Influence of drug transporters and stereoselectivity on the brain penetration of pioglitazone as a potential medicine against Alzheimer's disease

10.1038/srep09000Scientific Reports

Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation

One potential approach for treating obesity is to increase energy expenditure in brown and white adipose tissue. Here we aimed to achieve this outcome by targeting mitochondrial uncoupler compounds selectively to adipose tissue, thus avoiding side effects from uncoupling in other tissues. Selective drug accumulation in adipose tissue has been observed with many lipophilic compounds and dyes. Hence, we explored the feasibility of conjugating uncoupler compounds with a lipophilic C8-hydrocarbon chain via an ether bond. We found that substituting the trifluoromethoxy group in the uncoupler FCCP with a C8-hydrocarbon chain resulted in potent uncoupling activity. Nonetheless, the compound did not elicit therapeutic effects in mice, likely as a consequence of metabolic instability resulting from rapid ether bond cleavage. A lipophilic analog of the uncoupler compound 2,6-dinitrophenol, in which a C8-hydrocarbon chain was conjugated via an ether bond in the para-position (2,6-dinitro-4-(octyloxy)phenol), exhibited increased uncoupling activity compared to the parent compound. However, in vivo pharmacokinetics studies suggested that 2,6-dinitro-4-(octyloxy)phenol was also metabolically unstable. In conclusion, conjugation of a hydrophobic hydrocarbon chain to uncoupler compounds resulted in sustained or improved uncoupling activity. However, an ether bond linkage led to metabolic instability, indicating the need to conjugate lipophilic groups via other chemical bonds

Fine Mapping of the NRG1 Hirschsprung's Disease Locus

The primary pathology of Hirschsprung's disease (HSCR, colon aganglionosis) is the absence of ganglia in variable lengths of the hindgut, resulting in functional obstruction. HSCR is attributed to a failure of migration of the enteric ganglion precursors along the developing gut. RET is a key regulator of the development of the enteric nervous system (ENS) and the major HSCR-causing gene. Yet the reduced penetrance of RET DNA HSCR-associated variants together with the phenotypic variability suggest the involvement of additional genes in the disease. Through a genome-wide association study, we uncovered a ∼350 kb HSCR-associated region encompassing part of the neuregulin-1 gene (NRG1). To identify the causal NRG1 variants contributing to HSCR, we genotyped 243 SNPs variants on 343 ethnic Chinese HSCR patients and 359 controls. Genotype analysis coupled with imputation narrowed down the HSCR-associated region to 21 kb, with four of the most associated SNPs (rs10088313, rs10094655, rs4624987, and rs3884552) mapping to the NRG1 promoter. We investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues (40 patients and 21 controls) and found differences in expression as a function of genotype. We also found significant differences in NRG1 expression levels between diseased and control individuals bearing the same rs10088313 risk genotype. This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Dosage form design

Conventional dosage forms, including liquids, semisolids and solids, are the backbone of pharmaceutical industry and practice. These form the core of the pharmaceutics curriculum around the world, at undergraduate and postgraduate levels, although there are subtle differences in the depth and breadth of topics covered in different countries. In countries with a limited industrial basis, the focus is more on clinical aspects, extemporaneous compounding and dosage regimens. Irrespective of the scope, a good understanding of these dosage units is critical for every pharmacist

Pharmacokinetics and biopharmaceutics

[Extract] Oral dosage forms are widely used due to the convenience of drug administration. There are several steps a dosage form/delivery system has to undergo before it produces a therapeutic response. This can be explained by the LADMER system which includes liberation of a drug from the dosage form, absorption of the drug, distribution of the drug, metabolism of the drug, excretion of the drug and finally the response. Biopharmaceutics deals with the study of physiochemical and physiological factors that influence the liberation and absorption of drugs from different dosage forms. Pharmacokinetics deals with the absorption, distribution, metabolismn and excretion of a drug; the study of drug response is known as pharmacodynamics. In simple terms, biopharmaceutics is what the pharmceutical scientist does to the drug, pharmacokinetics is what the body does to the drug, and pharmadynamics is what the drug does to the body. Optimisation of biopharmaceutics and pharmacokinetic properties plays a significant role in the development of new drugs. This can be exemplified by the fact that 40% of drug candidates do not make it to market because of poor biopharmaceutical and pharmacokinetic properties. Drug solubility and permeability are the two most important biopharmaceutical properties that influence drug absorption and oral bioavailability. This led to the biopharmaceutics classification system (BCS), which classifies drugs into four classes based on their aqueous solubility and permability. These two properties are determined by sthe drug's physicochemical properties, such as its chemical structure, molecular weight, pKa, partition coefficient, crystal structure and particle size, among others. Drugs with good aqueous solubility and membrane permeability generally show good oral absorption and bioavailability provided the drug is stable in the gastrointestinal tract and does not undergo first-pass metabolism in the liver. Several technologies have emerged to address the poor solubility and permeability of drugs. The important pharmacokinetic parameters that influence the biological performance of dosage forms are volume of distribution, half-life, clearance and fraction absorbed. The volume of distribution and clearance influence the drug's half life, which in turn governs the frequency of drug administration. Clearance and fraction absorbed influence the bioavailability, which in turn determines the dose of a drug. Depending on how the drug is distributed into the body, different mathematical models can be used to characterise the drug disposition and estimate the pharmacokinetic parameters. In oral modified-release systems when or where the drug is released in the gastrointestinal tract is modified. These systems can be broadly divided into delayed-release systems aned extended release systems. In the case of delayed-release systems, the drug release is delayed but not sustained. In the case of extended-release systems, the drug release is sustained or controlled with respect to time, thus reducing the frequency of administration

