Tiempos Pasados (Past Times). Grass-Roots Oral History.

ERIC Educational Resources Information Center

Hunsaker, Alan, Ed.

Compiled with learning objectives, suggested lesson plans, learning center activities, and selected teacher and student bibliographies for use at the elementary level, transcripts of oral history interviews with 11 Mexican Americans in San Bernardino County's West End provide understanding of the mass movement of Mexicans to the United States in…

Effect of Antimicrobial Peptide KSL-W on Human Gingival Tissue and C. albicans Growth, Transition and Secreted Aspartyl Proteinase (SAPS) 2, 4, 5 and 6 Expressions

DTIC Science & Technology

2016-07-01

broad range of antibacterial activity and could play a role in preventing microbial infections(Decanis et al., 2009), (Zaslof, 2002). These antimicrobial...range of antibacterial activity and could play a role in preventing microbial infections(Decanis et al., 2009),(Zaslof, 2002). These antimicrobial...KSL- W (KKVVFWVKFK)(Na et al., 2007), which possess a broad range of antibacterial activity . It killed selected strains of non-oral and oral

A smooth muscle tone-dependent stretch-activated migrating motor pattern in isolated guinea-pig distal colon.

PubMed

Smith, Terence K; Oliver, Gavin R; Hennig, Grant W; O'Shea, Deirdre M; Vanden Berghe, Pieter; Kang, Sok Han; Spencer, Nick J

2003-09-15

We have investigated the tone dependence of the intrinsic nervous activity generated by localized wall distension in isolated segments of guinea-pig distal colon using mechanical recordings and video imaging of wall movements. A segment of colon was threaded through two partitions, which divided the colon for pharmacological purposes into oral, stimulation and anal regions. An intraluminal balloon was located in the stimulation region between the two partitions (12 mm apart). Maintained colonic distension by an intraluminal balloon or an artificial faecal pellet held at a fixed location generated rhythmic (frequency 0.3 contractions min(-1); duration approximately 60 s) peristaltic waves of contraction. Video imaging of colonic wall movements or the selective application of pharmacological agents suggested that peristaltic waves originated just oral (< or = 4 mm) to the pellet and propagated both orally (approximately 11 mm s(-1)) and anally (approximately 1 mm s(-1)). Also, during a peristaltic wave the colon appears to passively shorten in front of a pellet, as a result of an active contraction of the longitudinal muscle oral to the pellet. Faecal pellet movement only occurred when a rhythmic peristaltic wave was generated. Rhythmic peristaltic waves were abolished in all regions by the smooth muscle relaxants isoproterenol (1 microM), nicardipine (1 microM) or papavarine (10 microM), and by the neural antagonists tetrodotoxin (TTX; 0.6 microM), hexamethonium (100 microM) or atropine (1 microM), when added selectively to the stimulation region. Nicardipine, atropine, TTX, or hexamethonium (100 microM) also blocked the evoked peristaltic waves when selectively added to the oral region. Nomega-nitro-L-arginine (L-NA; 100 microM) added to the anal region reduced the anal relaxation but increased the anal contraction, leading to an increase in the apparent conduction velocity of each peristaltic wave. In conclusion, maintained distension by a fixed artificial pellet generates propulsive, rhythmic peristaltic waves, whose enteric neural activity is critically dependent upon smooth muscle tone. These peristaltic waves usually originate just oral to the pellet, and their apparent conduction velocity is generated by activation of descending inhibitory nerve pathways.

Discovery of an Acrylic Acid Based Tetrahydroisoquinoline as an Orally Bioavailable Selective Estrogen Receptor Degrader for ERα+ Breast Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burks, Heather E.; Abrams, Tinya; Kirby, Christina A.

Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.

Differential neural representation of oral ethanol by central taste-sensitive neurons in ethanol-preferring and genetically heterogeneous rats

PubMed Central

Wilson, David M.; Brasser, Susan M.

2011-01-01

In randomly bred rats, orally applied ethanol stimulates neural substrates for appetitive sweet taste. To study associations between ethanol's oral sensory characteristics and genetically mediated ethanol preference, we made electrophysiological recordings of oral responses (spike density) by taste-sensitive nucleus tractus solitarii neurons in anesthetized selectively bred ethanol-preferring (P) rats and their genetically heterogeneous Wistar (W) control strain. Stimuli (25 total) included ethanol [3%, 5%, 10%, 15%, 25%, and 40% (vol/vol)], a sucrose series (0.01, 0.03, 0.1, 0.3, 0.5, and 1 M), and other sweet, salt, acidic, and bitter stimuli; 50 P and 39 W neurons were sampled. k-means clustering applied to the sucrose response series identified cells showing high (S1) or relatively low (S0) sensitivity to sucrose. A three-way factorial analysis revealed that activity to ethanol was influenced by a neuron's sensitivity to sucrose, ethanol concentration, and rat line (P = 0.01). Ethanol produced concentration-dependent responses in S1 neurons that were larger than those in S0 cells. Although responses to ethanol by S1 cells did not differ between lines, neuronal firing rates to ethanol in S0 cells increased across concentration only in P rats. Correlation and multivariate analyses revealed that ethanol evoked responses in W neurons that were strongly and selectively associated with activity to sweet stimuli, whereas responses to ethanol by P neurons were not easily associated with activity to representative sweet, sodium salt, acidic, or bitter stimuli. These findings show differential central neural representation of oral ethanol between genetically heterogeneous rats and P rats genetically selected to prefer alcohol. PMID:21918002

Differential neural representation of oral ethanol by central taste-sensitive neurons in ethanol-preferring and genetically heterogeneous rats.

PubMed

Lemon, Christian H; Wilson, David M; Brasser, Susan M

2011-12-01

In randomly bred rats, orally applied ethanol stimulates neural substrates for appetitive sweet taste. To study associations between ethanol's oral sensory characteristics and genetically mediated ethanol preference, we made electrophysiological recordings of oral responses (spike density) by taste-sensitive nucleus tractus solitarii neurons in anesthetized selectively bred ethanol-preferring (P) rats and their genetically heterogeneous Wistar (W) control strain. Stimuli (25 total) included ethanol [3%, 5%, 10%, 15%, 25%, and 40% (vol/vol)], a sucrose series (0.01, 0.03, 0.1, 0.3, 0.5, and 1 M), and other sweet, salt, acidic, and bitter stimuli; 50 P and 39 W neurons were sampled. k-means clustering applied to the sucrose response series identified cells showing high (S(1)) or relatively low (S(0)) sensitivity to sucrose. A three-way factorial analysis revealed that activity to ethanol was influenced by a neuron's sensitivity to sucrose, ethanol concentration, and rat line (P = 0.01). Ethanol produced concentration-dependent responses in S(1) neurons that were larger than those in S(0) cells. Although responses to ethanol by S(1) cells did not differ between lines, neuronal firing rates to ethanol in S(0) cells increased across concentration only in P rats. Correlation and multivariate analyses revealed that ethanol evoked responses in W neurons that were strongly and selectively associated with activity to sweet stimuli, whereas responses to ethanol by P neurons were not easily associated with activity to representative sweet, sodium salt, acidic, or bitter stimuli. These findings show differential central neural representation of oral ethanol between genetically heterogeneous rats and P rats genetically selected to prefer alcohol.

Phytochemical composition and in vitro screening of the antimicrobial activity of essential oils on oral pathogenic bacteria.

PubMed

Tardugno, Roberta; Pellati, Federica; Iseppi, Ramona; Bondi, Moreno; Bruzzesi, Giacomo; Benvenuti, Stefania

2018-03-01

In this study, the activity of essential oils (EOs) against microorganisms involved in oral diseases was evaluated. Fourteen EOs were selected and subjected to gas chromatographic analysis, including Illicium verum, Eucaliptus globulus, Eugenia caryophyllata, Leptospermum scoparium, Mentha arvensis, Mentha piperita, Myrtus communis, Salvia officinalis, Melaleuca alternifolia, Rosmarinus officinalis, Lavandula x intermedia, Thymus capitatus and Thymus vulgaris. These EOs were tested for their antimicrobial activity on Streptococcus mutans and Lactobacillus species clinically isolated from dental surgery patients. The antibacterial activity was evaluated by means of the disc diffusion and the minimum inhibitory concentration (MIC). Five EOs, having shown an interesting antimicrobial activity, were selected for a second screening in combination between them and with chlorhexidine. From the second assays, two EO-EO and three EO-chlorhexidine associations gave interesting results as potential constituents of mouthwashes, especially for the contribution of oxygenated monoterpenes, including menthol, thymol and carvacrol.

In vitro antiplaque activity of octenidine dihydrochloride (WIN 41464-2) against preformed plaques of selected oral plaque-forming microorganisms.

PubMed Central

Slee, A M; O'Connor, J R

1983-01-01

The antibacterial activity of octenidine dihydrochloride (WIN 41464-2) against intact preformed in vitro plaques of four indigenous oral plaque-forming microorganisms, Streptococcus mutans, Streptococcus sanguis, Actinomyces viscosus, and Actinomyces naeslundii, was studied. Both absolute (plaque bactericidal index) and relative (chlorhexidine coefficient) indices of antiplaque efficacy were established. Octenidine dihydrochloride compared favorably with chlorhexidine digluconate with respect to overall antiplaque potency in this in vitro plaque bactericidal model. These data indicate that prudent selection of treatment concentration and duration and frequency of exposure should provide an effective means to aid in controlling dental caries and Actinomyces-associated disease in vivo. PMID:6847170

School based oral health promotional intervention: Effect on knowledge, practices and clinical oral health related parameters

PubMed Central

Gauba, Arjun; Bal, Ikreet Singh; Jain, Ashish; Mittal, Hitesh Chander

2013-01-01

Background: No organized school oral health program is existent in India. Aim: The aim of this study is to test the feasibility and efficacy of an economical school oral health promotional intervention with educational and preventive components. Settings and Design: School oral health promotional intervention carried out in one of the randomly selected school and evaluated through short duration prospective model. Materials and Methods: A total of 100 children with an age range of 10-12 years with no previous history of dental intervention were enrolled. Interventions comprised of oral health education (delivered through lecture and demonstrations by an undergraduate dental student) and topical antibacterial therapy (fluoride varnish and povidone iodine). Outcomes consisted of Knowledge and practices (KAP) regarding oral health, clinical oral health related parameters such as plaque index (PI), gingival index (GI) and caries activity as per Modified Snyder's test. These were reported at baseline, 3 weeks and 6 months follow-up examination by a calibrated examiner. Statistical Analysis: McNemar Bowker's test, Student's t-test, Pearson Chi-square tests were used. Results: Highly significant (P < 0.001) improvements in KAP scores, PI scores, GI scores and caries activity were reported at 3 weeks and 6 months follow-up examination. Conclusion: This small economical school oral health program positively influenced oral health related practices and parameters of oral health such as oral cleanliness, gingival health and caries activity. PMID:24403795

The macrocyclic peptide natural product CJ-15,208 is orally active and prevents reinstatement of extinguished cocaine-seeking behavior.

PubMed

Aldrich, Jane V; Senadheera, Sanjeewa N; Ross, Nicolette C; Ganno, Michelle L; Eans, Shainnel O; McLaughlin, Jay P

2013-03-22

The macrocyclic tetrapeptide natural product CJ-15,208 (cyclo[Phe-d-Pro-Phe-Trp]) exhibited both dose-dependent antinociception and kappa opioid receptor (KOR) antagonist activity after oral administration. CJ-15,208 antagonized a centrally administered KOR selective agonist, providing strong evidence it crosses the blood-brain barrier to reach KOR in the CNS. Orally administered CJ-15,208 also prevented both cocaine- and stress-induced reinstatement of extinguished cocaine-seeking behavior in the conditioned place preference assay in a time- and dose-dependent manner. Thus, CJ-15,208 is a promising lead compound with a unique activity profile for potential development, particularly as a therapeutic to prevent relapse to drug-seeking behavior in abstinent subjects.

Structure-Based Discovery of 4-(6-Methoxy-2-methyl-4-(quinolin-4-yl)-9 H -pyrimido[4,5- b ]indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, Yujun; Bai, Longchuan; Liu, Liu

We have designed and synthesized 9H-pyrimido[4,5-b]indole-containing compounds to obtain potent and orally bioavailable BET inhibitors. By incorporation of an indole or a quinoline moiety to the 9H-pyrimido[4,5-b]indole core, we identified a series of small molecules showing high binding affinities to BET proteins and low nanomolar potencies in inhibition of cell growth in acute leukemia cell lines. One such compound, 4-(6-methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (31) has excellent microsomal stability and good oral pharmacokinetics in rats and mice. Orally administered, 31 achieves significant antitumor activity in the MV4;11 leukemia and MDA-MB-231 triple-negative breast cancer xenograft models in mice. Determination of the cocrystal structure of 31more » with BRD4 BD2 provides a structural basis for its high binding affinity to BET proteins. Testing its binding affinities against other bromodomain-containing proteins shows that 31 is a highly selective inhibitor of BET proteins. Our data show that 31 is a potent, selective, and orally active BET inhibitor.« less

Contribution of the pre-SMA to the production of words and non-speech oral motor gestures, as revealed by repetitive transcranial magnetic stimulation (rTMS).

PubMed

Tremblay, Pascale; Gracco, Vincent L

2009-05-01

An emerging theoretical perspective, largely based on neuroimaging studies, suggests that the pre-SMA is involved in planning cognitive aspects of motor behavior and language, such as linguistic and non-linguistic response selection. Neuroimaging studies, however, cannot indicate whether a brain region is equally important to all tasks in which it is activated. In the present study, we tested the hypothesis that the pre-SMA is an important component of response selection, using an interference technique. High frequency repetitive TMS (10 Hz) was used to interfere with the functioning of the pre-SMA during tasks requiring selection of words and oral gestures under different selection modes (forced, volitional) and attention levels (high attention, low attention). Results show that TMS applied to the pre-SMA interferes selectively with the volitional selection condition, resulting in longer RTs. The low- and high-attention forced selection conditions were unaffected by TMS, demonstrating that the pre-SMA is sensitive to selection mode but not attentional demands. TMS similarly affected the volitional selection of words and oral gestures, reflecting the response-independent nature of the pre-SMA contribution to response selection. The implications of these results are discussed.

A highly selective, orally active inhibitor of Janus kinase 2, CEP-33779, ablates disease in two mouse models of rheumatoid arthritis

PubMed Central

2011-01-01

Introduction Janus kinase 2 (JAK2) is involved in the downstream activation of signal transducer and activator of transcription 3 (STAT3) and STAT5 and is responsible for transducing signals for several proinflammatory cytokines involved in the pathogenesis of rheumatoid arthritis (RA), including interleukin (IL)-6, interferon γ (IFNγ) and IL-12. In this paper, we describe the efficacy profile of CEP-33779, a highly selective, orally active, small-molecule inhibitor of JAK2 evaluated in two mouse models of RA. Methods Collagen antibody-induced arthritis (CAIA) and collagen type II (CII)-induced arthritis (CIA) were established before the oral administration of a small-molecule JAK2 inhibitor, CEP-33779, twice daily at 10 mg/kg, 30 mg/kg, 55 mg/kg or 100 mg/kg over a period of 4 to 8 weeks. Results Pharmacodynamic inhibition of JAK2 reduced mean paw edema and clinical scores in both CIA and CAIA models of arthritis. Reduction in paw cytokines (IL-12, IFNγ and tumor necrosis factor α) and serum cytokines (IL-12 and IL-2) correlated with reduced spleen CII-specific T helper 1 cell frequencies as measured by ex vivo IFNγ enzyme-linked immunosorbent spot assay. Both models demonstrated histological evidence of disease amelioration upon treatment (for example, reduced matrix erosion, subchondral osteolysis, pannus formation and synovial inflammation) and reduced paw phosphorylated STAT3 levels. No changes in body weight or serum anti-CII autoantibody titers were observed in either RA model. Conclusions This study demonstrates the utility of using a potent and highly selective, orally bioavailable JAK2 inhibitor for the treatment of RA. Using a selective inhibitor of JAK2 rather than pan-JAK inhibitors avoids the potential complication of immunosuppression while targeting critical signaling pathways involved in autoimmune disease progression. PMID:21510883

Innate Immunity and Saliva in Candida albicans–mediated Oral Diseases

PubMed Central

Salvatori, O.; Puri, S.; Tati, S.; Edgerton, M.

2016-01-01

The oral cavity is a unique niche where Candida albicans infections occur in immunocompetent as well as immunosuppressed individuals. Here we critically review the significance of human innate immune response in preventing oral candidiasis. One important line of defense against oropharyngeal candidiasis is the oral microbiota that prevents infection by competing for space and nutrients as well as by secreting antagonistic molecules and triggering local inflammatory responses. C. albicans is able to induce mucosal defenses through activation of immune cells and production of cytokines. Also, saliva contains various proteins that affect C. albicans growth positively by promoting mucosal adherence and negatively through immune exclusion and direct fungicidal activity. We further discuss the role of saliva in unifying host innate immune defenses against C. albicans as a communicating medium and how C. albicans overgrowth in the oral cavity may be a result of aberrations ranging from microbial dysbiosis and salivary dysfunction to epithelial damage. Last we underscore select oral diseases in which C. albicans is a contributory microorganism in immune-competent individuals. PMID:26747422

Curcumin modulates cellular AP-1, NF-kB, and HPV16 E6 proteins in oral cancer.

