPV was 0.1 microM against clinical HIV isolates. Since CYP3A is the major cytochrome P450 isoform for the phase I metabolism of TPV, its exposure is markedly enhanced in the presence of ritonavir (RTV). In one clinical study, using the new self emulsifying drug delivery system (SEDDS) formulation of TPV, plasma concentrations in excess of 20 microM were maintained for 12 hours, allowing for twice-a-day dosing following administration of TPV 300 mg/RTV(r) 200 mg twice a day. The 20 microM target represents 10-fold the IC90 for multiple protease inhibitor (PI)-resistant strains. Both in vitro data and pharmacokinetic results indicate that TPV will be active in vivo against PI-resistant viruses, when given twice a day in combination with low dose RTV. Of 105 HIV viral isolates taken from patients who had been heavily pretreated with PI-based regimens: 90% were fully susceptible to TPV; 8% exhibited intermediate resistance; and 2% were more than 10-fold resistant. In patients who had failed at least two PI-based regimens, only 12.2% of the HIV isolates exhibited four to 10-fold reduced susceptibility to TPV after one year of treatment with a regimen containing the NPPI (Study BI1182.2). A reduction of approximately 1.5 log10 copies/mL in the plasma viral load (pVL) was observed in treatment-naive patients after 15 days of monotherapy with TPV (300 or 1200 mg twice a day) co-administered with RTV (200 mg twice a day) (TPV/r) in a dose-ranging study (Study BI1182.3). The safety and efficacy of TPV (500 or 1250 mg) plus ritonavir (100 mg twice a day) plus two new nucleoside reverse transcriptase inhibitors (NRTIs) was studied in patients failing their first PI-containing regimen (Study BI1182.4). Similar decreases in pVLs (1.44-1.79 log10 copies/mL) were observed after 16 weeks of treatment with either dose of TPV/r. Two doses of TPV/r plus efavirenz (EFV) and a new NRTI have been studied in non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive patients who had failed two or more PI-containing regimens (BI1182.2). Between 50% and 78.9% of patients maintained a pVL < 50 copies/mL for 48 weeks. Clinical studies have shown that TPV/r-associated adverse events are generally gastrointestinal-associated, transient and mild. A phase II study will define the optimal dose of TPV/r for highly treatment-experienced patients. The safety and efficacy of this dose of TPV/r will be evaluated in two phase III studies that will enroll more than 1300 patients worldwide. Tipranavir's robust activity against PI-resistant strains results from its molecular flexibility, which allows it to fit into the active pocket of the protease enzyme in viruses that have become resistant to other PIs.

Drug Therapy, Combination↗
PubMed2004

A 14-day dose-response study of the efficacy, safety, and pharmacokinetics of the nonpeptidic protease inhibitor tipranavir in treatment-naive HIV-1-infected patients.

Tipranavir (TPV), a novel nonpeptidic protease inhibitor (NPPI), was administered to treatment-naive HIV-1-infected patients over 14 days in a randomized, multicenter, open-label, parallel-group trial to evaluate the efficacy and tolerability of a self-emulsifying drug delivery system (SEDDS) formulation, in combination with ritonavir (RTV). Of the 31 patients enrolled, 10 were randomized to receive TPV 1200 mg twice daily (TPV 1200), 10 patients received TPV 300 mg + RTV 200 mg twice daily (TPV/r 300/200), and 11 patients received TPV 1200 mg + RTV 200 mg twice daily (TPV/r 1200/200). The median baseline viral load and CD4 cell count were 4.96 log10 copies/mL and 244 cells/mm, respectively. After 14 days, the median decrease in viral load was -0.77 log10 in the TPV 1200 group, -1.43 log10 in the TPV/r 300/200 group, and -1.64 log10 in the TPV/r 1200/200 group. TPV exposure was increased by 24- and 70-fold in the TPV/r 300/200 and 1200/200 groups, respectively, compared with TPV 1200 alone. There were no significant differences across treatment arms with regard to drug-related adverse events. TPV/r appeared to be safe, effective, and well tolerated during 14 days of treatment.

CD4 Lymphocyte Count↗
PubMed2006

Unexpected drug-drug interaction between tipranavir/ritonavir and enfuvirtide.

Fifty-five patients placed on tipranavir/ritonavir 500/200 mg twice a day (27 with enfuvirtide and 28 without) underwent tipranavir and ritonavir plasma concentration measurements by high-pressure liquid chromatography. Markedly higher tipranavir and ritonavir trough concentrations were observed in enfuvirtide recipients. The modelling of sparse plasma samples using a first order absorption and elimination monocompartmental model without time lag predicted higher tipranavir elimination half-life and volume of distribution in enfuvirtide takers. This unexpected drug-drug interaction warrants further investigation.

Anti-HIV Agents↗
PubMed2004

Inactivation of endoplasmic reticulum bound Ca2+-independent phospholipase A2 in renal cells during oxidative stress.