Correlation between tea consumption and prevalence of hypertension among Singaporean Chinese residents aged ≥ 40 years

By a cross-sectional epidemiology study, we attempted to correlate the consumption of tea and/or health supplements, living habits and socio-demographic factors to the prevalence of hypertension among Singaporean Chinese residents. Singaporean Chinese residents aged ⩾40 years were randomly selected and interviewed face-to-face by clinical research assistants. Hypertension was defined as measured systolic blood pressure at least 140mmHg and/or diastolic blood pressure at least 90mmHg or self-reported history/treatment for hypertension. The prevalence of hypertension among the whole investigated population (N = 1184, 58.27% females) was 49.73% and the prevalence increased to 66.47% in the sub-population aged ⩾60 years. High risk of hypertension was associated with age ⩾60 years (odds ratio (OR): 4.15–4.19, P˂0.01), obesity (body mass index 425 kgm−2, OR: 2.10–2.11, P˂0.01), family history of hypertension (OR: 2.69–2.76, P˂0.01), diabetes history (OR: 2.29–2.33, P˂0.01), hyperlipidemia history (OR: 1.79–1.80, P˂0.01), male (OR: 1.56–1.59, P˂0.01) and coffee intake (OR: 1.44–1.46, P˂0.05). In contrast, drinking green tea at least 150 ml per week was associated with lower hypertension risk (OR: 0.63, 95% confidence interval (CI): 0.43–0.91, P˂0.05). Drinking combination of green tea and British tea was associated with higher reduction in the risk of hypertension (OR: 0.58, 95% CI: 0.39–0.85, P˂0.05). This cross-sectional study suggests that consumption of tea, especially green tea and British tea, was associated with lowering the risk of hypertension. On the other hand, consumption of coffee could be a risk factor of hypertension. These findings may provide useful information for health promotion to reduce risk of hypertension and warrant further study to confirm and elucidate such association

GC-MS Fingerprinting Combined with Chemical Pattern-Recognition Analysis Reveals Novel Chemical Markers of the Medicinal Seahorse

Seahorse is a valuable marine-animal drug widely used in traditional Chinese medicine (TCM), and which was first documented in the “Ben Cao Jing Ji Zhu” during the Liang Dynasty. Hippocampus kelloggi (HK) is the most common seahorse species in the medicinal material market and is one of the genuine sources of medicinal seahorse documented in the Chinese pharmacopeia. It is mainly cultivated in the Shandong, Fujian, and Guangxi Provinces in China. However, pseudo-HK, represented by Hippocampus ingens (HI) due to its similar appearance and traits, is often found in the market, compromising the safety and efficacy of clinical use. Currently, there is a lack of reliable methods for identifying these species based on their chemical composition. In this study, we employed, for the first time, a strategy combining gas chromatography-mass spectrometry (GC-MS) fingerprints and chemical patterns in order to identify HK and HI; it is also the first metabolomic study to date of HI as to chemical components. The obtained results revealed remarkable similarities in the chemical fingerprints, while significant differences were also observed. By employing hierarchical cluster analysis (HCA) and principal component analysis (PCA), based on the relative contents of their characteristic peaks, all 34 samples were successfully differentiated according to their species of origin, with samples from the same species forming distinct clusters. Moreover, nonadecanoic acid and behenic acid were exclusively detected in HK samples, further distinguishing them from HI samples. Additionally, the relative contents of lauric acid, tetradecanoic acid, pentadecanoic acid, n-hexadecanoic acid, palmitoleic acid, margaric acid, oleic acid, fenozan acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) exhibited significant differences between HK and HI (p t-test. Orthogonal partial least squares discriminant analysis (OPLS-DA) identified seven components (DHA, EPA, n-hexadecanoic acid, tetradecanoic acid, palmitoleic acid, octadecanoic acid, and margaric acid) with high discriminatory value (VIP value > 1). Thus, nonadecanoic acid, behenic acid, and these seven compounds can be utilized as chemical markers for distinguishing HK from HI. In conclusion, our study successfully developed a combined strategy of GC-MS fingerprinting and chemical pattern recognition for the identification of HK and HI, and we also discovered chemical markers that can directly differentiate between the two species. This study can provide a foundation for the authentication of Hippocampus and holds significant importance for the conservation of wild seahorse resources