PubMed

Mishra, Alok; Kumar, Rakesh; Tyagi, Abhishek; Kohaar, Indu; Hedau, Suresh; Bharti, Alok C; Sarker, Subhodeep; Dey, Dipankar; Saluja, Daman; Das, Bhudev

2015-01-01

In this study, we investigated the effects of the natural antioxidant curcumin on the HPV16-positive oral carcinoma cell line 93VU147T and demonstrated that curcumin is not only a potent inhibitor for the activity of host nuclear transcription factors AP-1 and NF-kB but it also selectively suppresses transcription of the HPV16/E6 oncogene during the carcinogenic process in oral cancer cells. This study suggests a therapeutic potential of curcumin for high-risk human papilloma virus (HPV)-infected oral cancers.

Curcumin modulates cellular AP-1, NF-kB, and HPV16 E6 proteins in oral cancer

PubMed Central

Mishra, Alok; Kumar, Rakesh; Tyagi, Abhishek; Kohaar, Indu; Hedau, Suresh; Bharti, Alok C; Sarker, Subhodeep; Dey, Dipankar; Saluja, Daman; Das, Bhudev

2015-01-01

In this study, we investigated the effects of the natural antioxidant curcumin on the HPV16-positive oral carcinoma cell line 93VU147T and demonstrated that curcumin is not only a potent inhibitor for the activity of host nuclear transcription factors AP-1 and NF-kB but it also selectively suppresses transcription of the HPV16/E6 oncogene during the carcinogenic process in oral cancer cells. This study suggests a therapeutic potential of curcumin for high-risk human papilloma virus (HPV)-infected oral cancers. PMID:25932049

Validation of two complementary oral-health related quality of life indicators (OIDP and OSS 0-10 ) in two qualitatively distinct samples of the Spanish population

PubMed Central

Montero, J; Bravo, M; Albaladejo, A

2008-01-01

Background Oral health-related quality of life can be assessed positively, by measuring satisfaction with mouth, or negatively, by measuring oral impact on the performance of daily activities. The study objective was to validate two complementary indicators, i.e., the OIDP (Oral Impacts on Daily Performances) and Oral Satisfaction 0–10 Scale (OSS), in two qualitatively different socio-demographic samples of the Spanish adult population, and to analyse the factors affecting both perspectives of well-being. Methods A cross-sectional study was performed, recruiting a Validation Sample from randomly selected Health Centres in Granada (Spain), representing the general population (n = 253), and a Working Sample (n = 561) randomly selected from active Regional Government staff, i.e., representing the more privileged end of the socio-demographic spectrum of this reference population. All participants were examined according to WHO methodology and completed an in-person interview on their oral impacts and oral satisfaction using the OIDP and OSS 0–10 respectively. The reliability and validity of the two indicators were assessed. An alternative method of describing the causes of oral impacts is presented. Results The reliability coefficient (Cronbach's alpha) of the OIDP was above the recommended 0.7 threshold in both Validation and Occupational samples (0.79 and 0.71 respectively). Test-retest analysis confirmed the external reliability of the OSS (Intraclass Correlation Coefficient, 0.89; p < 0.001) Some subjective factors (perceived need for dental treatment, complaints about mouth and intermediate impacts) were strongly associated with both indicators, supporting their construct and criterion validity. The main cause of oral impact was dental pain. Several socio-demographic, behavioural and clinical variables were identified as modulating factors. Conclusion OIDP and OSS are valid and reliable subjective measures of oral impacts and oral satisfaction, respectively, in an adult Spanish population. Exploring simultaneously these issues may provide useful insights into how satisfaction and impact on well-being are constructed. PMID:19019208

Synthesis and antitumor activity of bis(hydroxymethyl)propionate analogs of pterostilbene in cisplatin-resistant human oral cancer cells.

PubMed

Hsieh, Min-Tsang; Huang, Li-Jiau; Wu, Tian-Shung; Lin, Hui-Yi; Morris-Natschke, Susan L; Lee, Kuo-Hsiung; Kuo, Sheng-Chu

2018-06-08

The aim of this study was to develop a new drug substance with low toxicity and effective inhibitory activity against cisplatin-resistant oral cancer. The naturally produced pterostilbene was selected as the lead compound for design and synthesis of a series of bis(hydroxymethyl)propionate-based prodrugs. All derivatives were screened for antiproliferative effects against the cisplatin-resistant oral squamous (CAR) cell line and the results indicated that several compounds demonstrated superior inhibitory activity compared with pterostilbene and resveratrol. Among them, the most promising compound, 12, was evaluated for in vivo antitumor activity in a CAR xenograft nude mouse model. Obvious antitumor activity was observed at the lowest oral dose (25 mg/kg/day). Increasing the dose of 12 to 100 mg/kg/day reduced the tumor size to 22% of the control group. Based on these findings as well as the extremely low toxicity seen in the in vivo studies, we believe that compound 12 could serve as a new lead for further development. Copyright © 2018. Published by Elsevier Ltd.

The Macrocyclic Peptide Natural Product CJ-15,208 is Orally Active and Prevents Reinstatement of Extinguished Cocaine Seeking Behavior1

PubMed Central

Aldrich, Jane V.; Senadheera, Sanjeewa N.; Ross, Nicolette C.; Ganno, Michelle L.; Eans, Shainnel O.; McLaughlin, Jay P.

2013-01-01

The macrocyclic tetrapeptide natural product CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) exhibited both dose-dependent antinociception and kappa opioid receptor (KOR) antagonist activity after oral administration. CJ-15,208 antagonized a centrally administered KOR selective agonist, providing strong evidence it crosses the blood-brain barrier to reach KOR in the CNS. Orally administered CJ-15,208 also prevented both cocaine- and stress-induced reinstatement of extinguished cocaine seeking behavior in the conditioned place preference assay in a time- and dose-dependent manner. Thus, CJ-15,208 is a promising lead compound with a unique activity profile for potential development, particularly as a therapeutic to prevent relapse to drug seeking behavior in abstinent subjects. PMID:23327691

Isolation of an Orally Active Insecticidal Toxin from the Venom of an Australian Tarantula

PubMed Central

Hardy, Margaret C.; Daly, Norelle L.; Mobli, Mehdi; Morales, Rodrigo A. V.; King, Glenn F.

2013-01-01

Many insect pests have developed resistance to existing chemical insecticides and consequently there is much interest in the development of new insecticidal compounds with novel modes of action. Although spiders have deployed insecticidal toxins in their venoms for over 250 million years, there is no evolutionary selection pressure on these toxins to possess oral activity since they are injected into prey and predators via a hypodermic needle-like fang. Thus, it has been assumed that spider-venom peptides are not orally active and are therefore unlikely to be useful insecticides. Contrary to this dogma, we show that it is possible to isolate spider-venom peptides with high levels of oral insecticidal activity by directly screening for per os toxicity. Using this approach, we isolated a 34-residue orally active insecticidal peptide (OAIP-1) from venom of the Australian tarantula Selenotypus plumipes. The oral LD50 for OAIP-1 in the agronomically important cotton bollworm Helicoverpa armigera was 104.2±0.6 pmol/g, which is the highest per os activity reported to date for an insecticidal venom peptide. OAIP-1 is equipotent with synthetic pyrethroids and it acts synergistically with neonicotinoid insecticides. The three-dimensional structure of OAIP-1 determined using NMR spectroscopy revealed that the three disulfide bonds form an inhibitor cystine knot motif; this structural motif provides the peptide with a high level of biological stability that probably contributes to its oral activity. OAIP-1 is likely to be synergized by the gut-lytic activity of the Bacillus thuringiensis Cry toxin (Bt) expressed in insect-resistant transgenic crops, and consequently it might be a good candidate for trait stacking with Bt. PMID:24039872

[Effect of Food Thickeners on the Disintegration, Dissolution, and Drug Activity of Rapid Oral-disintegrating Tablets].

PubMed

Tomita, Takashi; Kohda, Yukinao; Kudo, Kenzo

2018-01-01

　For patients with dysphagia in medical facilities and nursing homes, food thickeners are routinely used to aid the ingestion of medicines such as tablets. However, some types of thickeners affect the disintegration and dissolution of tablets, such as rapidly-disintegrating magnesium oxide tablets and donepezil hydrochloride orally disintegrating tablets. Additionally, delayed disintegration and dissolution of tablets affect a drug's efficacy. As an example, with Voglibose orally disintegrating tablets, marked differences are observed in changes in glucose levels during glucose tolerance testing. When using food thickeners to aid tablet ingestion, it is therefore necessary to select a product that has little effect on drug disintegration, dissolution, and activity.

(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: A potent, selective, orally active dipeptidyl peptidase IV inhibitor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ammirati, Mark J.; Andrews, Kim M.; Boyer, David D.

2010-10-01

A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC{sub 50} = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.

(2S,4S)-4-Fluoro-1-{[(2-hydroxy-1,1-dimethylethyl)amino]acetyl}-pyrrolidine-2-carbonitrile monobenzenesulfonate (TS-021) is a selective and reversible dipeptidyl peptidase IV inhibitor.

PubMed

Tajima, Atsushi; Yamamoto, Koji; Kozakai, Akinori; Okumura-Kitajima, Lisa; Mita, Yasuo; Kitano, Kiyokazu; Jingu, Shigeji; Nakaike, Shiro

2011-03-25

The incretin hormone glucagon-like peptide-1 (GLP-1) has significant roles in the regulation of postprandial glucose metabolism, and the active form of GLP-1 is rapidly degraded by dipeptidyl peptidase (DPP)-IV. Therefore, DPP-IV inhibition is a promising approach for the treatment of type 2 diabetes. In the present study, we investigated the character of a DPP-IV inhibitor, TS-021, (2S, 4S)-4-fluoro-1-{[(2-hydroxy-1,1-dimethylethyl)amino]acetyl}-pyrrolidine-2-carbonitrile monobenzenesulfonate both in vitro and in vivo. TS-021 inhibits DPP-IV activity in human plasma with an IC(50) value of 5.34nM. In kinetics experiments, TS-021 had a relatively higher dissociation rate constant, with a k(off) value of 1.09×10(-3)s, despite exhibiting a potent human plasma DPP-IV inhibition activity with a K(i) value of 4.96nM. TS-021 exhibited significant inhibition selectivity against DPP-8 (>600 fold), DPP-9 (>1200 fold) and other peptidases examined (>15,000 fold). In normal rats, dogs and monkeys, a single oral dose of TS-021 exhibited favorable pharmacokinetic profiles. In Zucker fatty (fa/fa) rats, a rat model of obesity and impaired glucose tolerance, the oral administration of TS-021 resulted in the suppression of plasma DPP-IV activity and an increase in the active form of GLP-1. Furthermore, TS-021 exhibited a significant improvement in glucose tolerance by increasing the plasma insulin level during oral glucose tolerance tests at doses of 0.02-0.5mg/kg. These results suggest that TS-021 is a selective and reversible dipeptidyl peptidase IV inhibitor and has excellent characteristics as an oral anti-diabetic agent for postprandial hyperglycemia in patients with impaired glucose tolerance or type 2 diabetes. Copyright © 2011 Elsevier B.V. All rights reserved.

A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration.

PubMed

Heathcote, Dean A; Patel, Hetal; Kroll, Sebastian H B; Hazel, Pascale; Periyasamy, Manikandan; Alikian, Mary; Kanneganti, Seshu K; Jogalekar, Ashutosh S; Scheiper, Bodo; Barbazanges, Marion; Blum, Andreas; Brackow, Jan; Siwicka, Alekasandra; Pace, Robert D M; Fuchter, Matthew J; Snyder, James P; Liotta, Dennis C; Freemont, Paul S; Aboagye, Eric O; Coombes, R Charles; Barrett, Anthony G M; Ali, Simak

2010-12-23

Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Here, we report the identification of a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as a selective and potent CDK inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, and CDK9 (IC₅₀= 3, 30, 30, 250, and 90 nmol/L, respectively). Cell-based studies showed inhibition of the phosphorylation of CDK substrates, Rb and the RNA polymerase II C-terminal domain, down-regulation of cyclins A, E, and D1, and cell cycle block in the S and G₂/M phases. Consistent with these findings, 4k demonstrated potent antiproliferative activity in 60 cancer cell lines tested (mean GI₅₀= 280 nmol/L). Pharmacokinetic studies showed that 4k is orally bioavailable, with an elimination half-life of 178 min following oral dosing in mice. When administered at a concentration of 25 mg/kg orally, 4k inhibited human tumor xenografts and suppressed CDK substrate phosphorylation. These findings identify 4k as a novel, potent CDK selective inhibitor with potential for oral delivery in cancer patients.

A selective androgen receptor modulator for hormonal male contraception.

PubMed

Chen, Jiyun; Hwang, Dong Jin; Bohl, Casey E; Miller, Duane D; Dalton, James T

2005-02-01

The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies, including hormonal male contraception. The identification of an orally bioavailable SARM with the ability to mimic the central and peripheral androgenic and anabolic effects of testosterone would represent an important step toward the "male pill". We characterized the in vitro and in vivo pharmacologic activity of (S)-3-(4-chloro-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)propionamide (C-6), a novel SARM developed in our laboratories. C-6 was identified as an androgen receptor (AR) agonist with high AR binding affinity (K(i) = 4.9 nM). C-6 showed tissue-selective pharmacologic activity with higher anabolic activity than androgenic activity in male rats. The doses required to maintain the weight of the prostate, seminal vesicles, and levator ani muscle to half the size of the maximum effects (i.e., ED(50)) were 0.78 +/- 0.06, 0.88 +/- 0.1, and 0.17 +/- 0.04 mg/day, respectively. As opposed to other SARMs, gonadotropin levels in C-6-treated groups were significantly lower than control values. C-6 also significantly decreased serum testosterone concentration in intact rats after 2 weeks of treatment. Marked suppression of spermatogenesis was observed after 10 weeks of treatment with C-6 in intact male rats. Pharmacokinetic studies of C-6 in male rats revealed that C-6 was well absorbed after oral administration (bioavailability 76%), with a long (6.3 h) half-life at a dose of 10 mg/kg. These studies show that C-6 mimicked the in vivo pharmacologic and endocrine effects of testosterone while maintaining the oral bioavailability and tissue-selective actions of nonsteroidal SARMs.

NP-184[2-(5-methyl-2-furyl) benzimidazole], a novel orally active antithrombotic agent with dual antiplatelet and anticoagulant activities.

PubMed

Kuo, Heng-Lan; Lien, Jin-Cherng; Chung, Ching-Hu; Chang, Chien-Hsin; Lo, Shyh-Chyi; Tsai, I-Chun; Peng, Hui-Chin; Kuo, Sheng-Chu; Huang, Tur-Fu

2010-06-01

The established antiplatelet and anticoagulant agents show beneficial effects in the treatment of thromboembolic diseases; however, these drugs still have considerable limitations. The effects of NP-184, a synthetic compound, on platelet functions, plasma coagulant activity, and mesenteric venule thrombosis in mice were investigated. NP-184 concentration-dependently inhibited the human platelet aggregation induced by collagen, arachidonic acid (AA), and U46619, a thromboxane (TX)A(2) mimic, with IC(50) values of 4.5 +/- 0.2, 3.9 +/- 0.1, and 9.3 +/- 0.5 microM, respectively. Moreover, NP-184 concentration-dependently suppressed TXA(2) formations caused by collagen and AA. In exploring effects of NP-184 on enzymes involved in TXA(2) synthesis, we found that NP-184 selectively inhibited TXA(2) synthase activity with an IC(50) value of 4.3 +/- 0.2 microM. Furthermore, NP-184 produced a right shift of the concentration-response curve of U46619, indicating a competitive antagonism on TXA(2)/prostaglandin H(2) receptor. Intriguingly, NP-184 also caused a concentration-dependent prolongation of the activated partial thromboplastin time (aPTT) with no changes in the prothrombin and thrombin time, indicating that it selectively impairs the intrinsic coagulation pathway. Oral administration of NP-184 significantly inhibited thrombus formation of the irradiated mesenteric venules in fluorescein sodium-treated mice without affecting the bleeding time induced by tail transection. However, after oral administration, NP-184 inhibited the ex vivo mouse platelet aggregation triggered by collagen and U46619 and also prolonged aPTT. Taken together, the dual antiplatelet and anticoagulant activities of NP-184 may have therapeutic potential as an oral antithrombotic agent in the treatment of thromboembolic disorders.

Pharmacokinetics and pharmacodynamics of LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo-[3,2-f]quinolin-7(6H)-one], an orally available nonsteroidal-selective androgen receptor modulator.

PubMed

Vajda, Eric G; López, Francisco J; Rix, Peter; Hill, Robert; Chen, Yanling; Lee, Kyoung-Jin; O'Brien, Z; Chang, William Y; Meglasson, Martin D; Lee, Yong-Hee

2009-02-01

Selective androgen receptor modulators (SARMs) are a new class of molecules in development to treat a variety of diseases. SARMs maintain the beneficial effects of androgens, including increased muscle mass and bone density, while having reduced activity on unwanted side effects. The mechanisms responsible for the tissue-selective activity of SARMs are not fully understood, and the pharmacokinetic (PK)/pharmacodynamic (PD) relationships are poorly described. Tissue-specific compound distribution potentially could be a mechanism responsible for apparent tissue selectivity. We examined the PK/PD relationship of a novel SARM, LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[3,2-f]quinolin-7(6H)-one], in a castrated rat model of androgen deficiency. LGD-3303 has potent activity on levator ani muscle but is a partial agonist on the preputial gland and ventral prostate. LGD-3303 never stimulated ventral prostate above intact levels despite increasing plasma concentrations of compound. Tissue-selective activity was maintained when LGD-3303 was dosed orally or by continuous infusion, two routes of administration with markedly different time versus exposure profiles. Despite the greater muscle activity relative to prostate activity, local tissue concentrations of LGD-3303 were higher in the prostate than in the levator ani muscle. LGD-3303 has SARM properties that are independent of its pharmacokinetic profile, suggesting that the principle mechanism for tissue-selective activity is the result of altered molecular interactions at the level of the androgen receptor.