The purpose of this study was to determine the actions of oxidants on endoplasmic reticulum bound Ca(2+)-independent phospholipase A(2) (ER-iPLA(2)) and phospholipids in renal cells. Exposure of renal proximal tubule cells (RPTC) to the oxidants tert-butyl hydroperoxide (TBHP), cumene hydroperoxide, and cisplatin resulted in time- and concentration-dependent decreases in the activity of ER-iPLA(2). TBHP-induced ER-iPLA(2) inactivation was reversed by the addition of dithiothreitol to microsomes isolated from treated RPTC. TBHP also directly inactivated ER-iPLA(2) in microsomes isolated from untreated RPTC. Similar to RPTC, dithiothreitol prevented TBHP-induced ER-iPLA(2) inactivation in microsomes as did the reactive oxygen scavengers butylated hydroxytoluene and N,N'-diphenyl-p-phenylenediamine and the iron chelator deferoxamine. Electron paramagnetic resonance spin trapping demonstrated that TBHP initiated a carbon-centered radical after 1 min of exposure in microsomes, preceding ER-iPLA(2) inactivation, and further studies suggested that the formation of the carbon-centered radical species occurred after or in concert with the formation of oxygen-centered radicals. Phospholipid content was determined after TBHP exposure in the presence and absence of the ER-iPLA(2) inhibitor bromoenol lactone. Treatment of RPTC with TBHP resulted in 35% decreases in (16:0, 20:4)-phosphatidylethanolamine (PtdEtn), (18:0, 18:1)-plasmenylethanolamine (PlsEtn), a 30% decrease in (16:0, 18:3)-phosphatidylcholine (PtdCho), and a 25% decrease in (16:0, 20:4)-phosphatidylcholine (PtdCho). In contrast, treatment of RPTC with bromoenol lactone before TBHP exposure decreased the content of 11 phospholipids, decreasing a majority of PlsEtn phospholipids 60%, and 4 of the 8 PlsCho phospholipids 40%, while PtdCho and PtdEtn were marginally affected compared with TBHP. These data demonstrate that ER-iPLA(2) is inactivated by oxidants, that the mechanism of inactivation involves the oxidation of ER-iPLA(2) sulfhydryl groups, and that ER-iPLA(2) inhibition increases oxidant-induced RPTC phospholipid loss.

Animals↗
PubMed2004

The clinical development of new mitotic inhibitors that stabilize the microtubule.

Microtubule-stabilizing agents are increasingly studied for cancer treatment based largely on the prior success of paclitaxel and docetaxel. In this review, we focus on the clinical development of epothilones and discodermolide, and we discuss salient preclinical and clinical highlights of these two novel natural products. These agents are distinguished by their biochemical features making them poor P-glycoprotein substrates and capable of inducing cytotoxicity in cell lines or in vivo tumor models harboring mutations in tubulin. There is now considerable data regarding the efficacy of the epothilones in human beings and discodermolide holds such promise, as well.

Alkanes↗
PubMed2005

Pharmacological characterization of the novel dihydropyridine potassium channel opener, (9R)-9-(3-iodo-4-methylphenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (A-325100), and the regulation of cardiovascular function in conscious and anesthetized beagle dogs.

The pharmacological profile of the novel dihydropyridine K channel opener (KCO), (9R)-9-(3-iodo-4-methylphenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (A-325100), is described in numerous in vitro assays. Furthermore, the cardiovascular effects of A-325100 are characterized in both the anesthetized and conscious dog. In vitro, A-325100 selectively activated KATP currents and potently relaxed vascular smooth muscle (IC50 between 7.69x10 M and 7.78x10 M), an effect that was abolished by glyburide. Moreover, A-325100 did not interact with L-type Ca2+ channels at concentrations up to 30 microM. In anesthetized dogs A-325100 produced a dose-dependent reduction in systemic vascular resistance and mean arterial pressure concomitant with dose-dependent increases in dP/dtmax and heart rate. In conscious telemetry-instrumented dogs oral administration of A-325100 produced a similar response profile, including dose-dependent reductions in MAP and increases in heart rate and dP/dtmax. When concentration-dependent changes in MAP, heart rate, and dP/dtmax were compared relative to circulating plasma concentrations, A-325100 produced similar effects in both the anesthetized and conscious dog. In conclusion, the present study provides the first pharmacological description of the novel and selective tricyclic dihydropyridine KCO, A-325100. When studied in vivo, A-325100 produced similar concentration-dependent cardiovascular effects in both models consistent with its mode of action and independent of route of administration. Thus, these data demonstrate that the hemodynamic effects of vasoactive compounds, such as KCOs, can be effectively profiled in both the conscious and anesthetized dog.

Adenosine Triphosphate↗
PubMed2007

Food and Drug Administration analysis of tipranavir clinical resistance in HIV-1-infected treatment-experienced patients.

