Independence and inverted dependence on temperature of rates of photoinduced electron transfer in double-linked phthalocyanine-fullerene dyads.

Photoinduced electron transfer reactions of phthalalocyanine-fullerene dyads, in which donor and acceptor moieties are covalently linked to each other, with one or two malonic linkers, were studied. In the dyads with two linkers, phthalocyanine and fullerene have mutual orientations, face-to-face or face-to-tail, which differ from each other and influence photoinduced electron transfer processes. Quantitative spectroscopic and time-resolved spectroscopic measurements were done in polar and non-polar solvents at room temperature and at several reduced temperatures.

SLCO1B1 polymorphism and oral antidiabetic drugs.

Organic anion-transporting polypeptide 1B1 (OATP1B1; gene: SLCO1B1) is an influx transporter expressed on the sinusoidal membrane of human hepatocytes, where it mediates the uptake of its substrates from blood into liver. In vitro, the SLCO1B1 c.521T>C (p.

Itraconazole, a P-glycoprotein and CYP3A4 inhibitor, markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren.

In a randomized crossover study, 11 healthy volunteers took 100 mg (first dose 200 mg) of the antifungal drug itraconazole, a P-glycoprotein and CYP3A4 inhibitor, or placebo twice daily for 5 days. On day 3, they ingested a single 150-mg dose of aliskiren, a renin inhibitor used in the treatment of hypertension. Itraconazole raised the peak plasma aliskiren concentration 5.

Membrane transporters in drug development.

Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed.

Rifampicin reduces the plasma concentrations and the renin-inhibiting effect of aliskiren.

Purpose: This study aimed to investigate the effect of rifampicin, an inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics and pharmacodynamics of aliskiren, a renin inhibitor used in the treatment of hypertension.

Methods: In a randomized crossover study, 12 healthy volunteers took 600 mg rifampicin or placebo once daily for 5 days. On day 6, they ingested a single 150-mg dose of aliskiren.

Transient dimers of allergens.

Background: Allergen-mediated cross-linking of IgE antibodies bound to the FcepsilonRI receptors on the mast cell surface is the key feature of the type I allergy. If an allergen is a homodimer, its allergenicity is enhanced because it would only need one type of antibody, instead of two, for cross-linking.

Methodology/principal Findings: An analysis of 55 crystal structures of allergens showed that 80% of them exist in symmetric dimers or oligomers in crystals.

Long-term changes in cyclosporine pharmacokinetics after renal transplantation in children: evidence for saturable presystemic metabolism and effect of NR1I2 polymorphism.

To improve cyclosporine dose individualization, the authors carried out a comprehensive analysis of the effects of clinical and genetic factors on cyclosporine pharmacokinetics in 176 children before and up to 16 years after renal transplantation. Pretransplantation test doses of cyclosporine were given intravenously and orally, followed by blood sampling for 24 hours. After transplantation, cyclosporine was quantified at trough, 2 hours postdose, or with dose-interval curves.

Case fatality rates after first acute coronary syndrome in persons treated for type 2 diabetes show an improving trend.

Aims/hypothesis: We analysed whether the prognosis of a first acute coronary syndrome (ACS) in patients treated for type 2 diabetes has improved. We also compared the trends in patients with and without diabetes.

Methods: We used national registers to identify all patients with clinically known type 2 diabetes in Finland during the years 1988 to 2002 (n = 222,940).

High performance liquid chromatography-tandem mass spectrometry for the determination of bile acid concentrations in human plasma.

We report a sensitive and robust method to determine cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), ursodeoxycholic acid (UDCA), and their taurine- and glycine-conjugate concentrations in human plasma using liquid chromatography-tandem mass spectrometry. Activated charcoal was utilized to prepare bile acid-free plasma, which served as the biological matrix for the preparation of standard and quality control samples. Plasma sample preparation involved solid-phase extraction.

Transporter pharmacogenetics and statin toxicity.

Polymorphisms in transporter genes can have profound effects on statin pharmacokinetics. In particular, a common genetic variant of organic anion-transporting polypeptide 1B1 reduces the hepatic uptake of many statins, increasing the risk of statin-induced myopathy. Similarly, genetically impaired adenosine triphosphate (ATP)-binding cassette G2 transporter efflux activity results in a marked increase in systemic exposure to various statins.

The social contexts of depression during motherhood: a study of Explanatory Models in Vietnam.

Background: Major depression is increasing world-wide, and is the fourth leading cause of the global disease burden. Depression is rarely diagnosed in primary care settings in Vietnam, and those afflicted usually only seek professional care when the illness has become very severe. Depressive disorders affecting mothers are an important cause of low birth-weight, childhood stunting, under nutrition and adverse mental development, and a study has shown a 33% prevalence of postnatal depression symptoms in Ho Chi Minh City.

Different effects of the ABCG2 c.421C>A SNP on the pharmacokinetics of fluvastatin, pravastatin and simvastatin.

Aims: This study aimed to investigate possible effects of the ABCG2 c.421C>A (p.Gln141Lys; rs2231142) genotype on fluvastatin, pravastatin and simvastatin pharmacokinetics.

UDP-glucuronosyltransferase (UGT) polymorphisms affect atorvastatin lactonization in vitro and in vivo.