Building oral health research infrastructure: the first national oral health survey of Rwanda.

PubMed

Morgan, John P; Isyagi, Moses; Ntaganira, Joseph; Gatarayiha, Agnes; Pagni, Sarah E; Roomian, Tamar C; Finkelman, Matthew; Steffensen, Jane E M; Barrow, Jane R; Mumena, Chrispinus H; Hackley, Donna M

2018-01-01

Oral health affects quality of life and is linked to overall health. Enhanced oral health research is needed in low- and middle-income countries to develop strategies that reduce the burden of oral disease, improve oral health and inform oral health workforce and infrastructure development decisions. To implement the first National Oral Health Survey of Rwanda to assess the oral disease burden and inform oral health promotion strategies. In this cross-sectional study, sample size and site selection were based on the World Health Organization (WHO) Oral Health Surveys Pathfinder stratified cluster methodologies. Randomly selected 15 sites included 2 in the capital city, 2 other urban centers and 11 rural locations representing all provinces and rural/urban population distribution. A minimum of 125 individuals from each of 5 age groups were included at each site. A Computer Assisted Personal Instrument (CAPI) was developed to administer the study instrument. Nearly two-thirds (64.9%) of the 2097 participants had caries experience and 54.3% had untreated caries. Among adults 20 years of age and older, 32.4% had substantial oral debris and 60.0% had calculus. A majority (70.6%) had never visited an oral health provider. Quality-of-life challenges due to oral diseases/conditions including pain, difficulty chewing, self-consciousness, and difficulty participating in usual activities was reported at 63.9%, 42.2% 36.2%, 35.4% respectively. The first National Oral Health Survey of Rwanda was a collaboration of the Ministry of Health of Rwanda, the University of Rwanda Schools of Dentistry and Public Health, the Rwanda Dental Surgeons and Dental (Therapists) Associations, and Tufts University and Harvard University Schools of Dental Medicine. The international effort contributed to building oral health research capacity and resulted in a national oral health database of oral disease burden. This information is essential for developing oral disease prevention and management strategies as well as oral health workforce and infrastructure.

Building oral health research infrastructure: the first national oral health survey of Rwanda

PubMed Central

Morgan, John P.; Ntaganira, Joseph; Gatarayiha, Agnes; Pagni, Sarah E.; Roomian, Tamar C.; Finkelman, Matthew; Steffensen, Jane E. M.; Barrow, Jane R.; Mumena, Chrispinus H.

2018-01-01

ABSTRACT Background: Oral health affects quality of life and is linked to overall health. Enhanced oral health research is needed in low- and middle-income countries to develop strategies that reduce the burden of oral disease, improve oral health and inform oral health workforce and infrastructure development decisions. Objective: To implement the first National Oral Health Survey of Rwanda to assess the oral disease burden and inform oral health promotion strategies. Methods: In this cross-sectional study, sample size and site selection were based on the World Health Organization (WHO) Oral Health Surveys Pathfinder stratified cluster methodologies. Randomly selected 15 sites included 2 in the capital city, 2 other urban centers and 11 rural locations representing all provinces and rural/urban population distribution. A minimum of 125 individuals from each of 5 age groups were included at each site. A Computer Assisted Personal Instrument (CAPI) was developed to administer the study instrument. Results: Nearly two-thirds (64.9%) of the 2097 participants had caries experience and 54.3% had untreated caries. Among adults 20 years of age and older, 32.4% had substantial oral debris and 60.0% had calculus. A majority (70.6%) had never visited an oral health provider. Quality-of-life challenges due to oral diseases/conditions including pain, difficulty chewing, self-consciousness, and difficulty participating in usual activities was reported at 63.9%, 42.2% 36.2%, 35.4% respectively. Conclusion: The first National Oral Health Survey of Rwanda was a collaboration of the Ministry of Health of Rwanda, the University of Rwanda Schools of Dentistry and Public Health, the Rwanda Dental Surgeons and Dental (Therapists) Associations, and Tufts University and Harvard University Schools of Dental Medicine. The international effort contributed to building oral health research capacity and resulted in a national oral health database of oral disease burden. This information is essential for developing oral disease prevention and management strategies as well as oral health workforce and infrastructure. PMID:29860930

Acute oral administration of the novel, competitive and selective glucocorticoid receptor antagonist ORG 34517 reduces the severity of ethanol withdrawal and related hypothalamic- pituitary-adrenal axis activation

PubMed Central

Reynolds, Anna R.; Saunders, Meredith A.; Brewton, Honoree’ W.; Winchester, Sydney R.; Elgumati, Ibrahim S.; Prendergast, Mark A.

2015-01-01

Background The development of ethanol dependence is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis and activation of type II glucocorticoid receptors (GR). These effects may contribute to withdrawal-associated anxiety, craving and relapse to drinking. The present studies examined acute and oral administration of the novel, selective and competitive GR antagonist ORG 34517 on the severity of ethanol withdrawal. Methods Adult, male Sprague-Dawley rats were administered ethanol (4g/kg/i.g.) twice daily for 5 days followed by 2 days of withdrawal for 1, 2 or 3 consecutive cycles. Blood ethanol levels (BELs) were determined at 0930 on Day 4 of each week, while blood corticosterone levels (BCLs) were obtained at 1100 hrs on the first day of each ethanol withdrawal. During early withdrawal, subjects received oral administration of ORG 345617 (60 mg/kg/i.g.) or a placebo and withdrawal was monitored. Results Peak BELs of 225.52 mg/dl were observed during the third week. Withdrawal from three cycles of the regimen produced marked behavioral abnormalities (e.g. aggression, rigidity, and hypoactivity) and significant increases in BCLs of ethanol-dependent subjects. Acute, oral administration of ORG 34517 during early withdrawal significantly reduced both the severity of ethanol withdrawal, as reflected in reduced rigidity, aggression, and hypoactivity, and elevations in BCL without producing any sedative-like effects. Conclusions The present findings demonstrate that repeated ethanol exposure and withdrawal is associated with significant behavioral abnormalities and dysregulation of HPA axis activation. Further these data suggest that selective GR antagonists should be further considered as putative pharmacotherapies for treatment of ethanol dependence. PMID:26143299

Acute oral administration of the novel, competitive and selective glucocorticoid receptor antagonist ORG 34517 reduces the severity of ethanol withdrawal and related hypothalamic-pituitary-adrenal axis activation.

PubMed

Reynolds, Anna R; Saunders, Meredith A; Brewton, Honoree' W; Winchester, Sydney R; Elgumati, Ibrahim S; Prendergast, Mark A

2015-09-01

The development of ethanol dependence is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis and activation of type II glucocorticoid receptors (GR). These effects may contribute to withdrawal-associated anxiety, craving and relapse to drinking. The present studies examined acute and oral administration of the novel, selective and competitive GR antagonist ORG 34517 on the severity of ethanol withdrawal. Adult, male Sprague-Dawley rats were administered ethanol (4g/kg/i.g.) twice daily for 5 days followed by 2 days of withdrawal for 1, 2 or 3 consecutive cycles. Blood ethanol levels (BELs) were determined at 0930 on Day 4 of each week, while blood corticosterone levels (BCLs) were obtained at 11:00hours on the first day of each ethanol withdrawal. During early withdrawal, subjects received oral administration of ORG 345617 (60mg/kg/i.g.) or a placebo and withdrawal was monitored. Peak BELs of 225.52mg/dl were observed during the third week. Withdrawal from three cycles of the regimen produced marked behavioral abnormalities (e.g., aggression, rigidity, and hypoactivity) and significant increases in BCLs of ethanol-dependent subjects. Acute, oral administration of ORG 34517 during early withdrawal significantly reduced both the severity of ethanol withdrawal, as reflected in reduced rigidity, aggression, and hypoactivity, and elevations in BCL without producing any sedative-like effects. The present findings demonstrate that repeated ethanol exposure and withdrawal is associated with significant behavioral abnormalities and dysregulation of HPA axis activation. Further these data suggest that selective GR antagonists should be further considered as putative pharmacotherapies for treatment of ethanol dependence. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Discovery of novel, highly potent, and selective quinazoline-2-carboxamide-based matrix metalloproteinase (MMP)-13 inhibitors without a zinc binding group using a structure-based design approach.

PubMed

Nara, Hiroshi; Sato, Kenjiro; Naito, Takako; Mototani, Hideyuki; Oki, Hideyuki; Yamamoto, Yoshio; Kuno, Haruhiko; Santou, Takashi; Kanzaki, Naoyuki; Terauchi, Jun; Uchikawa, Osamu; Kori, Masakuni

2014-11-13

Matrix metalloproteinase-13 (MMP-13) has been implicated to play a key role in the pathology of osteoarthritis. On the basis of X-ray crystallography, we designed a series of potent MMP-13 selective inhibitors optimized to occupy the distinct deep S1' pocket including an adjacent branch. Among them, carboxylic acid inhibitor 21k exhibited excellent potency and selectivity for MMP-13 over other MMPs. An effort to convert compound 21k to the mono sodium salt 38 was promising in all animal species studied. Moreover, no overt toxicity was observed in a preliminary repeat dose oral toxicity study of compound 21k in rats. A single oral dose of compound 38 significantly reduced degradation products (CTX-II) released from articular cartilage into the joint cavity in a rat MIA model in vivo. In this article, we report the discovery of highly potent, selective, and orally bioavailable MMP-13 inhibitors as well as their detailed structure-activity data.

Oral immunization with Escherichia coli K-12 of the fifth instar larvae of the silkworm, Bombyx mori, reared on an artificial diet under completely aseptic conditions.

PubMed

Ichimori, H; Yuhki, T; Mori, H; Matsubara, F; Sumida, M

1992-01-01

1. Effect of oral administration of live or formalin-treated Escherichia coli (E. coli) K-12 to the fifth instar, days 1 and 3 larvae of the silkworm, Bombyx mori, on induction of antibacterial activity in the haemolymph was investigated using the silkworms reared on an artificial diet under completely aseptic conditions. 2. When live E. coli was administered to the male day 1 larvae, low but significant antibacterial activity of 3.8 mm was detectable in the haemolymph of one individual at 48 hr after immunization. The proportion of the larvae to express antibacterial activity increased thereafter and at 120 hr after immunization, all three individuals showed antibacterial activity. In day 3 male larvae, activity was detectable at 48 and 72 hr after immunization. 3. When formalin-treated E. coli was orally administered to days 1 and 3 male larvae, no activity was detectable at any time post-immunization. 4. In the second experiment, when day 1 larvae, females and males were orally immunized with live E. coli, only females showed antibacterial activity in the haemolymph, beginning from 24 hr after immunization and up to 96 hr. 5. Removal of an antibiotic, chloramphenicol, from ingredients of an artificial diet was required for induction of antibacterial activity with oral administration of live E. coli. 6. When live E. coli that grows at pH 9.0 was selected and used for oral immunization, antibacterial activity was induced both in females and males at 72 hr after immunization and the activity was observed at 96 hr. 7. These results suggest that establishment of oral immunization with live E. coli in the silkworm larvae requires multiplication of E. coli in the midgut lumen and possibly its colonization on the luminal surface.

Discovery of Potent and Selective Dipeptidyl Peptidase IV Inhibitors Derived from [beta]-Aminoamides Bearing Subsituted Triazolopiperazines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Dooseop; Kowalchick, Jennifer E.; Brockunier, Linda L.

2008-06-30

A series of {beta}-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure-activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC{sub 50} = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice. On the basis of these properties, compound 34b has been profiled in detail. Further refinement of the triazolopiperazines resulted in the discovery of a series of extremely potent compounds withmore » subnanomolar activity against DPP-4 (42b-49b), that is, 4-fluorobenzyl-substituted compound 46b, which is notable for its superior potency (IC{sub 50} = 0.18 nM). X-ray crystal structure determination of compounds 34b and 46b in complex with DPP-4 enzyme revealed that (R)-stereochemistry at the 8-position of triazolopiperazines is strongly preferred over (S) with respect to DPP-4 inhibition.« less

Formulation of microspheres containing Crataegus monogyna Jacq. extract with free radical scavenging activity.

PubMed

Lucconi, Giulia; Chlapanidas, Theodora; Martino, Emanuela; Gaggeri, Raffaella; Perteghella, Sara; Rossi, Daniela; Faragò, Silvio; Vigo, Daniele; Faustini, Massimo; Collina, Simona; Torre, Maria Luisa

2014-02-01

Extracts of Crataegus monogyna Jacq. (hawthorn) show an interesting free radical scavenging (FRS) effect, related to their flavonoids content. Unfortunately, their oral administration is affected by their low bioavailability. The aim of this work is to obtain a multiparticulate drug delivery system for hawthorn extracts for oral administration. The extracts from flowering tops (FL) or fruits (FR) of hawthorn were obtained with maceration, using ethanol as an extraction solvent, and their antioxidant activity was evaluated. FL extract showed the highest FRS activity (EC50 3.72 ± 1.21 µg/ml), so it was selected to prepare microparticulate systems by a spray-drying technique, which were characterized by granulometric analysis, scanning electron microscopy-energy dispersive X-ray spectroscopy, confocal fluorescence microscopy and hyperoside content. Antioxidant activity was evaluated before and after gastrointestinal transit in vitro simulation. Results indicate that the microparticulate systems maintained the antioxidant activity of hawthorn also after gastrointestinal transit in vitro simulation, exhibiting properties suitable for oral administration.

Effectiveness of Oral Baclofen in the Treatment of Spasticity in Children and Adolescents With Cerebral Palsy.

PubMed

Navarrete-Opazo, Angela A; Gonzalez, Waleska; Nahuelhual, Paula

2016-04-01

To systematically review the effectiveness of oral baclofen versus placebo or other antispastic oral medications in terms of body function, level of activity, and quality of life in children and adolescents with spastic cerebral palsy who are younger than 18 years. Cochrane Library, Health Science Databases, DARE, LILACS, Embase, MEDLINE, OTseeker, PEDro, PsycINFO, SpeechBITE, ScienceDirect, Scopus, Trip, ClinicalTrials.gov, Google Scholar, OpenGrey, and manual search. Randomized or not randomized controlled trials and cohort studies comparing the effect of any dosage of oral baclofen with that of no treatment, placebo, or another antispastic medication in children and adolescents with spastic cerebral palsy were selected. Following the Cochrane Handbook for Systematic Reviews of Interventions guidelines, 2 reviewers independently searched articles in databases from their inceptions until October 2014. Six randomized controlled trials involving a total of 130 patients were selected. Studies show a great variability in motor classification, dosage of baclofen, and outcome measures. There is conflicting evidence on the effectiveness of oral baclofen in reducing muscle tone or improving motor function or the level of activity. The overall methodological quality of the studies was low. The main qualitative limitations of the studies correspond to serious risk of bias, inconsistency of results, unpowered sample size, and publication bias. There are insufficient data to support or refute the use of oral baclofen for reducing spasticity or improving motor function in children and adolescents with spastic cerebral palsy. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Potent anti-proliferative effects against oral and cervical cancers of Thai medicinal plants selected from the Thai/Lanna medicinal plant recipe database "MANOSROI III".

PubMed

Manosroi, Aranya; Akazawa, Hiroyuki; Pattamapun, Kassara; Kitdamrongtham, Worapong; Akihisa, Toshihiro; Manosroi, Worapaka; Manosroi, Jiradej

2015-07-01

Thai/Lanna medicinal plant recipes have been used for the treatment of several diseases including oral and cervical cancers. To investigate anti-proliferative activity on human cervical (HeLa) and oral (KB) cancer cell lines of medicinal plants selected from Thai/Lanna medicinal plant recipe database "MANOSROI III". Twenty-three methanolic plant crude extracts were tested for phytochemicals and anti-proliferative activity on HeLa and KB cell lines for 24 h by the sulforhodamine B (SRB) assay at the doses of 1 × 10(1)-1 × 10(-6 )mg/ml. The nine extracts with the concentrations giving 50% growth inhibition (GI50) lower than 100 µg/ml were further semi-purified by liquid/liquid partition in order to evaluate and enhance the anti-proliferative potency. All extracts contained steroids/triterpenoids, but not xanthones. The methanolic extracts of Gloriosa superba L. (Colchinaceae) root and Albizia chinensis (Osbeck) Merr. (Leguminosae-Mimosoideae) wood gave the highest anti-proliferative activity on HeLa and KB cell lines with the GI50 values of 0.91 (6.0- and 0.31-fold of cisplatin and doxorubicin) and 0.16 µg/ml (28.78- and 82.29-fold of cisplatin and doxorubicin), respectively. Hexane and methanol-water fractions of G. superba exhibited the highest anti-proliferative activity on HeLa and KB cell lines with the GI50 values of 0.15 (37- and 1.9-fold of cisplatin and doxorubicin) and 0.058 µg/ml (77.45- and 221.46-fold of cisplatin and doxorubicin), respectively. This study has demonstrated the potential of plants selected from MANOSROI III database especially G. superba and A. chinensis for further development as anti-oral and cervical cancer agents.

Autophagy and its implication in human oral diseases.