OBJECTIVE: To assess the resistance profile of tipranavir. METHODS: Resistance analyses were performed on Boëhringer Ingelheim-sponsored studies examining the safety and efficacy of tipranavir in highly treatment-experienced individuals at 24 weeks. Virologic response rates based on the presence of baseline primary protease inhibitor mutations and based on baseline tipranavir susceptibility were evaluated, and the development of protease mutations during treatment with tipranavir was analyzed. RESULTS: Virologic response rates in tipranavir-treated individuals were reduced when isolates with substitutions at amino acid positions I13, V32, M36, I47, Q58, D60 V82 or I84 were present at baseline. In addition, virologic response rates to tipranavir decreased when the number of baseline protease inhibitor (PI) mutations was five or more. Individuals who received tipranavir without concomitant enfurvitide and had five or more baseline PI mutations group began to lose antiviral response between weeks 4 and 8. However, individuals taking enfuvirtide with tipranavir were able to achieve greater than 1.5 log10 reductions in viral load from baseline out to 24 weeks even if they had five or more baseline PI mutations. Virologic response rates to tipranavir decreased when the baseline phenotype for tipranavir had a greater than three-fold shift in the 50% effective concentration (EC50) from reference. The most common protease mutations that developed in tipranavir-treated individuals who experienced virologic failure were L10I/V/S, I13V, L33V/I/F, M36V/I/L V82T, V82L, and I84V. The resistance profile in treatment-naive individuals was not characterized. CONCLUSIONS: Baseline genotypic and phenotypic data provide valuable information on the likelihood of a virologic response to tipranavir.

Anti-HIV Agents↗
PubMed2004

(+)-discodermolide: a marine natural product against cancer.

(+)-discodermolide was isolated in 1990 by Gunasekera et al. from the deep-water Caribbean sponge Discodermia dissoluta. It attacks cancer cells in a similar way to the successful cancer drug Taxol that has become the best-selling anticancer drug in history. Taxol is also the first natural product described that stabilizes the microtubules involved in many aspects of cellular biology and that represent an important target of anticancer chemotherapeutics. However, (+)-discodermolide appears to be far more potent than Taxol against tumors that have developed multiple-drug resistance, with an IC50 in the low nanomolar range. Due to these excellent results, this natural product was licensed to Novartis Pharmaceutical Corporation in early 1998. The present review covers the history, biological activity, total synthesis, and synthetic analogs of (+)-discodermolide.

Alkanes↗
PubMed1992

Structure of the sodium salt of 1,4,5,8-naphthalenetetracarboxylic acid 4,5-anhydride hydrate.

Sodium hydrogen 1,3-dioxo-1H,3H-naphtho[1,8-cd]pyran-6,7-dicarboxylate hydrate, Na[C14H5O7].H2O, Mr = 326.2, triclinic, P1, a = 9.520 (2), b = 9.549 (3), c = 7.860 (1) A, alpha = 105.88 (2), beta = 110.29 (1), gamma = 100.89 (2) degrees, V = 611.9 (3) A3, Z = 2, Dx = 1.77 g cm-3, lambda(Mo K alpha) = 0.71073 A, mu = 1.67 cm-1, F(000) = 332, T = 295 K, R = 0.042 for 1665 unique reflections having I greater than 3 sigma I. The organic portion of this structure demonstrates near-C2 symmetry with a pseudo-twofold axis coincident with the central C-C naphthalene ring bond. The atoms of the naphthopyran three-ring system deviate by an average of 0.037 (19) A from the best least-squares plane through the three rings. Each of the carboxyl group planes is substantially inclined to the naphthopyran ring plane, the average dihedral angle measuring 62 (1) degree. The Na ion is coordinated by O atoms in a highly distorted octahedral geometry with a mean Na--O distance of 2.49 (12) A. A short hydrogen bond is formed between a carboxylic acid group and a carboxylate anion; the H...O(acceptor) distance is 1.35 (5) A and the O...O(acceptor) distance is 2.475 (3) A. The acid H-atom position is located asymmetrically with respect to the O atoms. The water H atoms are involved in unequal three-centered hydrogen bonds. The molecules are stacked such that the naphthopyran ring portion of the structure is nearly parallel to the ab cell face and the stacks are connected by the hydrogen bonds.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemical Phenomena↗
PubMed1992

(2S-[2 alpha,3 alpha,3a beta,6 beta(R*),7 alpha, 7a alpha])-6-(3-benzyloxy-2-propyl)-2-hydroxy-2,3,7-trimethylhexahydro-4H- furo [3,2-c]pyran-4-one, a rearrangement product of pyranone derivatives in the tirandamycin A series.

The six- and five-membered heterocyclic rings are cis-fused and adopt twist-boat and half-chair conformations, respectively. The average bond distances are: Csp3-Csp3 1.520 (6), Csp3-Csp2 1.494 (6), C-Cbenz 1.360 (10) and Csp3-O 1.425 (5) A; the C = O and Csp2-O bond lengths are 1.214 (5) and 1.324 (5) A, respectively.

Aminoglycosides↗