Browsing by Subject "Biological Availability"
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Item Open Access Buprenorphine-mediated transition from opioid agonist to antagonist treatment: state of the art and new perspectives.(Current drug abuse reviews, 2012-03) Mannelli, Paolo; Peindl, Kathleen S; Lee, Tong; Bhatia, Kamal S; Wu, Li-TzyConstant refinement of opioid dependence (OD) therapies is a condition to promote treatment access and delivery. Among other applications, the partial opioid agonist buprenorphine has been studied to improve evidence-based interventions for the transfer of patients from opioid agonist to antagonist medications. This paper summarizes PubMed-searched clinical investigations and conference papers on the transition from methadone maintenance to buprenorphine and from buprenorphine to naltrexone, discussing challenges and advances. The majority of the 26 studies we examined were uncontrolled investigations. Many small clinical trials have demonstrated the feasibility of in- or outpatient transfer to buprenorphine from low to moderate methadone doses (up to 60-70 mg). Results on the conversion from higher methadone doses, on the other hand, indicate significant withdrawal discomfort, and need for ancillary medications and inpatient treatment. Tapering high methadone doses before the transfer to buprenorphine is not without discomfort and the risk of relapse. The transition buprenorphine-naltrexone has been explored in several pilot studies, and a number of treatment methods to reduce withdrawal intensity warrant further investigation, including the co-administration of buprenorphine and naltrexone. Outpatient transfer protocols using buprenorphine, and direct comparisons with other modalities of transitioning from opioid agonist to antagonist medications are limited. Given its potential salience, the information gathered should be used in larger clinical trials on short and long-term outcomes of opioid agonist-antagonist transition treatments. Future studies should also test new pharmacological mechanisms to help reduce physical dependence, and identify individualized approaches, including the use of pharmacogenetics and long-acting opioid agonist and antagonist formulations.Item Open Access Design, mechanism of action, bioavailability and therapeutic effects of mn porphyrin-based redox modulators.(Medical principles and practice : international journal of the Kuwait University, Health Science Centre, 2013-01) Tovmasyan, A; Sheng, H; Weitner, T; Arulpragasam, A; Lu, M; Warner, DS; Vujaskovic, Z; Spasojevic, I; Batinic Haberle, IBased on aqueous redox chemistry and simple in vivo models of oxidative stress, Escherichia coli and Saccharomyces cerevisiae, the cationic Mn(III) N-substituted pyridylporphyrins (MnPs) have been identified as the most potent cellular redox modulators within the porphyrin class of drugs; their efficacy in animal models of diseases that have oxidative stress in common is based on their high ability to catalytically remove superoxide, peroxynitrite, carbonate anion radical, hypochlorite, nitric oxide, lipid peroxyl and alkoxyl radicals, thus suppressing the primary oxidative event. While doing so MnPs could couple with cellular reductants and redox-active proteins. Reactive species are widely accepted as regulators of cellular transcriptional activity: minute, nanomolar levels are essential for normal cell function, while submicromolar or micromolar levels impose oxidative stress, which is evidenced in increased inflammatory and immune responses. By removing reactive species, MnPs affect redox-based cellular transcriptional activity and consequently secondary oxidative stress, and in turn inflammatory processes. The equal ability to reduce and oxidize superoxide during the dismutation process and recently accumulated results suggest that pro-oxidative actions of MnPs may also contribute to their therapeutic effects. All our data identify the superoxide dismutase-like activity, estimated by log k(cat)O2-*), as a good measure for the therapeutic efficacy of MnPs. Their accumulation in mitochondria and their ability to cross the blood-brain barrier contribute to their remarkable efficacy. We summarize herein the therapeutic effects of MnPs in cancer, central nervous system injuries, diabetes, their radioprotective action and potential for imaging. Few of the most potent modulators of cellular redox-based pathways, MnTE2-PyP5+, MnTDE-2-ImP5+, MnTnHex-2-PyP5+ and MnTnBuOE-2-PyP5+, are under preclinical and clinical development.Item Open Access Four-decade responses of soil trace elements to an aggrading old-field forest: B, Mn, Zn, Cu, and Fe.(Ecology, 2008-10) Li, Jianwei; Richter, Daniel D; Mendoza, Arlene; Heine, PaulIn the ancient and acidic Ultisol soils of the Southern Piedmont, USA, we studied changes in trace element biogeochemistry over four decades, a period during which formerly cultivated cotton fields were planted with pine seedlings that grew into mature forest stands. In 16 permanent plots, we estimated 40-year accumulations of trace elements in forest biomass and O horizons (between 1957 and 1997), and changes in bioavailable soil fractions indexed by extractions of 0.05 mol/L HCl and 0.2 mol/L acid ammonium oxalate (AAO). Element accumulations in 40-year tree biomass plus O horizons totaled 0.9, 2.9, 4.8, 49.6, and 501.3 kg/ha for Cu, B, Zn, Mn, and Fe, respectively. In response to this forest development, samples of the upper 0.6-m of mineral soil archived in 1962 and 1997 followed one of three patterns. (1) Extractable B and Mn were significantly depleted, by -4.1 and -57.7 kg/ha with AAO, depletions comparable to accumulations in biomass plus O horizons, 2.9 and 49.6 