PubMed

Tan, Ya-Qin; Zhang, Jing; Zhou, Gang

2017-02-01

Macroautophagy/autophagy is a conserved lysosomal degradation process essential for cell physiology and human health. By regulating apoptosis, inflammation, pathogen clearance, immune response and other cellular processes, autophagy acts as a modulator of pathogenesis and is a potential therapeutic target in diverse diseases. With regard to oral disease, autophagy can be problematic either when it is activated or impaired, because this process is involved in diverse functions, depending on the specific disease and its level of progression. In particular, activated autophagy functions as a cytoprotective mechanism under environmental stress conditions, which regulates tumor growth and mediates resistance to anticancer treatment in established tumors. During infections and inflammation, activated autophagy selectively delivers microbial antigens to the immune systems, and is therefore connected to the elimination of intracellular pathogens. Impaired autophagy contributes to oxidative stress, genomic instability, chronic tissue damage, inflammation and tumorigenesis, and is involved in aberrant bacterial clearance and immune priming. Hence, substantial progress in the study of autophagy provides new insights into the pathogenesis of oral diseases. This review outlines the mechanisms of autophagy, and highlights the emerging roles of this process in oral cancer, periapical lesions, periodontal diseases, and oral candidiasis.

Autophagy and its implication in human oral diseases

PubMed Central

Tan, Ya-Qin; Zhang, Jing; Zhou, Gang

2017-01-01

ABSTRACT Macroautophagy/autophagy is a conserved lysosomal degradation process essential for cell physiology and human health. By regulating apoptosis, inflammation, pathogen clearance, immune response and other cellular processes, autophagy acts as a modulator of pathogenesis and is a potential therapeutic target in diverse diseases. With regard to oral disease, autophagy can be problematic either when it is activated or impaired, because this process is involved in diverse functions, depending on the specific disease and its level of progression. In particular, activated autophagy functions as a cytoprotective mechanism under environmental stress conditions, which regulates tumor growth and mediates resistance to anticancer treatment in established tumors. During infections and inflammation, activated autophagy selectively delivers microbial antigens to the immune systems, and is therefore connected to the elimination of intracellular pathogens. Impaired autophagy contributes to oxidative stress, genomic instability, chronic tissue damage, inflammation and tumorigenesis, and is involved in aberrant bacterial clearance and immune priming. Hence, substantial progress in the study of autophagy provides new insights into the pathogenesis of oral diseases. This review outlines the mechanisms of autophagy, and highlights the emerging roles of this process in oral cancer, periapical lesions, periodontal diseases, and oral candidiasis. PMID:27764582

OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models.

PubMed

Garton, Andrew J; Crew, Andrew P A; Franklin, Maryland; Cooke, Andrew R; Wynne, Graham M; Castaldo, Linda; Kahler, Jennifer; Winski, Shannon L; Franks, April; Brown, Eric N; Bittner, Mark A; Keily, John F; Briner, Paul; Hidden, Chris; Srebernak, Mary C; Pirrit, Carrie; O'Connor, Matthew; Chan, Anna; Vulevic, Bojana; Henninger, Dwight; Hart, Karen; Sennello, Regina; Li, An-Hu; Zhang, Tao; Richardson, Frank; Emerson, David L; Castelhano, Arlindo L; Arnold, Lee D; Gibson, Neil W

2006-01-15

OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930.

The macrocyclic tetrapeptide [D-Trp]CJ-15,208 produces short-acting κ opioid receptor antagonism in the CNS after oral administration

PubMed Central

Eans, Shainnel O; Ganno, Michelle L; Reilley, Kate J; Patkar, Kshitij A; Senadheera, Sanjeewa N; Aldrich, Jane V; McLaughlin, Jay P

2013-01-01

Background and Purpose Cyclic peptides are resistant to proteolytic cleavage, therefore potentially exhibiting activity after systemic administration. We hypothesized that the macrocyclic κ opioid receptor (KOR)-selective antagonist [D-Trp]CJ-15,208 would demonstrate antagonist activity after systemic, that is, s.c. and oral (per os, p. o.), administration. Experimental Approach C57BL/6J mice were pretreated with [D-Trp]CJ-15,208 s.c. or p.o. before administration of the KOR-selective agonist U50,488 and the determination of antinociception in the warm-water tail-withdrawal assay. The locomotor activity of mice treated with [D-Trp]CJ-15,208 was determined by rotorod testing. Additional mice demonstrating cocaine conditioned place preference and subsequent extinction were pretreated daily with vehicle or [D-Trp]CJ-15,208 and then exposed to repeated forced swim stress or a single additional session of cocaine place conditioning before redetermining place preference. Key Results Pretreatment with [D-Trp]CJ-15,208 administered s.c. or p.o. dose-dependently antagonized the antinociception induced by i.p. administration of U50,488 in mice tested in the warm-water tail-withdrawal assay for less than 12 and 6 h respectively. [D-Trp]CJ-15,208 also produced limited (<25%), short-duration antinociception mediated through KOR agonism. Orally administered [D-Trp]CJ-15,208 dose-dependently antagonized centrally administered U50,488-induced antinociception, and prevented stress-, but not cocaine-induced, reinstatement of extinguished cocaine-seeking behaviour, consistent with its KOR antagonist activity, without affecting locomotor activity. Conclusions and Implications The macrocyclic tetrapeptide [D-Trp]CJ-15,208 is a short-duration KOR antagonist with weak KOR agonist activity that is active after oral administration and demonstrates blood–brain barrier permeability. These data validate the use of systemically active peptides such as [D-Trp]CJ-15,208 as potentially useful therapeutics. PMID:23425081

The macrocyclic tetrapeptide [D-Trp]CJ-15,208 produces short-acting κ opioid receptor antagonism in the CNS after oral administration.

PubMed

Eans, Shainnel O; Ganno, Michelle L; Reilley, Kate J; Patkar, Kshitij A; Senadheera, Sanjeewa N; Aldrich, Jane V; McLaughlin, Jay P

2013-05-01

Cyclic peptides are resistant to proteolytic cleavage, therefore potentially exhibiting activity after systemic administration. We hypothesized that the macrocyclic κ opioid receptor (KOR)-selective antagonist [D-Trp]CJ-15,208 would demonstrate antagonist activity after systemic, that is, s.c. and oral (per os, p. o.), administration. C57BL/6J mice were pretreated with [D-Trp]CJ-15,208 s.c. or p.o. before administration of the KOR-selective agonist U50,488 and the determination of antinociception in the warm-water tail-withdrawal assay. The locomotor activity of mice treated with [D-Trp]CJ-15,208 was determined by rotorod testing. Additional mice demonstrating cocaine conditioned place preference and subsequent extinction were pretreated daily with vehicle or [D-Trp]CJ-15,208 and then exposed to repeated forced swim stress or a single additional session of cocaine place conditioning before redetermining place preference. Pretreatment with [D-Trp]CJ-15,208 administered s.c. or p.o. dose-dependently antagonized the antinociception induced by i.p. administration of U50,488 in mice tested in the warm-water tail-withdrawal assay for less than 12 and 6 h respectively. [D-Trp]CJ-15,208 also produced limited (<25%), short-duration antinociception mediated through KOR agonism. Orally administered [D-Trp]CJ-15,208 dose-dependently antagonized centrally administered U50,488-induced antinociception, and prevented stress-, but not cocaine-induced, reinstatement of extinguished cocaine-seeking behaviour, consistent with its KOR antagonist activity, without affecting locomotor activity. The macrocyclic tetrapeptide [D-Trp]CJ-15,208 is a short-duration KOR antagonist with weak KOR agonist activity that is active after oral administration and demonstrates blood-brain barrier permeability. These data validate the use of systemically active peptides such as [D-Trp]CJ-15,208 as potentially useful therapeutics. © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.

Tenuifolide B from Cinnamomum tenuifolium Stem Selectively Inhibits Proliferation of Oral Cancer Cells via Apoptosis, ROS Generation, Mitochondrial Depolarization, and DNA Damage.

PubMed

Chen, Chung-Yi; Yen, Ching-Yu; Wang, Hui-Ru; Yang, Hui-Ping; Tang, Jen-Yang; Huang, Hurng-Wern; Hsu, Shih-Hsien; Chang, Hsueh-Wei

2016-11-05

The development of drugs that selectively kill oral cancer cells but are less harmful to normal cells still provide several challenges. In this study, the antioral cancer effects of tenuifolide B (TFB), extracted from the stem of the plant Cinnamomum tenuifolium are evaluated in terms of their effects on cancer cell viability, cell cycle analysis, apoptosis, oxidative stress, and DNA damage. Cell viability of oral cancer cells (Ca9-22 and CAL 27) was found to be significantly inhibited by TFB in a dose-responsive manner in terms of ATP assay, yielding IC 50 = 4.67 and 7.05 μM (24 h), but are less lethal to normal oral cells (HGF-1). Dose-responsive increases in subG1 populations as well as the intensities of flow cytometry-based annexin V/propidium iodide (PI) analysis and pancaspase activity suggested that apoptosis was inducible by TFB in these two types of oral cancer cells. Pretreatment with the apoptosis inhibitor (Z-VAD-FMK) reduced the annexin V intensity of these two TFB-treated oral cancer cells, suggesting that TFB induced apoptosis-mediated cell death to oral cancer cells. Cleaved-poly (ADP-ribose) polymerase (PARP) and cleaved-caspases 3, 8, and 9 were upregulated in these two TFB-treated oral cancer cells over time but less harmful for normal oral HGF-1 cells. Dose-responsive and time-dependent increases in reactive oxygen species (ROS) and decreases in mitochondrial membrane potential (MitoMP) in these two TFB-treated oral cancer cells suggest that TFB may generate oxidative stress as measured by flow cytometry. N -acetylcysteine (NAC) pretreatment reduced the TFB-induced ROS generation and further validated that ROS was relevant to TFB-induced cell death. Both flow cytometry and Western blotting demonstrated that the DNA double strand marker γH2AX dose-responsively increased in TFB-treated Ca9-22 cells and time-dependently increased in two TFB-treated oral cancer cells. Taken together, we infer that TFB can selectively inhibit cell proliferation of oral cancer cells through apoptosis, ROS generation, mitochondrial membrane depolarization, and DNA damage.

Activity of Potent and Selective Host Defense Peptide Mimetics in Mouse Models of Oral Candidiasis

PubMed Central

Ryan, Lisa K.; Freeman, Katie B.; Masso-Silva, Jorge A.; Falkovsky, Klaudia; Aloyouny, Ashwag; Markowitz, Kenneth; Hise, Amy G.; Fatahzadeh, Mahnaz; Scott, Richard W.

2014-01-01

There is a strong need for new broadly active antifungal agents for the treatment of oral candidiasis that not only are active against many species of Candida, including drug-resistant strains, but also evade microbial countermeasures which may lead to resistance. Host defense peptides (HDPs) can provide a foundation for the development of such agents. Toward this end, we have developed fully synthetic, small-molecule, nonpeptide mimetics of the HDPs that improve safety and other pharmaceutical properties. Here we describe the identification of several HDP mimetics that are broadly active against C. albicans and other species of Candida, rapidly fungicidal, and active against yeast and hyphal cultures and that exhibit low cytotoxicity for mammalian cells. Importantly, specificity for Candida over commensal bacteria was also evident, thereby minimizing potential damage to the endogenous microbiome which otherwise could favor fungal overgrowth. Three compounds were tested as topical agents in two different mouse models of oral candidiasis and were found to be highly active. Following single-dose administrations, total Candida burdens in tongues of infected animals were reduced up to three logs. These studies highlight the potential of HDP mimetics as a new tool in the antifungal arsenal for the treatment of oral candidiasis. PMID:24752272

Oral Microbiome Metabolism: From "Who Are They?" to "What Are They Doing?".

PubMed

Takahashi, N

2015-12-01

Recent advances in molecular biology have facilitated analyses of the oral microbiome ("Who are they?"); however, its functions (e.g., metabolic activities) are poorly understood ("What are they doing?"). This review aims to summarize our current understanding of the metabolism of the oral microbiome. Saccharolytic bacteria-including Streptococcus, Actinomyces, and Lactobacillus species-degrade carbohydrates into organic acids via the Embden-Meyerhof-Parnas pathway and several of its branch pathways, resulting in dental caries, while alkalization and acid neutralization via the arginine deiminase system, urease, and so on, counteract acidification. Proteolytic/amino acid-degrading bacteria, including Prevotella and Porphyromonas species, break down proteins and peptides into amino acids and degrade them further via specific pathways to produce short-chain fatty acids, ammonia, sulfur compounds, and indole/skatole, which act as virulent and modifying factors in periodontitis and oral malodor. Furthermore, it is suggested that ethanol-derived acetaldehyde can cause oral cancer, while nitrate-derived nitrite can aid caries prevention and systemic health. Microbial metabolic activity is influenced by the oral environment; however, it can also modify the oral environment, enhance the pathogenicity of bacteria, and induce microbial selection to create more pathogenic microbiome. Taking a metabolomic approach to analyzing the oral microbiome is crucial to improving our understanding of the functions of the oral microbiome. © International & American Associations for Dental Research 2015.

Factors influencing the impact of oral health on the daily activities of adolescents, adults and older adults

PubMed Central

Bulgareli, Jaqueline Vilela; de Faria, Eduardo Tanajura; Cortellazzi, Karine Laura; Guerra, Luciane Miranda; Meneghim, Marcelo de Castro; Ambrosano, Glaucia Maria Bovi; Frias, Antonio Carlos; Pereira, Antonio Carlos

2018-01-01

ABSTRACT OBJECTIVE: Analyze if clinical, sociodemographic and access to dental services variables influence the impact of oral health on the daily activities of adolescents, adults and older adults. METHODS: A cross-sectional study with secondary data from the State Oral Health Survey (SB São Paulo 2015) conducted in 163 cities of São Paulo. A total of 17,560 individuals from three age groups: 15–19-year-old (n = 5,558), 35–44-year-old (n = 6,051), and older people of 65 years or more (n = 5,951) participated in the survey. The selection was made by probabilistic sample by conglomerates in two stages. The endpoint variable was the impact of oral health on daily activities, evaluated by the Oral Impacts on Daily Performances questionnaire, containing questions about eating, talking, oral hygiene, relaxation, sports practice, smile, study or work, social contact, and sleep. Oral Impacts on Daily Performances was dichotomized with and without impact. The independent variables were sociodemographic, clinical and access variables, divided into three blocks. A hierarchical multiple logistic regression analysis was performed considering the complex sampling plan of clusters. Each observation received a specific weight, depending on the location that resulted in weighted frequencies and adjusted for the design effect. RESULTS: The presence of oral health impact was observed in 27.9% of the individuals. In block 1, female gender and black/brown ethnic group had a greater chance of impact of oral health on quality of life, as well as the adults and the older adults in relation to adolescents. In block 2, family income up to R$1,500 was associated with the presence of impact. In block 3, individuals who reported toothache, used the public service and sought dental treatment had a greater chance of impact. CONCLUSIONS: Sociodemographic, clinical and access to health services variables influence the impact of oral health on the daily activities of adolescents, adults and older adults. PMID:29668813

Foreign-Language Pedagogy: Practical Applications to Theoretical Concerns. Selected Papers from the Loyola College Conference Entitled "Bridging Theory and Practice in the Foreign-Language Classroom" (Baltimore, Maryland, October 18-20, 1991).

ERIC Educational Resources Information Center

Wieczorek, Joseph A., Ed.

1993-01-01

Papers from the conference include the following: "Activites orales et motivation dans l'etude du vocabulaire d'une langue etrangere (Oral Activities and Motivation in the Study of Vocabulary in a Foreign Language)" (M. Guisset); "Bridging High School and College Classes through the Multicultural Approach: The Case of Francophone…

Inhibition of Oral Pathogens Adhesion to Human Gingival Fibroblasts by Wine Polyphenols Alone and in Combination with an Oral Probiotic.

PubMed

Esteban-Fernández, Adelaida; Zorraquín-Peña, Irene; Ferrer, Maria D; Mira, Alex; Bartolomé, Begoña; González de Llano, Dolores; Moreno-Arribas, M Victoria

2018-03-07

Several benefits have been described for red wine polyphenols and probiotic strains in the promotion of colonic metabolism and health. On the contrary, knowledge about their role in the management of oral health is still scarce. In this work, the antiadhesive capacity of selected red wine polyphenols and oenological extracts against the oral pathogens Porphyromonas gingivalis, Fusobacterium nucleatum, and Streptococcus mutans in an in vitro model of human gingival fibroblasts has been explored as well as their complementary action with the candidate oral probiotic Streptococcus dentisani. Results highlighted the antiadhesive capacity of caffeic and p-coumaric acids as well as grape seed and red wine oenological extracts. Both, caffeic and p-coumaric acids increased their inhibition potential against S. mutans adhesion when combined with S. dentisani. Additionally, UHPLC-MS/MS analysis demonstrated the oral metabolism of wine phenolics due to both, cellular and bacterial activity.

Evaluation of the endogenous glucocorticoid hypothesis of denervation atrophy

NASA Technical Reports Server (NTRS)

Konagaya, Masaaki; Konagaya, Yoko; Max, Stephen R.

1988-01-01

The effects are studied of the oral administration of RU38486, a potent selective glucocorticoid antagonist, on muscle weight, non-collagen protein content, and selected enzyme activities (choline acetyltransferase, glucose 6-phosphate dehydrogenase, and glutamine synthetase) following denervation of rat skeletal muscle. Neither decreases in muscle weight, protein content, and choline acetyltransferase activity, nor increases in the activities of glucose 6-phosphate dehydrogernase and glutamine synthetase were affected by RU38486. These data do not support the hypothesis that denervation atrophy results from enhanced sensitivity of muscle to endogenous glucocorticoids.

