Phamacokinetics

The present study deals with the development of an artificial neural network based quantitative structure activity relationship (QSAR) model for virtual screening of active compounds which contain androstenedione carbonskeleton or their similar skeleton at the core. An empirical data modeling (with fitted data mapping) has been performed on the basis of bioassay record for human breast cancer cell line MCF7. The whole experimental data set was considered as test set. Standard feed-forward back-propagation neural network technique was applied to build the model...

Small molecule chaperones are a promising therapeutic approach for the Lysosomal Storage Disorders (LSDs). Here, we report the discovery of a new series of non-iminosugar glucocerebrosidase inhibitors with chaperone capacity, and describe their structure activity relationship (SAR), selectivity, cell activity phamacokinetics.

OBJECTIVE: To determine bergapten's concentration in plasma and observe its pharmacokinetics in rats using a combined LC-MS/MS analytical method. METHOD: Blood samples were separated on a Hypersil ODS column (4.6 mm x 250 mm, 5 mm) at a temperature of 30 degrees C, and mobile phase consisted of water and methanol (22.5: 77.5) at a flow rate of 0.8 mL x min(-1). RESULT: The methodological study showed a good linear relationship of 8.12-162...

Therapeutic chaperone effect of a valienamine derivative N-octyl 4-epi-β-valienamine (NOEV) was studied in G(M1)-gangliosidosis model mice. Phamacokinetic analysis revealed rapid intestinal absorption and renal excretion after oral administration. Intracellular accumulation was not observed after continuous treatment. NOEV was delivered to the central nervous system through the blood-brain barrier to induce high expression of the apparently deficient β-galactosidase activity. NOEV treatment starting at the early stage of disease resulted in remarkable arrest of neurological progression within a few months...

From a medicinal chemistry point of view, one of the primary goals of high throughput screening (HTS) hit list assessment is the identification of chemotypes with an informative structure-activity relationship (SAR). Such chemotypes may enable optimization of the primary potency, as well as selectivity and phamacokinetic properties. A common way to prioritize them is molecular clustering of the hits. Typical clustering techniques, however, rely on a general notion of chemical similarity or standard rules of scaffold decomposition and are thus insensitive to molecular features that are enriched in biologically active compounds...

The preparation and characterization of a series of thiophenyl oxime phosphonate beta-lactamase inhibitors is described. A number of these analogs were potent and selective inhibitors of class C beta-lactamases from Pseudomonas aeruginosa and Enterobacter cloacae. Compounds 3b and 7 reduced the MIC of imipenem against an AmpC expressing strain of imipenem-resistant P. aeruginosa. A number of the title compounds retained micromolar potency against the class D OXA-40 beta-lactamase from Acinetobacter baumannii and at high concentrations compound 3b was shown to reduce the MIC of imipenem against a highly imipenem-resistant strain of A...

The objectives of the simulation study were to evaluate the impact of BQL data on pharmacokinetic (PK) parameter estimates when the incidence of BQL data is low (e.g. ≤10%), and to compare the performance of commonly used modeling methods for handling BQL data such as data exclusion (M1) and likelihood-based method (M3). Simulations were performed by adapting the method of a recent publication by Ahn et al. (J Phamacokinet Pharmacodyn 35(4):401-421, 2008). The BQL data in the terminal elimination phase were created at frequencies of 1, 2...

The benzodiazepine prescribing habits of 64 maritime doctors were studied through collection and examination of carbon copies of all prescriptions over a 22 week period. Diazepam was the most frequently prescribed anxiolytic benzodiazepine, followed by chlordiazepoxide, then oxazepam. These three drugs accounted for almost 60% of all benzodiazepine prescriptions. Triazolam and flurazepam were prescribed eight times more frequently than the other hypnotics, nitrazepam and temazepam. The number of prescriptions judged to be inappropriately excessive was small (3...

The invention of imidacloprid, the most important neonicotinoid insecticide, was initiated by replacement of the framework of nithiazine with an imidazolidine ring. Through the finding of 1-(6-chloro-3-pyridylmethyl)-2-nitromethyleneimidazolidine, imidacloprid was invented. At the same time cyanoiminothiazolidinyl neonicotinoid thiacloprid was discovered. These products possess pronounced systemic properties and improved photostability in addition to supreme insecticidal ability. Crystal structure analysis led to the drug-receptor interaction model consisting of the guanidine (amidine) part conjugated to a powerful electron-withdrawing group bearing an H-bond accepting tip such as NO(2) or CN, and the chloronicotinyl group enhances the binding to the receptor...

Numerous investigations on metabolic enzymes, cytochrome P450 (CYP) have been conducted since 1990. In the psychiatric field, CYP2D6, which is a major enzyme involved in the metabolism of antidepressants and antipsychotics, has been focused on. Poor metabolizers (deficit metabolizers) for CYP2D6 are 7% in Caucasians, while they are less than 1% in Asians. Frequency of a mutated allele for CYP2D6*10, which leads to a decrease in CYP2D6 activity, is 40% in Asians. It has been reported that the steady-state plasma concentration of haloperidol in subjects with mutated alleles for CYP2D6 is significantly higher than that in subjects without mutated alleles...