kg/ha, respectively. Tree uptake of B and Mn from mineral soil greatly outpaced resupplies from atmospheric deposition, mineral weathering, and deep-root uptake. (2) Extractable Zn and Cu changed little during forest growth, indicating that nutrient resupplies kept pace with accumulations by the aggrading forest. (3) Oxalate-extractable Fe increased substantially during forest growth, by 275.8 kg/ha, about 10-fold more than accumulations in tree biomass (28.7 kg/ha). The large increases in AAO-extractable Fe in surficial 0.35-m mineral soils were accompanied by substantial accretions of Fe in the forest's O horizon, by 473 kg/ha, amounts that dwarfed inputs via litterfall and canopy throughfall, indicating that forest Fe cycling is qualitatively different from that of other macro- and micronutrients. Bioturbation of surficial forest soil layers cannot account for these fractions and transformations of Fe, and we hypothesize that the secondary forest's large inputs of organic additions over four decades has fundamentally altered soil Fe oxides, potentially altering the bioavailability and retention of macro- and micronutrients, contaminants, and organic matter itself. The wide range of responses among the ecosystem's trace elements illustrates the great dynamics of the soil system over time scales of decades.Item Open Access H2O2-Driven Anticancer Activity of Mn Porphyrins and the Underlying Molecular Pathways.(Oxidative medicine and cellular longevity, 2021-01) Batinic-Haberle, Ines; Tovmasyan, Artak; Huang, Zhiqing; Duan, Weina; Du, Li; Siamakpour-Reihani, Sharareh; Cao, Zhipeng; Sheng, Huaxin; Spasojevic, Ivan; Alvarez Secord, AngelesMn(III) ortho-N-alkyl- and N-alkoxyalkyl porphyrins (MnPs) were initially developed as superoxide dismutase (SOD) mimics. These compounds were later shown to react with numerous reactive species (such as ONOO-, H2O2, H2S, CO3 •-, ascorbate, and GSH). Moreover, the ability of MnPs to oxidatively modify activities of numerous proteins has emerged as their major mechanism of action both in normal and in cancer cells. Among those proteins are transcription factors (NF-κB and Nrf2), mitogen-activated protein kinases, MAPKs, antiapoptotic bcl-2, and endogenous antioxidative defenses. The lead Mn porphyrins, namely, MnTE-2-PyP5+ (BMX-010, AEOL10113), MnTnBuOE-2-PyP5+ (BMX-001), and MnTnHex-2-PyP5+, were tested in numerous injuries of normal tissue and cellular and animal cancer models. The wealth of the data led to the progression of MnTnBuOE-2-PyP5+ into four Phase II clinical trials on glioma, head and neck cancer, anal cancer, and multiple brain metastases, while MnTE-2-PyP5+ is in Phase II clinical trial on atopic dermatitis and itch.Item Open Access Pharmacology of riluzole in acute spinal cord injury.(Journal of neurosurgery. Spine, 2012-09) Chow, Diana SL; Teng, Yang; Toups, Elizabeth G; Aarabi, Bizhan; Harrop, James S; Shaffrey, Christopher I; Johnson, Michele M; Boakye, Maxwell; Frankowski, Ralph F; Fehlings, Michael G; Grossman, Robert GObject
The aim of this paper was to characterize individual and population pharmacokinetics of enterally administered riluzole in a Phase 1 clinical trial of riluzole as a neuroprotective agent in adults 18-70 years old with acute spinal cord injury (SCI).Methods
Thirty-five individuals with acute SCI, American Spinal Injury Association Impairment Scale Grades A-C, neurological levels from C-4 to T-12, who were enrolled in the Phase 1 clinical trial sponsored by the North American Clinical Trials Network for Treatment of Spinal Cord Injury, received 50 mg riluzole twice daily for 28 doses. The first dose was administered at a mean of 8.7 ± 2.2 hours postinjury. Trough plasma samples were collected within 1 hour predose, and peak plasma samples were collected 2 hours postdose on Days 3 and 14 of treatment. Riluzole concentrations were quantified by high-performance liquid chromatography assay. The data were analyzed for individual and population pharmacokinetics using basic structural and covariate models. The pharmacokinetic measures studied were the peak concentration (C(max)), trough concentration (C(min)), systemic exposure (AUC(0-12)), clearance (CL/F), and volume of distribution (V_F) normalized by the bioavailability (F).Results
The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher CL and larger V. The pharmacokinetics of riluzole (C(max), C(min), AUC(0-12), CL, and V) changed during the acute and subacute phases of SCI during the 14 days of therapy. It was consistently observed in patients at all clinical sites that C(max), C(min), and AUC(0-12) (128.9 ng/ml, 45.6 ng/ml, and 982.0 ng × hr/ml, respectively) were significantly higher on Day 3 than on Day 14 (76.5 ng/ml, 19.1 ng/ml, and 521.0 ng × hr/ml, respectively). These changes resulted from lower CL (49.5 vs 106.2 L/hour) and smaller V (557.1 vs 1297.9/L) on Day 3. No fluid imbalance or cytochrome P 1A2 induction due to concomitant medications was identified during the treatment course to account for such increases in V and CL, respectively. Possible mechanisms underlying these changes are discussed.Conclusions
This is the first report of clinical pharmacokinetics of riluzole in patients with SCI. The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher clearance and larger volume of distribution in SCI patients. The finding in SCI patients of an increase in the clearance and distribution of riluzole between the 3rd and 14th days after SCI, with a lower plasma concentration of riluzole on the 14th day, stresses the importance of monitoring changes in drug metabolism after SCI in interpreting the safety and efficacy of therapeutic drugs that are used in clinical trials in SCI. Clinical trial registration no.: NCT00876889.