Effects of oral hygiene products containing lactoperoxidase, lysozyme, and lactoferrin on the composition of whole saliva and on subjective oral symptoms in patients with xerostomia.

PubMed

Kirstilä, V; Lenander-Lumikari, M; Söderling, E; Tenovuo, J

1996-12-01

This study evaluates the effects of two oral hygiene products containing nonimmunoglobulin antimicrobial agents on whole saliva and on subjective oral symptoms in patients with xerostomia. Twenty patients used a lactoperoxidase-system-containing toothpaste (Biotene) combined with the use of a mouthrinse (Biotene), comprising also lysozyme and lactoferrin, for 4 weeks. Saliva samples were collected at base line, after 4 weeks' use of the products, and at the end of a 4-week washout period. Samples were analyzed for selected biochemical and microbiologic factors. The effects on subjective oral symptoms were also recorded. A 4-week daily use of toothpaste and mouthrinse relieved the symptoms of oral dryness in 16 patients. The levels of salivary hypothiocyanite, lysozyme, lactoferrin, or myeloperoxidase activity did not change, but there was a significant decrease in salivary pH (P < 0.05), total peroxidase activity (P < 0.05), and total protein content (P = 0.01). In patients with the lowest salivary flow rates (n = 5) a significant (P > or = 0.04) increase was detected in salivary hypothiocyanite concentrations. No major changes occurred in salivary microflora. The products relieved subjective oral symptoms in most xerostomic patients, but this was not necessarily related to the presence of antimicrobial agents.

Novel series of potent, nonsteroidal, selective androgen receptor modulators based on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones.

PubMed

Higuchi, Robert I; Arienti, Kristen L; López, Francisco J; Mani, Neelakhanda S; Mais, Dale E; Caferro, Thomas R; Long, Yun Oliver; Jones, Todd K; Edwards, James P; Zhi, Lin; Schrader, William T; Negro-Vilar, Andrés; Marschke, Keith B

2007-05-17

Recent interest in orally available androgens has fueled the search for new androgens for use in hormone replacement therapy and as anabolic agents. In pursuit of this, we have discovered a series of novel androgen receptor modulators derived from 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. These compounds were synthesized and evaluated in competitive binding assays and an androgen receptor transcriptional activation assay. A number of compounds from the series demonstrated single-digit nanomolar agonist activity in vitro. In addition, lead compound (R)-16e was orally active in established rodent models that measure androgenic and anabolic properties of these agents. In this assay, (R)-16e demonstrated full efficacy in muscle and only partially stimulated the prostate at 100 mg/kg. These data suggest that these compounds may be utilized as selective androgen receptor modulators or SARMs. This series represents a novel class of compounds for use in androgen replacement therapy.

Primary packaging considerations in developing medicines for children: oral liquid and powder for constitution.

PubMed

Campbell, Gossett A; Vallejo, Erick

2015-01-01

The packaging presentation of oral liquid pediatric medicines is a critical step in maintaining chemical and physical stability, compliance, adherence, and proper handling by the target patient population, guardians, caregivers, and health-care professionals. The common packaging presentations for commercial oral liquid pediatric drug products are glass bottle, plastic bottle, sachet, and stick pack configurations. The type of pack presentation selected is driven by the quality target product profile (QTPP) that is designed around the physicochemical properties of the drug substance and the desired drug product suitability for the target population. The QTPP defines the intended use of the drug product, drug product quality criteria, dose strength, dosage form, container closure system, storage conditions, stability criteria, dosing device, shelf life, and attributes affecting the pharmacokinetic characteristics. Oral liquid pediatric formulations are typically prepared from a powder that is constituted at the time of use as a suspension or a solution for single or multiple use depending on the stability of the constituted formulation. Active ingredients with high aqueous solubility can be developed as a powder for oral solution and presented in a bottle for multiple use product and a stick pack, packet, or sachet for single-use product. Active ingredients with low aqueous solubility can be developed as a powder for oral suspension and presented in a bottle for multiple use product and a stick pack or sachet for single-use product. A secondary package may be used in cases where the primary pack failed to provide adequate protection against light degradation. This work will help formulation scientists select the most appropriate pack presentation in the early stages of pediatric clinical development. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Novel orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation without adversely affecting endometrium or myometrium

PubMed Central

Catherino, William H.; Malik, Minnie; Driggers, Paul; Chappel, Scott; Segars, James; Davis, Joseph

2012-01-01

Context Uterine leiomyomas are highly prevalent and often symptomatic. Current medical therapies are limited. A novel, potent, selective, orally active therapy is needed. Objective and Methods To determine the progesterone receptor (PR) specificity and activation, endometrial response, and impact on proliferation and extracellular matrix (ECM) production of the novel non-steroidal selective progesterone receptor modulators (SPRMs) CP8863 and CP8947 in human immortalized leiomyoma and patient-matched myometrial cells. Receptor binding in vitro was assessed using LNCaP, Ishikawa, T-47D, and HeLa cell extracts for AR, ER-α, PR, and GR, respectively. Progestational activity assessed by alkaline phosphatase assay in T47D cells and ER-α expression in human leiomyoma and myometrial cells. In vivo progestational activity assayed by the McPhail assay. Proliferation and gene expression studies (q RT-PCR and western blot) were performed in immortalized leiomyoma and myometrial cells. Results Both CP8863 and CP8947 is highly selective for PR but not for ER-α, AR, and GR. Both induced alkaline phosphatase comparably to progesterone, while CP8947 induced ER-α in leiomyoma cells but not myometrial cells. CP8947 was progestational in rabbit endometrium. Nanomolar CP8947 treatment inhibited human leiomyoma but not myometrial cell proliferation. The decreased proliferation correlated with increased TRAIL and caspase -7, suggesting induction of apoptosis in leiomyoma cells. ECM components were decreased in leiomyoma cells, including COL1A1 and COL7A1 at nanomolar concentrations. Conclusions CP8947 was a potent novel non-steroidal SPRM that was selective for PR, showed progestational activity in endometrium, inhibited leiomyoma cell proliferation (potentially via induction of apoptosis), and decreased ECM component production, without disrupting myometrial cell proliferation. PMID:20493256

New orally active DNA minor groove binding small molecule CT-1 acts against breast cancer by targeting tumor DNA damage leading to p53-dependent apoptosis.

PubMed

Saini, Karan Singh; Hamidullah; Ashraf, Raghib; Mandalapu, Dhanaraju; Das, Sharmistha; Siddiqui, Mohd Quadir; Dwivedi, Sonam; Sarkar, Jayanta; Sharma, Vishnu Lal; Konwar, Rituraj

2017-04-01

Targeting tumor DNA damage and p53 pathway is a clinically established strategy in the development of cancer chemotherapeutics. Majority of anti-cancer drugs are delivered through parenteral route for reasons like severe toxicity, lack of stability, and poor enteral absorption. Current DNA targeting drugs in clinical like anthracycline suffers from major drawbacks like cardiotoxicity. Here, we report identification of a new orally active small molecule curcumin-triazole conjugate (CT-1) with significant anti-breast cancer activity in vitro and in vivo. CT-1 selectively and significantly inhibits viability of breast cancer cell lines; retards cells cycle progression at S phase and induce mitochondrial-mediated cell apoptosis. CT-1 selectively binds to minor groove of DNA and induces DNA damage leading to increase in p53 along with decrease in its ubiquitination. Inhibition of p53 with pharmacological inhibitor as well as siRNA revealed the necessity of p53 in CT-1-mediated anti-cancer effects in breast cancer cells. Studies using several other intact p53 and deficient p53 cancer cell lines further confirmed necessity of p53 in CT-1-mediated anti-cancer response. Pharmacological inhibition of pan-caspase showed CT-1 induces caspase-dependent cell death in breast cancer cells. Most interestingly, oral administration of CT-1 induces significant inhibition of tumor growth in LA-7 syngeneic orthotropic rat mammary tumor model. CT-1 treated mammary tumor shows enhancement in DNA damage, p53 upregulation, and apoptosis. Collectively, CT-1 exhibits potent anti-cancer effect both in vitro and in vivo and could serve as a safe orally active lead for anti-cancer drug development. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Usefulness of oral loading of oxcarbazepine suspension in selected patients with epilepsy.

PubMed

Kim, Dong Wook; Gu, Namyi; Lee, Howard; Jang, In-Jin; Chu, Kon; Yu, Kyung-Sang; Cho, Joo-Youn; Yoon, Seo Hyun; Na, Hyun Jeong; Lee, Sang Kun

2013-10-01

Oral loading of oxcarbazepine tablet is effective and well tolerated to adequately achieve the therapeutic levels of its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD) in epilepsy patients. The present study was performed to investigate the safety, tolerability, and pharmacokinetic profiles of oral loading of oxcarbazepine suspension in epilepsy patients with a high risk of recurrent seizures. Oxcarbazepine suspension was administered orally at a single loading dose of 30 mg/kg to 38 adult patients with recurrent seizures, who required rapid seizure control or temporarily discontinued antiepileptic drugs for diagnostic or pre-surgical evaluation. Plasma concentrations of oxcarbazepine and MHD were determined, and adverse events were assessed at 2, 4, 6, 8, 10, 12, 14, 16, and 24 hours after oral loading of oxcarbazepine suspension. 30 patients experienced ≥ 1 adverse event during the first 24 hours after oral loading of oxcarbazepine (e.g., dizziness, transient diplopia, nausea or vomiting), most of which occurred within 4 hours after loading, suggesting no temporal association with MHD plasma levels. 35 (92.1%) patients were still compliant with a maintenance dose of oxcarbazepine after discharge from hospital. 34 (89.4%) patients reached the lower therapeutic level of MHD (12 mg/l) at 4 hours after oral loading of oxcarbazepine suspension, which lasted up to 24 hours in most patients. No patient reached the supratherapeutic levels of MHD (> 35 mg/l) during the study. The mean plasma concentration-time curves and pharmacokinetic profiles of oral loading of oxcarbazepine suspension were similar to those of oral loading of oxcarbazepine tablet. Oral loading of oxcarbazepine suspension followed by maintenance dosing is well tolerated and effective in steadily achieving the therapeutic level of MHD in selected patients with epilepsy.

4β-Hydroxywithanolide E selectively induces oxidative DNA damage for selective killing of oral cancer cells.

PubMed

Tang, Jen-Yang; Huang, Hurng-Wern; Wang, Hui-Ru; Chan, Ya-Ching; Haung, Jo-Wen; Shu, Chih-Wen; Wu, Yang-Chang; Chang, Hsueh-Wei

2018-03-01

Reactive oxygen species (ROS) induction had been previously reported in 4β-hydroxywithanolide (4βHWE)-induced selective killing of oral cancer cells, but the mechanism involving ROS and the DNA damage effect remain unclear. This study explores the role of ROS and oxidative DNA damage of 4βHWE in the selective killing of oral cancer cells. Changes in cell viability, morphology, ROS, DNA double strand break (DSB) signaling (γH2AX foci in immunofluorescence and DSB signaling in western blotting), and oxidative DNA damage (8-oxo-2'deoxyguanosine [8-oxodG]) were detected in 4βHWE-treated oral cancer (Ca9-22) and/or normal (HGF-1) cells. 4βHWE decreased cell viability, changed cell morphology and induced ROS generation in oral cancer cells rather than oral normal cells, which were recovered by a free radical scavenger N-acetylcysteine (NAC). For immunofluorescence, 4βHWE also accumulated more of the DSB marker, γH2AX foci, in oral cancer cells than in oral normal cells. For western blotting, DSB signaling proteins such as γH2AX and MRN complex (MRE11, RAD50, and NBS1) were overexpressed in 4βHWE-treated oral cancer cells in different concentrations and treatment time. In the formamidopyrimidine-DNA glycolyase (Fpg)-based comet assay and 8-oxodG-based flow cytometry, the 8-oxodG expressions were higher in 4βHWE-treated oral cancer cells than in oral normal cells. All the 4βHWE-induced DSB and oxidative DNA damage to oral cancer cells were recovered by NAC pretreatment. Taken together, the 4βHWE selectively induced DSB and oxidative DNA damage for the ROS-mediated selective killing of oral cancer cells. © 2017 Wiley Periodicals, Inc.

Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thompson, Scott K.; Washburn, David G.; Frazee, James S.

2010-09-03

Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.

In vitro and in silico investigation of electrospun terbinafine hydrochloride-loaded buccal nanofibrous sheets.

PubMed

Szabó, Péter; Daróczi, Tünde Beáta; Tóth, Gergő; Zelkó, Romána

2016-11-30

Terbinafine hydrochloride-loaded nanofibrous buccal films were formulated with the aim to improve the solubility and dissolution behavior; thus, the local effectiveness of the antifungal agent. Poly(vinyl alcohol) and chitosan polymer composites were selected as delivery base in order to enhance the mucoadhesion of the fibrous films. The dissolution of terbinafine hydrochloride was carried out applying a stainless steel disc assembly and the terbinafine concentration was determined by HPLC-MS in selective ion monitoring mode. The prediction of the absorption behavior of the prepared fibrous samples in the human oral cavity was modeled using GastroPlus™ software. The result indicates that the fibrous films enabled fast and complete dissolution of the active agent. The drug absorption from the oral cavity could be minimized by the employment of the proper oral transit model. Because of the limited absorption of terbinafine hydrochloride from the oral mucosa the formulation can be beneficial in local administration in the case of hold and expectorate administration mode. Copyright © 2016 Elsevier B.V. All rights reserved.

Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-β type I receptor kinase as cancer immunotherapeutic/antifibrotic agent.

PubMed

Jin, Cheng Hua; Krishnaiah, Maddeboina; Sreenu, Domalapally; Subrahmanyam, Vura B; Rao, Kota S; Lee, Hwa Jeong; Park, So-Jung; Park, Hyun-Ju; Lee, Kiho; Sheen, Yhun Yhong; Kim, Dae-Kee

2014-05-22

A series of 2-substituted-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)imidazoles was synthesized and evaluated to optimize a prototype inhibitor of TGF-β type I receptor kinase (ALK5), 6. Combination of replacement of a quinoxalin-6-yl moiety of 6 with a [1,2,4]triazolo[1,5-a]pyridin-6-yl moiety, insertion of a methyleneamino linker, and a o-F substituent in the phenyl ring markedly increased ALK5 inhibitory activity, kinase selectivity, and oral bioavailability. The 12b (EW-7197) inhibited ALK5 with IC50 value of 0.013 μM in a kinase assay and with IC50 values of 0.0165 and 0.0121 μM in HaCaT (3TP-luc) stable cells and 4T1 (3TP-luc) stable cells, respectively, in a luciferase assay. Selectivity profiling of 12b using a panel of 320 protein kinases revealed that it is a highly selective ALK5/ALK4 inhibitor. Pharmacokinetic study with 12b·HCl in rats showed an oral bioavailability of 51% with high systemic exposure (AUC) of 1426 ng × h/mL and maximum plasma concentration (Cmax) of 1620 ng/mL. Rational optimization of 6 has led to the identification of a highly potent, selective, and orally bioavailable ALK5 inhibitor 12b.

Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands.

PubMed

Serradeil-Le Gal, C; Wagnon, J; Valette, G; Garcia, G; Pascal, M; Maffrand, J P; Le Fur, G

2002-01-01

The involvement of vasopressin (AVP) in several pathological states has been reported recently and the selective blockade of the different AVP receptors could offer new clinical perspectives. During the past few years, various selective, orally active AVP V1a (OPC-21268, SR49059 (Relcovaptan)), V2 (OPC-31260, OPC-41061 (Tolvaptan), VPA-985 (Lixivaptan), SR121463, VP-343, FR-161282) and mixed V1a/V2 (YM-087 (Conivaptan), JTV-605, CL-385004) receptor antagonists have been intensively studied in various animal models and have reached, Phase IIb clinical trials for some of them. For many years now, our laboratory has focused on the identification of nonpeptide vasopressin antagonists with suitable oral bioavailability. Using random screening on small molecule libraries, followed by rational SAR and modelization, we identified a chemical series of 1-phenylsulfonylindolines which first yielded SR49059, a V1a receptor antagonist prototype. This compound displayed high affinity for animal and human V1a receptors and antagonized various V1a AVP-induced effects in vitro and in vivo (intracellular [Ca2+] increase, platelet aggregation, vascular smooth muscle cell proliferation, hypertension and coronary vasospasm). We and others have used this compound to study the role of AVP in various animal models. Recent findings from clinical trials show a potential interest for SR49059 in the treatment of dysmenorrhea and in Raynaud's disease. Structural modifications and simplifications performed in the SR49059 chemical series yielded highly specific V2 receptor antagonists (N-arylsulfonyl-oxindoles), amongst them SR121463 which possesses powerful oral aquaretic properties in various animal species and in man. SR121463 is well-tolerated and dose-dependently increases urine output and decreases urine osmolality. It induces free water-excretion without affecting electrolyte balance in contrast to classical diuretics (e.g. furosemide and hydrochlorothiazide). Notably, in cirrhotic rats with ascites and impaired renal function, a 10-day oral treatment with SR121463 (0.5 mg/kg) totally corrected hyponatremia and restored normal urine excretion. This compound also displayed interesting new properties in a rabbit model of ocular hypertension, decreasing intraocular pressure after single or repeated instillation. Thus, V2 receptor blockade could be of interest in several water-retaining diseases such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), liver cirrhosis and congestive heart failure and deserves to be widely explored. Finally, further chemical developments in the oxindole family have led to the first specific and orally active V1b receptor antagonists (with SSR149415 as a representative), an awaited class of drugs with expected therapeutic interest mainly in ACTH-secreting tumors and various emotional diseases such as stress-related disorders, anxiety and depression. However, from the recently described tissue localization for this receptor, we could also speculate on other unexpected uses. In conclusion, the development of AVP receptor antagonists is a field of intensive pharmacological and clinical investigation. Selective and orally active compounds are now available to give new insight into the pathophysiological role of AVP and to provide promising drugs.

