Rapid robust separation of hydroxyproline and proline.

The presence of hydroxyproline, and the determination of the ratio of the secondary amino acids proline to hydroxyproline, in amino acid hydrolysates specifically identifies collagen and collagen peptides. o-Phthalaldehyde, and then 9-fluorenylmethyl chloroformate, were used to carry out sequential prederivatization of amino acid hydrolysates in an in-line high-performance liquid chromatography sample loop. After derivatization, reversed-phase high-performance liquid chromatography with a C-18 ODS Hypersil cartridge column was used to resolve the hydroxyproline and proline from all primary amino acids, with resolution and detection of hydroxyproline and proline within 2.0 and 2.8 min, respectively, at concentrations in the range of picomoles per microliter of derivatized amino acid. The assay has a turnaround time of 10.75 min.     

Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine D3/D2 receptors

Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D(3)/D(2) compound (1) led to a series of new piperazine derivatives having affinity to both dopamine D(3) and D(2) receptors. Several members of this group showed excellent pharmacokinetic and pharmacodynamic properties as demonstrated by outstanding activities in different antipsychotic tests. The most promising representative, 2m (cariprazine) had good absorption, excellent brain penetration and advantageous safety profile. Based on its successful clinical development we are looking forward to the NDA filing of cariprazine in 2012.     

Kynurenic acid amides as novel NR2B selective NMDA receptor antagonists

A novel series of kynurenic acid amides, ring-enlarged derivatives of indole-2-carboxamides, was prepared and identified as in vivo active NR2B subtype selective NMDA receptor antagonists. The synthesis and SAR studies are discussed.     

Indole-2-carboxamides as novel NR2B selective NMDA receptor antagonists

A novel series of indole-2-carboxamide derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of the number and position of OH groups on the indole skeleton as well as the substitution of the piperidine ring on the biological activity of the compounds was studied.     

Randomized,Single Blind,Controlled Trial to Evaluate the Prime-Boost Strategy for Pneumococcal Vaccination in Renal Transplant Recipients

Renal transplant recipients are at increased risk of developing invasive pneumococcal diseases but may have poor response to the 23-valent pneumococcal polysaccharide vaccine (PPV). It may be possible to enhance immunogenicity by priming with 7-valent pneumococcal conjugate vaccine (7vPnC) and boosting with PPV 1 year later. In a randomized single-blind, controlled study, adult recipients of renal transplants received either 7nPVC or PPV followed by PPV 1 year later. The vaccine response was defined as 2-fold increase in antibody concentration from baseline and an absolute post-vaccination values ≥1 µg/ml. The primary endpoint was vaccine response of the primed group (7vPnC/PPV) compared with single PPV vaccination. Antibody concentrations for 10 serotypes were measured at baseline, 8 weeks after first vaccination, before second vaccination, and 8 weeks after second vaccination. Of 320 screened patients, 80 patients were randomized and 62 completed the study. Revaccination with PPV achieved no significant increase of immune response in the 7vPnC/PPV group compared with the single PPV recipients A response to at least 1 serotype was seen in 77.1% of patients who received 7vPnC and 93.1% of patients who received PPV (P = 0.046). After second vaccination response to at least 1 serotype was seen in 87.5% patients of 7vPnC/PPV group and 87.1% patients of PPV group (non significant p). The median number of serotypes eliciting a response was 3.5 (95% CI 2.5–4.5) in the 7vPnC/PPV group versus 5 (95% CI 3.9–6.1) in the PPV group (non-significant p). Immunogenicity of pneumococcal vaccination was not enhanced by the prime–boost strategy compared with vaccination with PPV alone. Administration of a single dose of PPV should continue to be the standard of care for adult recipients of renal transplants.

Trial Registration

EudraCT 2007-004590-25.     

Traditional knowledge hiding in plain sight – twenty-first century ethnobotany of the Chácobo in Beni,Bolivia

Background

The Chácobo are a Panoan speaking tribe of about 1000 members (300+ adults) in Beni, Bolivia. Originally nomadic, the Chácabo were relocated to their current main location in the 1960s. Researchers have visited the Chácabo since 1911. A first more detailed anthropological report exists from the late 1960s, and ecological–ethnobotanical studies were conducted in the 1980s and 1990s. The presented work represents a complete ethnobotanical inventory of the entire adult Chácobo population, with interviews and plant collection conducted directly by Chácobo counterparts.