Systems of fractional differential equations (SFDE) have been increasingly used to represent physical and control system, and have been recently proposed for use in pharmacokinetics (PK) by (J Pharmacokinet Pharmacodyn 36:165-178, 2009) and (J Phamacokinet Pharmacodyn, 2010). We contribute to the development of a theory for the use of SFDE in PK by, first, further clarifying the nature of systems of FDE, and in particular point out the distinction and properties of commensurate versus non-commensurate ones...

A selective and sensitive high-performance liquid chromatography method with UV detection for the determination of metronidazole in dried blood spots (DBS) has been developed and validated. DBS samples [spiked or patient samples] were prepared by applying blood (30 microL) to Guthrie cards. Discs (6 mm diameter) were punched from the cards and extracted using water containing the internal standard, tinidazole. The extracted sample was chromatographed without further treatment using a reversed phase system involving a Symmetry(R) C18 (5 microm, 3...

2-Cyano-3,10-dioxooleana-1,9(11)-dien-28-oic acid anhydride (CDDO anhydride) has been synthesized, which is the first example of an oleanane triterpenoid anhydride. CDDO anhydride shows potency similar to or higher than the corresponding acid (CDDO) in various in vitro and in vivo assays related to inflammation and carcinogenesis. Notably, preliminary phamacokinetics studies show that CDDO anhydride levels are higher than CDDO levels in mouse tissues and blood. Further evaluation of CDDO anhydride is in progress...

BACKGROUND: Ritonavir has been evaluated at boosting doses of 50–800 mg daily with seven protease inhibitors: amprenavir, atazanavir, darunavir, indinavir, lopinavir,saquinavir and tipranavir. Minimizing the boosting dose of ritonavir could improve tolerability and lower costs. METHODS: A MEDLINE search identified 17 phamacokinetic trials using different ritonavir doses with protease inhibitors. The dose of ritonavir used was correlated with plasma levels of each boosted protease inhibitor...

While photodynamic therapy (PDT) has been recognized as a promising therapeutic modality for the treatment of various cancers and diseases, developments of effective photosensitizers are highly desired to improve the prospect for the use of PDT. In this study, we evaluated DH-II-24, a new photosensitizer, for antitumor PDT in vitro and in vivo. Loaded into human colorectal carcinoma cells (HCT116), DH-II-24 was primarily accumulated in mitochondria, lysosomes, and endoplasmic reticula. Administration of DH-II-24 followed by light exposure induced necrotic cell death in a dose-dependent manner, whereas DH-II-24 in the absence of light induced minimal cell death...

Nitric oxide (NO) is a ubiquitous molecule involved in multiple cellular functions. Inappropriate production of NO may lead to disease states. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by rapid NO release, toxicity and induction of tolerance. Therefore, novel NO donors with better pharmacological and phamacokinetic properties are highly desirable. The S-nitrosothiol fraction in plasma is largely composed of S-nitrosylated human serum albumin (SNO-HSA) and that is why we are testing whether this albumin form can be used as a NO traffic protein...

PURPOSE OF REVIEW: Sedation is a well recognized technique to improve patients' acceptance and comfort during regional anesthesia. The use of this technique is growing exponentially and is nowadays applied not only in the operating room but also in many other different locations within and outside the hospital. RECENT FINDINGS: Different methods of applying sedation are used. Recent studies have shown that the target-controlled infusion technique is advantageous in this context, as the incidence of side effects is lower and the amount of infused drugs is decreased...

Invasive fungal infections are an important cause of morbidity and mortality in critically ill and immunocompromised patients. Amphotericin B has remained the gold standard treatment for systemic fungal infections. The primary obstacle to amphotericin B therapy is its poor solubility and dose-related toxicities, especially renal impairment. As a result, newer lipid-based formulations of amphotericin B have been developed. This monograph compares available phamacokinetic, efficacy, and safety data for the 3 lipid-based formulations of amphotericin B, with reference to various patient populations...

Alzheimer's disease (AD) is the most common cause of dementia and is characterized by an insidious onset and slow deterioration in cognition, activities of daily living (ADL), mood stability and social functioning. The cholinesterase inhibitors (ChEIs), developed based on the cholinergic hypothesis, are currently considered to be the best established treatment for AD, although the significant advances in the symptomatic pharmacotherapy of AD may be followed by disease-modification treatments. Donepezil is a mixed competitive and noncompetitive acetylcholinesterase inhibitor that shows a relative selectivity for acetylcholinesterase inhibitor compared with butyrylcholinesterase...

BACKGROUND: Cryopyrin-associated periodic syndromes (CAPS) encompass a group of rare inherited, autoinflammatory disorders that represent a spectrum of one disease with varying degrees of severity. Until recently, there was no effective treatment for CAPS, but identification of the genetic basis of CAPS highlighted the pathogenic role of IL-1beta. OBJECTIVES: Rilonacept is a recently FDA approved biologic therapy for CAPS with high affinity for IL-1beta. Limited pharmacological data has been reported to date...