HIV Infection and Compromised Mucosal Immunity: Oral Manifestations and Systemic Inflammation

PubMed Central

Heron, Samantha E.; Elahi, Shokrollah

2017-01-01

Mucosal surfaces account for the vast majority of HIV transmission. In adults, HIV transmission occurs mainly by vaginal and rectal routes but rarely via oral route. By contrast, pediatric HIV infections could be as the result of oral route by breastfeeding. As such mucosal surfaces play a crucial role in HIV acquisition, and spread of the virus depends on its ability to cross a mucosal barrier. HIV selectively infects, depletes, and/or dysregulates multiple arms of the human immune system particularly at the mucosal sites and causes substantial irreversible damage to the mucosal barriers. This leads to microbial products translocation and subsequently hyper-immune activation. Although introduction of antiretroviral therapy (ART) has led to significant reduction in morbidity and mortality of HIV-infected patients, viral replication persists. As a result, antigen presence and immune activation are linked to “inflammaging” that attributes to a pro-inflammatory environment and the accelerated aging process in HIV patients. HIV infection is also associated with the prevalence of oral mucosal infections and dysregulation of oral microbiota, both of which may compromise the oral mucosal immunity of HIV-infected individuals. In addition, impaired oral immunity in HIV infection may predispose the patients to periodontal diseases that are associated with systemic inflammation and increased risk of cardiovascular diseases. The purpose of this review is to examine existing evidence regarding the role of innate and cellular components of the oral cavity in HIV infection and how HIV infection may drive systemic hyper-immune activation in these patients. We will also discuss current knowledge on HIV oral transmission, HIV immunosenescence in relation to the oral mucosal alterations during the course of HIV infection and periodontal disease. Finally, we discuss oral manifestations associated with HIV infection and how HIV infection and ART influence the oral microbiome. Therefore, unraveling how HIV compromises the integrity of the oral mucosal tissues and innate immune components of the oral cavity and its association with induction of chronic inflammation are critical for the development of effective preventive interventions and therapeutic strategies. PMID:28326084

HIV Infection and Compromised Mucosal Immunity: Oral Manifestations and Systemic Inflammation.

PubMed

Heron, Samantha E; Elahi, Shokrollah

2017-01-01

Mucosal surfaces account for the vast majority of HIV transmission. In adults, HIV transmission occurs mainly by vaginal and rectal routes but rarely via oral route. By contrast, pediatric HIV infections could be as the result of oral route by breastfeeding. As such mucosal surfaces play a crucial role in HIV acquisition, and spread of the virus depends on its ability to cross a mucosal barrier. HIV selectively infects, depletes, and/or dysregulates multiple arms of the human immune system particularly at the mucosal sites and causes substantial irreversible damage to the mucosal barriers. This leads to microbial products translocation and subsequently hyper-immune activation. Although introduction of antiretroviral therapy (ART) has led to significant reduction in morbidity and mortality of HIV-infected patients, viral replication persists. As a result, antigen presence and immune activation are linked to "inflammaging" that attributes to a pro-inflammatory environment and the accelerated aging process in HIV patients. HIV infection is also associated with the prevalence of oral mucosal infections and dysregulation of oral microbiota, both of which may compromise the oral mucosal immunity of HIV-infected individuals. In addition, impaired oral immunity in HIV infection may predispose the patients to periodontal diseases that are associated with systemic inflammation and increased risk of cardiovascular diseases. The purpose of this review is to examine existing evidence regarding the role of innate and cellular components of the oral cavity in HIV infection and how HIV infection may drive systemic hyper-immune activation in these patients. We will also discuss current knowledge on HIV oral transmission, HIV immunosenescence in relation to the oral mucosal alterations during the course of HIV infection and periodontal disease. Finally, we discuss oral manifestations associated with HIV infection and how HIV infection and ART influence the oral microbiome. Therefore, unraveling how HIV compromises the integrity of the oral mucosal tissues and innate immune components of the oral cavity and its association with induction of chronic inflammation are critical for the development of effective preventive interventions and therapeutic strategies.

Orally active vasopressin V1a receptor antagonist, SRX251, selectively blocks aggressive behavior.

PubMed

Ferris, Craig F; Lu, Shi-Fang; Messenger, Tara; Guillon, Christophe D; Heindel, Ned; Miller, Marvin; Koppel, Gary; Robert Bruns, F; Simon, Neal G

2006-02-01

Arginine vasopressin functions as a neurochemical signal in the brain to affect social behavior. There is an expanding literature from animal and human studies showing that vasopressin, through the vasopressin 1A receptor (V1A), can stimulate aggressive behavior. Using a novel monocylic beta lactam platform, a series of orally active vasopressin V1a antagonists was developed with high affinity for the human receptor. SRX251 was chosen from this series of V1a antagonists to screen for effects on serenic activity in a resident-intruder model of offensive aggression. Resident, male Syrian golden hamsters were given oral doses of SRX251 or intraperitoneal Manning compound, a selective V1a receptor antagonist with reduced brain penetrance, at doses of 0.2 microg, 20 microg, 2 mg/kg or vehicle. When tested 90-120 min later, SRX251, but not Manning compound, caused a significant dose-dependent reduction in offensive aggression toward intruders as measured by latency to bite and number of bites. The reduction in aggression persisted for over 6 h and was no longer present 12 h post treatment. SRX251 did not alter the amount of time the resident investigated the intruder, olfactory communication, general motor activity, or sexual motivation. These data corroborate previous studies showing a role for vasopressin neurotransmission in aggression and suggest that V1a receptor antagonists may be used to treat interpersonal violence co-occurring with such illness as ADHD, autism, bipolar disorder, and substance abuse.

Susceptibility of Respiratory Tract Anaerobes to Orally Administered Penicillins and Cephalosporins

PubMed Central

Busch, David F.; Kureshi, Lubna Afzal; Sutter, Vera L.; Finegold, Sydney M.

1976-01-01

Anaerobic bacteria recovered from airway-related infections were tested by agar dilution against selected penicillins and cephalosporins available for oral administration. Against 136 isolates, penicillins G and V showed comparable activity, particularly when pharmacological differences were considered. Although many isolates were exquisitely susceptible to the penicillins, only 55% of the Bacteroides species and 72% of all isolates were inhibited at 0.5 μg of penicillin G per ml. Results for penicillin V at 1 μg/ml were similar (59 and 73%). The two cephalosporins were more active at achievable levels, inhibiting 94 to 95% of Bacteroides and 95 to 96% of all isolates at 8 μg/ml. These levels represent approximately 50% of the reported peak serum levels after oral administration of 625 mg of the penicillins and 500 mg of the cephalosporins. Dicloxacillin and nafcillin were tested against 50 isolates. The two were comparably active on a weight basis; dicloxacillin was more active when pharmacological differences were considered, but did not match the other penicillins or the cephalosporins. PMID:984805

29 CFR 30.5 - Selection of apprentices.

Code of Federal Regulations, 2011 CFR

2011-07-01

... selection for apprenticeship from the pool, he or she may be required to submit to an oral interview. Oral interviews shall be limited to such objective questions as may be required to determine the fitness of... applicants. (iv) Oral interviews. Oral interviews shall not be used as a qualification standard for admission...

29 CFR 30.5 - Selection of apprentices.

Code of Federal Regulations, 2010 CFR

2010-07-01

... selection for apprenticeship from the pool, he or she may be required to submit to an oral interview. Oral interviews shall be limited to such objective questions as may be required to determine the fitness of... applicants. (iv) Oral interviews. Oral interviews shall not be used as a qualification standard for admission...

A Delphi Study to Develop a Standard List of Activities that Comprise Routine Clinical Pharmacy Services

DTIC Science & Technology

2012-06-08

The 2009 ASHP national survey on monitoring and patient education incorporates this generalist concept in its description of the three hospital...counseling Intravenous-to-oral medication conversion Drug selection recommendation Patient education Prospective order review Provider encounters...of Drug Information to Health Professionals Drug selection recommendation Decision to Prescribe a Medicine Patient education Provision of Drug

Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models.

PubMed

Lin, Jie; Sampath, Deepak; Nannini, Michelle A; Lee, Brian B; Degtyarev, Michael; Oeh, Jason; Savage, Heidi; Guan, Zhengyu; Hong, Rebecca; Kassees, Robert; Lee, Leslie B; Risom, Tyler; Gross, Stefan; Liederer, Bianca M; Koeppen, Hartmut; Skelton, Nicholas J; Wallin, Jeffrey J; Belvin, Marcia; Punnoose, Elizabeth; Friedman, Lori S; Lin, Kui

2013-04-01

We describe the preclinical pharmacology and antitumor activity of GDC-0068, a novel highly selective ATP-competitive pan-Akt inhibitor currently in clinical trials for the treatment of human cancers. The effect of GDC-0068 on Akt signaling was characterized using specific biomarkers of the Akt pathway, and response to GDC-0068 was evaluated in human cancer cell lines and xenograft models with various genetic backgrounds, either as a single agent or in combination with chemotherapeutic agents. GDC-0068 blocked Akt signaling both in cultured human cancer cell lines and in tumor xenograft models as evidenced by dose-dependent decrease in phosphorylation of downstream targets. Inhibition of Akt activity by GDC-0068 resulted in blockade of cell-cycle progression and reduced viability of cancer cell lines. Markers of Akt activation, including high-basal phospho-Akt levels, PTEN loss, and PIK3CA kinase domain mutations, correlate with sensitivity to GDC-0068. Isogenic PTEN knockout also sensitized MCF10A cells to GDC-0068. In multiple tumor xenograft models, oral administration of GDC-0068 resulted in antitumor activity ranging from tumor growth delay to regression. Consistent with the role of Akt in a survival pathway, GDC-0068 also enhanced antitumor activity of classic chemotherapeutic agents. GDC-0068 is a highly selective, orally bioavailable Akt kinase inhibitor that shows pharmacodynamic inhibition of Akt signaling and robust antitumor activity in human cancer cells in vitro and in vivo. Our preclinical data provide a strong mechanistic rationale to evaluate GDC-0068 in cancers with activated Akt signaling. ©2012 AACR.

Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility.

PubMed

Rzasa, Robert M; Frohn, Michael J; Andrews, Kristin L; Chmait, Samer; Chen, Ning; Clarine, Jeffrey G; Davis, Carl; Eastwood, Heather A; Horne, Daniel B; Hu, Essa; Jones, Adrie D; Kaller, Matthew R; Kunz, Roxanne K; Miller, Silke; Monenschein, Holger; Nguyen, Thomas; Pickrell, Alexander J; Porter, Amy; Reichelt, Andreas; Zhao, Xiaoning; Treanor, James J S; Allen, Jennifer R

2014-12-01

We report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl) quinolines as potent and selective PDE10A inhibitors. Structure-activity studies improved the solubility (pH 7.4) and maintained high PDE10A activity compared to initial lead compound 3, with select compounds demonstrating good oral bioavailability. X-ray crystallographic studies revealed two distinct binding modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy assay in rats demonstrated that this series of compounds covered the target within the striatum.

SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor.

PubMed

Rinaldi-Carmona, M; Barth, F; Millan, J; Derocq, J M; Casellas, P; Congy, C; Oustric, D; Sarran, M; Bouaboula, M; Calandra, B; Portier, M; Shire, D; Brelière, J C; Le Fur, G L

1998-02-01

Based on both binding and functional data, this study introduces SR 144528 as the first, highly potent, selective and orally active antagonist for the CB2 receptor. This compound which displays subnanomolar affinity (Ki = 0.6 nM) for both the rat spleen and cloned human CB2 receptors has a 700-fold lower affinity (Ki = 400 nM) for both the rat brain and cloned human CB1 receptors. Furthermore it shows no affinity for any of the more than 70 receptors, ion channels or enzymes investigated (IC50 > 10 microM). In vitro, SR 144528 antagonizes the inhibitory effects of the cannabinoid receptor agonist CP 55,940 on forskolin-stimulated adenylyl cyclase activity in cell lines permanently expressing the h CB2 receptor (EC50 = 10 nM) but not in cells expressing the h CB1 (no effect at 10 microM). Furthermore, SR 144528 is able to selectively block the mitogen-activated protein kinase activity induced by CP 55,940 in cell lines expressing h CB2 (IC50 = 39 nM) whereas in cells expressing h CB1 an IC50 value of more than 1 microM is found. In addition, SR 144528 is shown to antagonize the stimulating effects of CP 55,940 on human tonsillar B-cell activation evoked by cross-linking of surface Igs (IC50 = 20 nM). In vivo, after oral administration SR 144528 totally displaced the ex vivo [3H]-CP 55,940 binding to mouse spleen membranes (ED50 = 0.35 mg/kg) with a long duration of action. In contrast, after the oral route it does not interact with the cannabinoid receptor expressed in the mouse brain (CB1). It is expected that SR 144528 will provide a powerful tool to investigate the in vivo functions of the cannabinoid system in the immune response.

A systematic approach to prioritize drug targets using machine learning, a molecular descriptor-based classification model, and high-throughput screening of plant derived molecules: a case study in oral cancer.

PubMed

Randhawa, Vinay; Kumar Singh, Anil; Acharya, Vishal

2015-12-01

Systems-biology inspired identification of drug targets and machine learning-based screening of small molecules which modulate their activity have the potential to revolutionize modern drug discovery by complementing conventional methods. To utilize the effectiveness of such pipelines, we first analyzed the dysregulated gene pairs between control and tumor samples and then implemented an ensemble-based feature selection approach to prioritize targets in oral squamous cell carcinoma (OSCC) for therapeutic exploration. Based on the structural information of known inhibitors of CXCR4-one of the best targets identified in this study-a feature selection was implemented for the identification of optimal structural features (molecular descriptor) based on which a classification model was generated. Furthermore, the CXCR4-centered descriptor-based classification model was finally utilized to screen a repository of plant derived small-molecules to obtain potential inhibitors. The application of our methodology may assist effective selection of the best targets which may have previously been overlooked, that in turn will lead to the development of new oral cancer medications. The small molecules identified in this study can be ideal candidates for trials as potential novel anti-oral cancer agents. Importantly, distinct steps of this whole study may provide reference for the analysis of other complex human diseases.

Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway.

PubMed

Thress, Kenneth; Macintyre, Terry; Wang, Haiyun; Whitston, Dave; Liu, Zhong-Ying; Hoffmann, Ethan; Wang, Tao; Brown, Jeffrey L; Webster, Kevin; Omer, Charles; Zage, Peter E; Zeng, Lizhi; Zweidler-McKay, Patrick A

2009-07-01

Tropomyosin-related kinases (TrkA, TrkB, and TrkC) are receptor tyrosine kinases that, along with their ligands, the neurotrophins, are involved in neuronal cell growth, development, and survival. The Trk-neurotrophin pathway may also play a role in tumorigenesis through oncogenic fusions, mutations, and autocrine signaling, prompting the development of novel Trk inhibitors as agents for cancer therapy. This report describes the identification of AZ-23, a novel, potent, and selective Trk kinase inhibitor. In vitro studies with AZ-23 showed improved selectivity over previous compounds and inhibition of Trk kinase activity in cells at low nanomolar concentrations. AZ-23 showed in vivo TrkA kinase inhibition and efficacy in mice following oral administration in a TrkA-driven allograft model and significant tumor growth inhibition in a Trk-expressing xenograft model of neuroblastoma. AZ-23 represents a potent and selective Trk kinase inhibitor from a novel series with the potential for use as a treatment for cancer.

Lecithin-gold hybrid nanocarriers as efficient and pH selective vehicles for oral delivery of diacerein-In-vitro and in-vivo study.

PubMed

Javed, Ibrahim; Hussain, Syed Zajif; Shahzad, Atif; Khan, Jahanzeb Muhammad; Ur-Rehman, Habib; Rehman, Mubashar; Usman, Faisal; Razi, Muhammad Tahir; Shah, Muhammad Raza; Hussain, Irshad

2016-05-01

We report the synthesis and evaluation of lecithin-gold hybrid nanocarriers for the oral delivery of drugs with improved pharmacokinetics, Au-drug interactive bioactivity and controlled drug releasing behavior at physiological pH inside human body. For this purpose, diacerein, a hydrophobic anti-arthritic drug, was loaded in lecithin NPs (LD NPs), which were further coated by Au NPs either by in-situ production of Au NPs on LD NPs or by employing pre-synthesized Au NPs. All LDAu NPs were found to release drug selectively at the physiological pH of 7.4 and showed 2.5 times increase in the oral bioavailability of diacerein. Pharmacological efficacy was significantly improved i.e., greater than the additive effect of diacerein and Au NPs alone. LDAu NPs started suppressing inflammation at first phase, whereas LD NPs showed activity in the second phase of inflammation. These results indicate the interaction of Au NPs with prostaglandins and histaminic mediators of first phase of carrageenan induced inflammation. Acute toxicity study showed no hepatic damage but the renal toxicity parameters were close to the upper safety limits. Toxicity parameters were dependent on surface engineering of LDAu NPs. Apart from enhancing the oral bioavailability of hydrophobic drugs and improving their anti-inflammatory activity, these hybrid nanocarriers may have potential applications in gold-based photothermal therapy and the tracing of inflammation at atherosclerotic and arthritic site. Copyright © 2016 Elsevier B.V. All rights reserved.