Methods

Based on previous reports and our preliminary studies, we hypothesized that twenty-first century Chácobo plant use centered on income generation, and that traditional plant use related to household utensils, medicine and traditional crop varieties had almost disappeared. To test this hypothesis, we started the “Chácobo Ethnobotany Project,” training 10 indigenous Chácobo participants in ethnobotanical interview and plant collection techniques, in order to more fully document Chácobo knowledge and avoid the influence of foreign interviewers.

Results

Our study found 331 useful plant species in 241genera of 95 plant families, with leaves, roots and bark being the most commonly used plant parts The comprehensive documentation that these methods enabled completely nullified our initial hypothesis of knowledge loss. Traditional crop varieties are still widely grown and traditional knowledge is alive. Moreover, it is being actively recuperated in certain domains by the younger generation. Most Chácobo know, and can name, traditional utensils and tools, although only the older generation has still the skills to manufacture them. While many Chácobo still know the names and uses of medicinal species, the younger generation is however often unsure how to identify them.

Conclusions

In this paper we illustrate the complexity of perspectives on knowledge at different ages, and the persistence of knowledge over almost a century. We found that traditional knowledge was only partially affected by the processes of exposure to a market economy, and that different knowledge domains experienced different trends as a result of these changes. Overall knowledge was widely distributed, and we did not observe a directional knowledge loss.We stress the importance to not directly conclude processes of knowledge loss, cultural erosion or acculturation when comparing the knowledge of different age groups.

     

Oxamides as novel NR2B selective NMDA receptor antagonists

A novel series of oxamides derived from indole-2-carboxamides was identified as potent NR2B selective NMDA receptor antagonists. Several members of this group showed good analgesic activity in the mouse formalin test.     

Acceleration of healing,reduction of fibrotic scar,and normalization of tissue architecture by an angiotensin analogue,NorLeu3-A(1-7)

Angiotensin peptides have been demonstrated to modulate cellular proliferation, angiogenesis, and dermal repair. In this report, the effects of an analogue of the active angiotensin peptide angiotensin(1-7), namely norLeu3-angiotensin(1-7) (NorLeu3-A(1-7)), on the healing of epithelial wounds are presented. Three models were used to evaluate the normal (rats) and delayed (diabetic mice) healing responses of full-thickness excision wounds and the healing responses of full-thickness incision wounds (rats). NorLeu3-A(1-7) was superior to the naturally occurring angiotensin peptide angiotensin(1-7) and to Regranex (Ortho McNeil, Somerville, N.J.) (a formulation of recombinant platelet-derived growth factor used clinically for the treatment of diabetic ulcers) in accelerating tissue repair. By day 9 (normal rats) and day 11 (diabetic mice), the differences in the rates of closure of full-thickness excision wounds between NorLeu3-A(1-7) and Regranex were statistically significant (n = 5 per group). Full healing was observed for 60 percent of the diabetic mice treated topically with NorLeu3-A(1-7) by day 18 after injury, at which time full healing of wounds on placebo-treated or Regranex-treated diabetic mice was not observed. In the rat incision model, accelerated healing and reduced gross appearance of scarification were observed. Administration of NorLeu3-A(1-7) reduced fibrosis and scarring in the healing wounds. This action was more pronounced with longer administration of the peptide after injury. In fact, if systemic administration of the peptide (NorLeu3-A(1-7)) was continued during the remodeling phase, then the formation of new adnexal structures at the center of full-thickness excision wounds was observed, with an increase in the appearance of small immature hair follicles at the sites of the excision wounds. The action of this peptide was blocked by the AT receptor antagonist d-Ala7-angiotensin(1-7), which suggests that this receptor is involved in the healing responses to exogenous NorLeu3-A(1-7). These data suggest that this novel angiotensin peptide has the potential to be of benefit in accelerating wound repair and reducing scar formation.