The response to statins shows large interpatient variability. Atorvastatin delta-lactone is pharmacologically inactive but has been associated with toxicity. We investigated the role of UDP-glucuronosyltransferases (UGTs) in atorvastatin lactonization.

Impact of OATP transporters on pharmacokinetics.

Membrane transporters are now recognized as important determinants of the transmembrane passage of drugs. Organic anion transporting polypeptides (OATP) form a family of influx transporters expressed in various tissues important for pharmacokinetics. Of the 11 human OATP transporters, OATP1B1, OATP1B3 and OATP2B1 are expressed on the sinusoidal membrane of hepatocytes and can facilitate the liver uptake of their substrate drugs.

CYP2C8 activity recovers within 96 hours after gemfibrozil dosing: estimation of CYP2C8 half-life using repaglinide as an in vivo probe.

Gemfibrozil 1-O-beta-glucuronide is a mechanism-based inhibitor of cytochrome P450 2C8. We studied the recovery of CYP2C8 activity after discontinuation of gemfibrozil treatment using repaglinide as a probe drug, to estimate the in vivo turnover half-life of CYP2C8. In a randomized five-phase crossover study, nine healthy volunteers ingested 0.

No significant effect of ABCB1 haplotypes on the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin.

Aims: This study aimed to investigate possible effects of ABCB1 genotype on fluvastatin, pravastatin, lovastatin, and rosuvastatin pharmacokinetics.

Methods: In a fixed-order crossover study, 10 healthy volunteers with the ABCB1 c.1236C/C-c.

Synthesis, conformational interconversion, and photophysics of tethered porphyrin-fullerene dyads with parachute topology.

The synthesis of a porphyrin-fullerene dyad with "parachute" topology is reported. To determine whether the dyad is "flexing" at room temperature, low-temperature NMR experiments were used. Computational modeling has shown the low-energy conformation of the dyad to be nonsymmetric.

Time-dependent alterations of peripheral immune parameters after nigrostriatal dopamine depletion in a rat model of Parkinson's disease.

Dysfunction of the central dopaminergic system is associated with neurodegenerative disorders and mental illnesses such as Parkinson's disease and schizophrenia. Patients suffering from these diseases were reported to exhibit altered immune functions compared to healthy subjects and imbalance of the central dopaminergic system has been suggested as one causative factor for the immune disturbances. However, it is unclear whether the observed immune changes are primary or secondary to the disease.

ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin.

The ABCG2 c.421C>A single-nucleotide polymorphism (SNP) was determined in 660 healthy Finnish volunteers, of whom 32 participated in a pharmacokinetic crossover study involving the administration of 20 mg atorvastatin and rosuvastatin. The frequency of the c.

Effect of SLCO1B1 polymorphism on the plasma concentrations of bile acids and bile acid synthesis marker in humans.

Background And Objective: Organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1) is a sinusoidal influx transporter of human hepatocytes. Our aim was to characterize the role of OATP1B1 in the hepatic uptake of bile acids in vivo.

Methods: Fasting blood samples were drawn from 24 healthy volunteers with SLCO1B1 c.

Acoustic and neurophysiologic observations related to lingual nerve impairment.

The purpose of this study was to determine the acoustic effects of lingual nerve impairment on speech. Neurophysiologic examination and thermal quantitative sensory testing (QST) were carried out to determine if the profile, type or severity of sensory nerve impairment had effects on the degree of speech changes. The study group consisted of 5 women and 5 men with lingual nerve damage following an oral and maxillofacial surgery procedure.

Effects of gemfibrozil and atorvastatin on the pharmacokinetics of repaglinide in relation to SLCO1B1 polymorphism.

In a randomized crossover study, 24 SLCO181-genotyped healthy volunteers were given daily doses of 1,200 mg gemfibrozil, 40 mg atorvastatin, or placebo, followed by 0.25 mg of repaglinide on day 3. The mean increase in the repaglinide area under the plasma concentration-time curve from 0 h to infinity (AUC(0-infinity)) produced by gemfibrozil was larger in individuals with the SLCO1B1 c.

ABCB1 haplotypes differentially affect the pharmacokinetics of the acid and lactone forms of simvastatin and atorvastatin.

ABCB1 haplotypes were determined in 534 healthy Finnish volunteers, of whom 24 participated in a pharmacokinetic study on simvastatin and atorvastatin. The frequencies of occurrence of haplotypes c.1236T-c.

The contribution of polystyrene nanospheres towards the crystallization of proteins.

Background: Protein crystallization is a slow process of trial and error and limits the amount of solved protein structures. Search of a universal heterogeneous nucleant is an effort to facilitate crystallizability of proteins.

Methodology: The effect of polystyrene nanospheres on protein crystallization were tested with three commercial proteins: lysozyme, xylanase, xylose isomerase, and with five research target proteins: hydrophobins HFBI and HFBII, laccase, sarcosine dimethylglycine N-methyltransferase (SDMT), and anti-testosterone Fab fragment 5F2.

Calcineurin inhibition in splenocytes induced by pavlovian conditioning.

Pavlovian conditioning is one of the major neurobiological mechanisms of placebo effects, potentially influencing the course of specific diseases and the response to a pharmacological therapy, such as immunosuppression. In our study with behaviorally conditioned rats, a relevant taste (0.2% saccharin) preceded the application of the immunosuppressive drug cyclosporin A (CsA), a specific calcineurin (CaN) inhibitor.