Discovery of a tetrahydropyrimidin-2(1H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor.

PubMed

Fujimoto, Takuya; Imaeda, Yasuhiro; Konishi, Noriko; Hiroe, Katsuhiko; Kawamura, Masaki; Textor, Garret P; Aertgeerts, Kathleen; Kubo, Keiji

2010-05-13

Coagulation enzyme factor Xa (FXa) is a particularly promising target for the development of new anticoagulant agents. We previously reported the imidazo[1,5-c]imidazol-3-one derivative 1 as a potent and orally active FXa inhibitor. However, it was found that 1 predominantly undergoes hydrolysis upon incubation with human liver microsomes, and the human specific metabolic pathway made it difficult to predict the human pharmacokinetics. To address this issue, our synthetic efforts were focused on modification of the imidazo[1,5-c]imidazol-3-one moiety of the active metabolite 3a, derived from 1, which resulted in the discovery of the tetrahydropyrimidin-2(1H)-one derivative 5k as a highly potent and selective FXa inhibitor. Compound 5k showed no detectable amide bond cleavage in human liver microsomes, exhibited a good pharmacokinetic profile in monkeys, and had a potent antithrombotic efficacy in a rabbit model without prolongation of bleeding time. Compound 5k is currently under clinical development with the code name TAK-442.

Anti-inflammatory effects of LJP 1586 [Z-3-fluoro-2-(4-methoxybenzyl)allylamine hydrochloride], an amine-based inhibitor of semicarbazide-sensitive amine oxidase activity.

PubMed

O'Rourke, Anne M; Wang, Eric Y; Miller, Andrew; Podar, Erika M; Scheyhing, Kelly; Huang, Li; Kessler, Christina; Gao, Hongfeng; Ton-Nu, Huong-Thu; Macdonald, Mary T; Jones, David S; Linnik, Matthew D

2008-02-01

Semicarbazide-sensitive amine oxidase (SSAO, amine oxidase, copper-containing 3, and vascular adhesion protein-1) is a copper-containing enzyme that catalyzes the oxidative deamination of primary amines to an aldehyde, ammonia, and hydrogen peroxide. SSAO is also involved in leukocyte migration to sites of inflammation, and the enzymatic activity of SSAO is essential to this role. Thus, inhibition of SSAO enzyme activity represents a target for the development of small molecule anti-inflammatory compounds. Here, we have characterized the novel SSAO inhibitor, Z-3-fluoro-2-(4-methoxybenzyl)allylamine hydrochloride (LJP 1586), and assessed its anti-inflammatory activity. LJP 1586 is a potent inhibitor of rodent and human SSAO activity, with IC(50) values between 4 and 43 nM. The selectivity of LJP 1586 was confirmed with a broad panel of receptors and enzymes that included the monoamine oxidases A and B. Oral administration of LJP 1586 resulted in complete inhibition of rat lung SSAO, with an ED(50) between 0.1 and 1 mg/kg, and a pharmacodynamic half-life of greater than 24 h. In a mouse model of inflammatory leukocyte trafficking oral dosing with LJP 1586 resulted in significant dose-dependent inhibition of neutrophil accumulation, with an effect comparable to that of anti-leukocyte function-associated antigen-1 antibody. In a rat model of LPS-induced lung inflammation, administration of 10 mg/kg LJP 1586 resulted in a 55% significant reduction in transmigrated cells recovered by bronchoalveolar lavage. The results demonstrate that a selective, orally active small molecule inhibitor of SSAO is an effective anti-inflammatory compound in vivo and provide further support for SSAO as a therapeutic anti-inflammatory target.

Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancer.

PubMed

Weekes, Colin D; Von Hoff, Daniel D; Adjei, Alex A; Leffingwell, Diane P; Eckhardt, S Gail; Gore, Lia; Lewis, Karl D; Weiss, Glen J; Ramanathan, Ramesh K; Dy, Grace K; Ma, Wen W; Sheedy, Beth; Iverson, Cory; Miner, Jeffrey N; Shen, Zancong; Yeh, Li-Tain; Dubowy, Ronald L; Jeffers, Michael; Rajagopalan, Prabhu; Clendeninn, Neil J

2013-03-01

To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors. BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal-regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes. Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ~12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate-stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy. This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types. ©2012 AACR.

1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors: lead optimization studies resulting in the identification of N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide as a preclinical development candidate.

PubMed

Ramnauth, Jailall; Renton, Paul; Dove, Peter; Annedi, Subhash C; Speed, Joanne; Silverman, Sarah; Mladenova, Gabriela; Maddaford, Shawn P; Zinghini, Salvatore; Rakhit, Suman; Andrews, John; Lee, David K H; Zhang, Dongqin; Porreca, Frank

2012-03-22

Numerous studies have shown that selective nNOS inhibitors could be therapeutic in many neurological disorders. Previously, we reported a series of 1,2,3,4-tetrahydroquinoline-based potent and selective nNOS inhibitors, highlighted by 1 ( J. Med. Chem. 2011 , 54 , 5562 - 5575 ). Despite showing activity in two rodent pain models, 1 suffered from low oral bioavailability (18%) and moderate hERG channel inhibition (IC(50) = 4.7 μM). To optimize the properties of 1, we synthesized a small focused library containing various alkylamino groups on the 1-position of the 1,2,3,4-tetrahydroquinoline scaffold. The compounds were triaged based on their activity in the NOS and hERG manual patch clamp assays and their calculated physicochemical parameters. From these studies, we identified 47 as a potent and selective nNOS inhibitor with improved oral bioavailability (60%) and no hERG channel inhibition (IC(50) > 30 μM). Furthermore, 47 was efficacious in the Chung model of neuropathic pain and has an excellent safety profile, making it a promising preclinical development candidate.

Alleviating CYP and hERG liabilities by structure optimization of dihydrofuran-fused tricyclic benzo[d]imidazole series - Potent, selective and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-2.

PubMed

Muthukaman, Nagarajan; Deshmukh, Sanjay; Tambe, Macchindra; Pisal, Dnyandeo; Tondlekar, Shital; Shaikh, Mahamadhanif; Sarode, Neelam; Kattige, Vidya G; Sawant, Pooja; Pisat, Monali; Karande, Vikas; Honnegowda, Srinivasa; Kulkarni, Abhay; Behera, Dayanidhi; Jadhav, Satyawan B; Sangana, Ramchandra R; Gudi, Girish S; Khairatkar-Joshi, Neelima; Gharat, Laxmikant A

2018-04-15

In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d]imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160-950 nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases. Most of the tested analogs demonstrated required metabolic stability in liver microsomes, low hERG and CYP liability. Oral pharmacokinetics and bioavailability of lead compounds 21j, 21m and 21p are discussed in multiple species like rat, guinea pig, dog, and cynomolgus monkey. Besides, these compounds revealed low to moderate activity against human pregnane X receptor (hPXR). The selected lead 21j further demonstrated in vivo efficacy in acute hyperalgesia (ED 50 : 39.6 mg/kg) and MIA-induced osteoarthritic pain models (ED 50 : 106 mg/kg). Copyright © 2018 Elsevier Ltd. All rights reserved.

SSR126768A (4-chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide, hydrochloride): a new selective and orally active oxytocin receptor antagonist for the prevention of preterm labor.

PubMed

Serradeil-Le Gal, Claudine; Valette, Gérard; Foulon, Loïc; Germain, Guy; Advenier, Charles; Naline, Emmanuel; Bardou, Marc; Martinolle, Jean-Pierre; Pouzet, Brigitte; Raufaste, Danielle; Garcia, Corinne; Double-Cazanave, Eléonore; Pauly, Maxime; Pascal, Marc; Barbier, Alain; Scatton, Bernard; Maffrand, Jean-Pierre; Le Fur, Gérard

2004-04-01

4-chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)benzamide, hydrochloride (SSR126768A), a new potent and selective, orally active oxytocin (OT) receptor antagonist was characterized in several biochemical and pharmacological models. In binding studies, SSR126768A showed nanomolar affinity for rat and human recombinant and native OT receptors (K(i) = 0.44 nM) and exhibited much lower affinity for V(1a), V(1b), and V(2) receptors. In addition, it did not interact with a large number of other receptors, enzymes, and ion channels (1 microM). In autoradiographic experiments performed on at-term human pregnant uterus sections, SSR126768A dose dependently displaced [I(125)]d(CH(2))(5)[Tyr(Me)(2), Thr(4), Orn(8) (125)I-Tyr-NH(2)(9)]VT in situ labeling to OT receptors highly expressed in these tissues. In functional studies, SSR126768A behaved as a full antagonist and potently antagonized OT-induced intracellular Ca(2+) increase (K(i) = 0.50 nM) and prostaglandin release (K(i) = 0.45 nM) in human uterine smooth muscle cells. In rat isolated myometrium, OT-induced uterine contractions were competitively antagonized by SSR126768A (pA(2) = 8.47). Similarly, in human pregnant myometrial strips, SSR126768A inhibited the contractile uterine response to OT. In conscious telemetrated rats, oral administration of SSR126768A (1-10 mg/kg) produced a competitive inhibition of the dose response to OT on uterine contractions up to 24 h at 3 mg/kg p.o.; no tachyphylaxis was observed after 4-day repeated treatment. Finally, SSR126768A (30 mg/kg p.o.) significantly delayed parturition in pregnant rats in labor similar to ritodrine (10 mg/kg p.o.). Thus, SSR126768A is a potent, highly selective, orally active OT receptor antagonist with a long duration of action. This molecule could find therapeutic application as a tocolytic agent for acute and chronic oral management of preterm labor.

Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation

DOE Office of Scientific and Technical Information (OSTI.GOV)

McElroy, William T.; Tan, Zheng; Ho, Ginny

IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing N-1 pyridine and fluorophenyl substituentsmore » were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation.« less

Silymarin-Loaded Eudragit Nanoparticles: Formulation, Characterization, and Hepatoprotective and Toxicity Evaluation.

PubMed

El-Nahas, Amira E; Allam, Ahmed N; Abdelmonsif, Doaa A; El-Kamel, Amal H

2017-11-01

The objectives of this study were to formulate, characterize silymarin-loaded Eudragit nanoparticles (SNPs) and evaluate their hepatoprotective and cytotoxic effects after oral administration. SNPs were prepared by nanoprecipitation technique and were evaluated for particle size, entrapment efficiency, TEM, solid-state characterization, and in vitro drug release. The hepatoprotective activity was evaluated after oral administration of selected SNPs in carbon tetrachloride-intoxicated rats. Potential in vivo acute cytotoxicity study was also assessed. The selected SNPs contained 50 mg silymarin and 50 mg Eudragit polymers (1:1 w/w Eudragit RS 100 & Eudragit LS 100). Morphology of the selected SNPs (particle size of 84.70 nm and entrapment efficiency of 83.45% with 100% drug release after 12 h) revealed spherical and uniformly distributed nanoparticles. DSC and FT-IR studies suggested the presence of silymarin in an amorphous state and absence of chemical interaction. The hepatoprotective evaluation of the selected SNPs in CCl 4 -intoxicated rats revealed significant improvement in the activities of different biochemical parameters (P ≤ 0.01) compared to the marketed product. The histopathological studies suggested that the selected SNPs produced better hepatoprotective effect in CCl 4 -intoxicated rats compared with the commercially marketed product. Toxicity study revealed no evident toxic effect for blank or silymarin-loaded nanoparticles at the dose level of 50 mg/kg body weight. The obtained results suggested that the selected SNPs were safe and potentially offered enhancement in the pharmacological hepatoprotective properties of silymarin.

Absolute Bioavailability of Osimertinib in Healthy Adults.

PubMed

Vishwanathan, Karthick; So, Karen; Thomas, Karen; Bramley, Alex; English, Stephen; Collier, Jo

2018-04-23

Osimertinib is a third-generation, central nervous system-active, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) selective for EGFR-TKI sensitizing and T790M resistance mutations. This phase 1, open-label study (NCT02491944) investigated absolute bioavailability and pharmacokinetics (PK) of oral and intravenous (IV) osimertinib. Ten healthy subjects (21-61 years) received a single oral 80-mg dose concomitantly with a 100 μg (containing 1 μCi) IV microtracer dose of [ 14 C]osimertinib. Oral and IV PK were determined simultaneously for osimertinib and its active metabolites, AZ5104 and AZ7550. High-performance liquid chromatography and accelerator mass spectrometry were used to characterize IV dose PK. Geometric mean absolute oral bioavailability of osimertinib was 69.8% (90% confidence interval, 66.7, 72.9). Oral osimertinib was slowly absorbed (median time to maximum plasma concentration [t max ] 7.0 hours). Following t max , plasma concentrations fell in an apparent monophasic manner. IV clearance and volume of distribution were 16.8 L/h and 1285 L, respectively. Arithmetic mean elimination half-life estimates were 59.7, 52.6, and 72.6 hours for osimertinib, AZ5104, and AZ7550, respectively (oral dosing), and 54.9, 68.4, and 99.7 hours for [ 14 C]osimertinib, [ 14 C]AZ5104, and [ 14 C]AZ7550, respectively (IV dosing). Oral osimertinib was well absorbed. Simultaneous IV and oral PK analysis proved useful for complete understanding of osimertinib PK and showed that the first-pass effect was minimal for osimertinib. © 2018, The American College of Clinical Pharmacology.

Effect of obesity and lifestyle on the oral health of pre adolescent children.

PubMed

Anand, Nithya; Suresh, M; Chandrasekaran, S C

2014-02-01

Worldwide estimates of childhood obesity are as high as 43 million, and rates continue to increase each year. Childhood obesity is a growing problem in the present era and it causes serious consequences in the later years. In today's society, electronic media have been thoroughly integrated into the fabric of life, with television, video games, and computers being central to both work and play. While these media outlets can provide education and entertainment to children, many researches are concerned with the negative impact of electronic media on children. The current study aimed to evaluate the correlation, as to how oral hygiene and periodontal health were influenced by obesity and lifestyle factors, among pre-adolescents of ages of 9-12 years. This study was conducted in schools located around Velachery, Chennai, India. A total of 426 children of age group of 9-12 years were selected. Information on their socio-economic, dietary, oral health statuses and time spent in leisure activities were assessed by using a questionnaire, followed by BMI estimation and these variables were correlated with their oral hygiene statuses. The prevalence of poor oral hygiene and poor dietary habits was observed in children who spent more time in watching television, playing videogames and using computer. Good oral hygiene was observed in children who had visited dentists in the past. There is a strong association of lifestyle factors with oral hygiene in pre-adolescent children. Sedentary lifestyle, with more leisure activities, has a negative impact on the oral health of children.

Novel, non-steroidal, selective androgen receptor modulators (SARMs) with anabolic activity in bone and muscle and improved safety profile.

PubMed

Rosen, J; Negro-Vilar, A

2002-03-01

A novel approach to the treatment of osteoporosis in men, and possibly women, is the development of selective androgen receptor modulators (SARMs) that can stimulate formation of new bone with substantially diminished proliferative activity in the prostate, as well as reduced virilizing activity in women. Over the last several years, we have developed a program to discover and develop novel, non-steroidal, orally-active selective androgen receptor modulators (SARMs) that provide improved therapeutic benefits and reduce risk and side effects. In recent studies, we have used a skeletally mature orchiectomized (ORX) male rat as an animal model of male hypogonadism for assessing the efficacy of LGD2226, a nonsteroidal, non-aromatizable, and non-5alpha-reducible SARM. We assessed the activity of LGD2226 on bone turnover, bone mass and bone strength, and also evaluated the effects exerted on classic androgen-dependent targets, such as prostate, seminal vesicles and muscle. A substantial loss of bone density was observed in ORX animals, and this loss was prevented by SARMs, as well as standard androgens. Biochemical markers of bone turnover revealed an early increase of bone resorption in androgen-deficient rats that was repressed in ORX animals treated with the oral SARM, LGD2226, during a 4-month treatment period. Differences in architectural properties and bone strength were detected by histomorphometric and mechanical analyses, demonstrating beneficial effects of LGD2226 on bone quality in androgen-deficient rats. Histomorphometric analysis of cortical bone revealed distinct anabolic activity of LGD2226 in periosteal bone. LGD2226 was able to prevent bone loss and maintain bone quality in ORX rats by stimulating bone formation, while also inhibiting bone turnover. LGD2226 also exerted anabolic activity on the levator ani muscle. Taken together, these results suggest that orally-active, non-steroidal SARMs may be useful therapeutics for both muscle and bone in elderly hypogonadal men through their anabolic activities. Since SARMs both prevent bone loss, and also stimulate formation of new bone, they may have significant advantages relative to currently used anti-resorptive therapies. Coupled with their activity in muscle and their ability to maintain or restore libido, they offer new therapeutic approaches for male and female hormone replacement.

Planning and implementation of community oral health programs for caries management in children.

PubMed

Chu, C H; Chau, Alex M H; Lo, Edward C M; Lam, Anty

2012-01-01

Tooth decay or cavities (dental caries) can have a significant impact on children's quality of life, causing pain, infection, and other problems in the oral environment. Good oral health is a fundamental element of good general health for children, yet dental caries is still prevalent among children in many countries. Dental caries is well-understood, and effective prevention is an attainable goal. Dental professionals should actively engage with communities--in particular, the underprivileged--to identify dental caries problems and implement appropriate and effective community oral health programs (COHPs) to improve oral health and reduce oral health inequalities. This paper discusses COHPs as well as the steps involved in caries prevention for children. These steps cannot ensure the success of every COHP, but they are helpful for developing, integrating, expanding, and enhancing them. The effectiveness of COHPs for the prevention of caries in children varies from country to country, according to cultural, social, economic, and health care settings. Careful consideration of the local situation is required when selecting the elements of COHPs.

Discovery of potent and selective CDK8 inhibitors through FBDD approach.

PubMed

Han, Xingchun; Jiang, Min; Zhou, Chengang; Zhou, Zheng; Xu, Zhiheng; Wang, Lisha; Mayweg, Alexander V; Niu, Rui; Jin, Tai-Guang; Yang, Song

2017-09-15

A fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability. Copyright © 2017 Elsevier Ltd. All rights reserved.

Discovery of selective and orally bioavailable protein kinase Cθ (PKCθ) inhibitors from a fragment hit.

PubMed

George, Dawn M; Breinlinger, Eric C; Friedman, Michael; Zhang, Yang; Wang, Jianfei; Argiriadi, Maria; Bansal-Pakala, Pratima; Barth, Martine; Duignan, David B; Honore, Prisca; Lang, QingYu; Mittelstadt, Scott; Potin, Dominique; Rundell, Lian; Edmunds, Jeremy J

2015-01-08

Protein kinase Cθ (PKCθ) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKCθ inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design. Compound 41 demonstrates excellent in vitro activity, good oral pharmacokinetics, and efficacy in both an acute in vivo mechanistic model and a chronic in vivo disease model but suffers from tolerability issues upon chronic dosing.

Oral management of children with Henoch-Schönlein Purpura and associated Glomerulonephritis: a scoping review.

PubMed

Echavarría-García, A C; Pozos-Guillén, A; Tejeda-Nava, F; Flores Arriaga, J C; Garrocho-Rangel, A

2018-06-01

To perform a scoping review of the existing literature in order to gather the most relevant information in the paediatric dentistry field related to the oral management of children affected by Henoch-Schönlein Purpura and associated Glomerulonephritis (HSPG). Using scoping review methodology for the screening and selection of valid articles, the steps of this review were the following: first, to pose a research question; second, to identify relevant studies; third, to select and retrieve the studies; fourth, to chart the critical data, and finally, to collate, summarise, and report the results from the included articles. Relevant articles published over a 25-year period, up to July 31, 2017, were identified and retrieved from four Internet databases: PubMed; EMBASE/Ovid; Ebsco/Dentistry & Oral Science Source, and the Cochrane Collaboration Library. By title and abstract screening and after removing duplicates, four articles were finally included in the scoping review. According to the extracted data, the following are the most important clinical issues to be considered: (1) the disease can appear as a consequence of a dental treatment, such as those indicated for oral infectious processes; (2) children with HSPG are highly susceptible to dental caries and apical periodontitis, and (3) in affected children, oral infectious foci must be exhaustively eradicated in order to avoid the dissemination of the infection. Paediatric Dentists should be aware of HSPG, because the disease can be triggered or worsen subsequent to dental treatment. Adequate treatment of oral active infectious processes, together with an exhaustive oral preventive programme and long-term patient screening, are the best management approaches for children with HSPG.

Histatin 5-Spermidine Conjugates Have Enhanced Fungicidal Activity and Efficacy as a Topical Therapeutic for Oral Candidiasis

PubMed Central

Tati, Swetha; Li, Rui; Puri, Sumant; Kumar, Rohitashw; Davidow, Peter

2014-01-01

Oropharyngeal candidiasis (OPC) is caused by the opportunistic fungi Candida albicans and is prevalent in immunocompromised patients, individuals with dry mouth, or patients with prolonged antibiotic therapies that reduce oral commensal bacteria. Human salivary histatins, including histatin 5 (Hst 5), are small cationic proteins that are the major source of fungicidal activity of saliva. However, Hsts are rapidly degraded in vivo, limiting their usefulness as therapeutic agents despite their lack of toxicity. We constructed a conjugate peptide using spermidine (Spd) linked to the active fragment of Hst 5 (Hst 54–15), based upon our findings that C. albicans spermidine transporters are required for Hst 5 uptake and fungicidal activity. We found that Hst 54–15-Spd was significantly more effective in killing C. albicans and Candida glabrata than Hst 5 alone in both planktonic and biofilm growth and that Hst 54–15-Spd retained high activity in both serum and saliva. Hst 54–15-Spd was not bactericidal against streptococcal oral commensal bacteria and had no hemolytic activity. We tested the effectiveness of Hst 54–15-Spd in vivo by topical application to tongue surfaces of immunocompromised mice with OPC. Mice treated with Hst 54–15-Spd had significant clearance of candidal tongue lesions macroscopically, which was confirmed by a 3- to 5-log fold reduction of C. albicans colonies recovered from tongue tissues. Hst 54–15-Spd conjugates are a new class of peptide-based drugs with high selectivity for fungi and potential as topical therapeutic agents for oral candidiasis. PMID:24247141

Histatin 5-spermidine conjugates have enhanced fungicidal activity and efficacy as a topical therapeutic for oral candidiasis.

PubMed

Tati, Swetha; Li, Rui; Puri, Sumant; Kumar, Rohitashw; Davidow, Peter; Edgerton, Mira

2014-01-01

Oropharyngeal candidiasis (OPC) is caused by the opportunistic fungi Candida albicans and is prevalent in immunocompromised patients, individuals with dry mouth, or patients with prolonged antibiotic therapies that reduce oral commensal bacteria. Human salivary histatins, including histatin 5 (Hst 5), are small cationic proteins that are the major source of fungicidal activity of saliva. However, Hsts are rapidly degraded in vivo, limiting their usefulness as therapeutic agents despite their lack of toxicity. We constructed a conjugate peptide using spermidine (Spd) linked to the active fragment of Hst 5 (Hst 54-15), based upon our findings that C. albicans spermidine transporters are required for Hst 5 uptake and fungicidal activity. We found that Hst 54-15-Spd was significantly more effective in killing C. albicans and Candida glabrata than Hst 5 alone in both planktonic and biofilm growth and that Hst 54-15-Spd retained high activity in both serum and saliva. Hst 54-15-Spd was not bactericidal against streptococcal oral commensal bacteria and had no hemolytic activity. We tested the effectiveness of Hst 54-15-Spd in vivo by topical application to tongue surfaces of immunocompromised mice with OPC. Mice treated with Hst 54-15-Spd had significant clearance of candidal tongue lesions macroscopically, which was confirmed by a 3- to 5-log fold reduction of C. albicans colonies recovered from tongue tissues. Hst 54-15-Spd conjugates are a new class of peptide-based drugs with high selectivity for fungi and potential as topical therapeutic agents for oral candidiasis.

Effects of Age and Removable Artificial Dentition on Taste

DTIC Science & Technology

1990-08-01

gland activity, to decline with age. Similarly, Cohen the taste intensity spectrum and provide sensitivity to weak gustatory stimuli was and Gitman ...Field J, I. Cohen T, Gitman L. Oral complaints and taste AMWQr ed Sci 1976;272:285-99. ed. Handbook of physiology, selection I, perception in the

Oral antibodies to human intestinal alkaline phosphatase reduce dietary phytate phosphate bioavailability in the presence of dietary 1α-hydroxycholecalciferol.

PubMed

Bobeck, Elizabeth A; Hellestad, Erica M; Helvig, Christian F; Petkovich, P Martin; Cook, Mark E

2016-03-01

While it is well established that active vitamin D treatment increases dietary phytate phosphate utilization, the mechanism by which intestinal alkaline phosphatase (IAP) participates in phytate phosphate use is less clear. The ability of human IAP (hIAP) oral antibodies to prevent dietary phytate phosphate utilization in the presence of 1α-hydroxycholecalciferol (1α-(OH) D3) in a chick model was investigated. hIAP specific chicken immunoglobulin Y (IgY) antibodies were generated by inoculating laying hens with 17 synthetic peptides derived from the human IAP amino acid sequence and harvesting egg yolk. Western blot analysis showed all antibodies recognized hIAP and 6 of the 8 antibodies selected showed modest inhibition of hIAP activity in vitro (6 to 33% inhibition). In chicks where dietary phosphate was primarily in the form of phytate, 4 selected hIAP antibodies inhibited 1α-(OH) D3-induced increases in blood phosphate, one of which, generated against selected peptide (MFPMGTPD), was as effective as sevelamer hydrochloride in preventing the 1α-(OH) D3-induced increase in blood phosphate, but ineffective in preventing an increase in body weight gain and bone ash induced by 1α-(OH) D3. These studies demonstrated that orally-delivered antibodies to IAP limit dietary phytate-phosphate utilization in chicks treated with 1α-(OH) D3, and implicate IAP as an important host enzyme in increasing phytate phosphate bioavailability in 1α-(OH) D3 fed chicks. © 2015 Poultry Science Association Inc.

The Application of Magnetic Bead Selection to Investigate Interactions between the Oral Microbiota and Salivary Immunoglobulins.

PubMed

Madhwani, Tejal; McBain, Andrew J

2016-01-01

The effect of humoral immunity on the composition of the oral microbiota is less intensively investigated than hygiene and diet, in part due to a lack of simple and robust systems for investigating interactions between salivary immunoglobulins and oral bacteria. Here we report the application of an ex situ method to investigate the specificity of salivary immunoglobulins for salivary bacteria. Saliva collected from six volunteers was separated into immunoglobulin and microbial fractions, and the microbial fractions were then directly exposed to salivary immunoglobulins of "self" and "non-self" origin. Antibody-selected bacteria were separated from their congeners using a magnetic bead system, selective for IgA or IgG isotypes. The positively selected fractions were then characterized using gel-based eubacterial-specific DNA profiling. The eubacterial profiles of positively selected fractions diverged significantly from profiles of whole salivary consortia based on volunteer (P≤ 0.001%) and immunoglobulin origin (P≤ 0.001%), but not immunoglobulin isotype (P = 0.2). DNA profiles of separated microbial fractions were significantly (p≤ 0.05) less diverse than whole salivary consortia and included oral and environmental bacteria. Consortia selected using self immunoglobulins were generally less diverse than those selected with immunoglobulins of non-self origin. Magnetic bead separation facilitated the testing of interactions between salivary antibodies and oral bacteria, showing that these interactions are specific and may reflect differences in recognition by self and non-self immunoglobulins. Further development of this system could improve understanding of the relationship between the oral microbiota and the host immune system and of mechanisms underlying the compositional stability of the oral microbiota.

Novel probiotic dissolvable carboxymethyl cellulose films as oral health biotherapeutics: in vitro preparation and characterization.

PubMed

Saha, Shyamali; Tomaro-Duchesneau, Catherine; Daoud, Jamal T; Tabrizian, Maryam; Prakash, Satya

2013-11-01

Oral health is influenced by the mouth's resident microorganisms. Dental caries and periodontitis are oral disorders caused by imbalances in the oral microbiota. Probiotics have potential for the prevention and treatment of oral disorders. Current formulations, including supplements and foods, have limitations for oral delivery including short storage time, low residence time in the mouth, effects on food consistency, and low patient compliance. Oral thin films (OTFs) may be efficient in delivering probiotics to the mouth. This research aims to develop a novel carboxymethyl cellulose (CMC)-probiotic-OTF to deliver probiotics for the treatment/prevention of oral disorders. CMC-OTFs were developed with varying CMC concentration (1.25 - 10 mg/mL), weight (5 - 40 g), thickness (16 - 262 μm), hygroscopicity (30.8 - 78.9 mg/cm(2) film), and dissolving time (135 - 600 s). The 10 g 5 mg/mL CMC-OTF was selected and used to incorporate Lactobacillus fermentum NCIMB 5221 (6.75 × 10(8) cells/film), a probiotic with anti-inflammatory potential for periodontitis treatment and capable of inhibiting microorganisms responsible for dental caries and oral candidiasis. The CMC-OTF maintained probiotic viability and antioxidant activity following 150 days of storage with a production of 549.52 ± 26.08 μM Trolox equivalents. This research shows the successful development and characterization of a novel probiotic-CMC-OTF with potential as an oral health biotherapeutic.

Silencing urease: a key evolutionary step that facilitated the adaptation of Yersinia pestis to the flea-borne transmission route.

PubMed

Chouikha, Iman; Hinnebusch, B Joseph

2014-12-30

The arthropod-borne transmission route of Yersinia pestis, the bacterial agent of plague, is a recent evolutionary adaptation. Yersinia pseudotuberculosis, the closely related food-and water-borne enteric species from which Y. pestis diverged less than 6,400 y ago, exhibits significant oral toxicity to the flea vectors of plague, whereas Y. pestis does not. In this study, we identify the Yersinia urease enzyme as the responsible oral toxin. All Y. pestis strains, including those phylogenetically closest to the Y. pseudotuberculosis progenitor, contain a mutated ureD allele that eliminated urease activity. Restoration of a functional ureD was sufficient to make Y. pestis orally toxic to fleas. Conversely, deletion of the urease operon in Y. pseudotuberculosis rendered it nontoxic. Enzymatic activity was required for toxicity. Because urease-related mortality eliminates 30-40% of infective flea vectors, ureD mutation early in the evolution of Y. pestis was likely subject to strong positive selection because it significantly increased transmission potential.

Silencing urease: A key evolutionary step that facilitated the adaptation of Yersinia pestis to the flea-borne transmission route

PubMed Central

Chouikha, Iman; Hinnebusch, B. Joseph

2014-01-01

The arthropod-borne transmission route of Yersinia pestis, the bacterial agent of plague, is a recent evolutionary adaptation. Yersinia pseudotuberculosis, the closely related food-and water-borne enteric species from which Y. pestis diverged less than 6,400 y ago, exhibits significant oral toxicity to the flea vectors of plague, whereas Y. pestis does not. In this study, we identify the Yersinia urease enzyme as the responsible oral toxin. All Y. pestis strains, including those phylogenetically closest to the Y. pseudotuberculosis progenitor, contain a mutated ureD allele that eliminated urease activity. Restoration of a functional ureD was sufficient to make Y. pestis orally toxic to fleas. Conversely, deletion of the urease operon in Y. pseudotuberculosis rendered it nontoxic. Enzymatic activity was required for toxicity. Because urease-related mortality eliminates 30–40% of infective flea vectors, ureD mutation early in the evolution of Y. pestis was likely subject to strong positive selection because it significantly increased transmission potential. PMID:25453069

Current status of herpesvirus identification in the oral cavity of HIV-infected children.

PubMed

Pinheiro, Raquel dos Santos; Ferreira, Dennis de Carvalho; Nóbrega, Flávia; Santos, Norma Suely de Oliveira; Souza, Ivete Pomarico Ribeiro de; Castro, Gloria Fernanda Barbosa de Araujo

2013-01-01

Some viruses of the Herpesviridae family are frequently the etiologic agents of oral lesions associated with HIV. The aim of this study was to identify the presence of herpes simplex virus types 1 and 2 (HSV-1, HSV-2), Varicella Zoster virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), human herpesvirus type 6, type 7 and type 8 (HHV-6, HHV-7 and HHV-8) in the oral cavity of HIV-infected children/adolescents and verify the association between viral subtypes and clinical factors. The cells of oral mucosa were collected from 50 HIV infected children/adolescents, 3-13 years old (mean age 8.66). The majority (66%) of selected were girls, and they were all outpatients at the pediatric AIDS clinic of a public hospital in Rio de Janeiro. Nested-PCR was used to identify the viral types. Absence of immunosuppression was observed in 66% of the children. Highly active antiretroviral therapy (HAART) was used by 72.1% of selected and moderate viral load was observed in 56% of the children/adolescents. Viral types were found in 86% of the children and the subtypes were: HSV-1 (4%), HSV-2 (2%), VZV (4%), EBV (0%), HCMV (24%), HHV6 (18%), HHV-7 (68%), HHV8 (0%). The use of HAART has helped to reduce oral lesions, especially with herpes virus infections. The health professionals who work with these patients should be aware of such lesions because of their predictive value and the herpes virus can be found circulating in the oral cavity without causing lesions.

N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor.

PubMed

Hennequin, Laurent F; Allen, Jack; Breed, Jason; Curwen, Jon; Fennell, Michael; Green, Tim P; Lambert-van der Brempt, Christine; Morgentin, Rémy; Norman, Richard A; Olivier, Annie; Otterbein, Ludovic; Plé, Patrick A; Warin, Nicolas; Costello, Gerard

2006-11-02

Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. We report here a novel subseries of C-5-substituted anilinoquinazolines that display high affinity and specificity for the tyrosine kinase domain of the c-Src and Abl enzymes. These compounds exhibit high selectivity for SFKs over a panel of recombinant protein kinases, excellent pharmacokinetics, and in vivo activity following oral dosing. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine (AZD0530) inhibits c-Src and Abl enzymes at low nanomolar concentrations and is highly selective over a range of kinases. AZD0530 displays excellent pharmacokinetic parameters in animal preclinically and in man (t(1/2) = 40 h). AZD0530 is a potent inhibitor of tumor growth in a c-Src-transfected 3T3-fibroblast xenograft model in vivo and led to a significant increase in survival in a highly aggressive, orthotopic model of human pancreatic cancer when dosed orally once daily. AZD0530 is currently undergoing clinical evaluation in man.

Oral Health Status of Older Adults Attending Senior Centers and Congregate Meal Sites in New Hampshire.

PubMed

Anderson, Ludmila; Martin, Nancy R; Kelly, Stephanie M; Brown, Heather A

2016-04-01

This study assessed the oral health status of older adults in randomly selected New Hampshire senior centers and congregate meal sites for the purpose of future planning, implementation and evaluation of targeted public health programs. A cross-sectional surveillance project was developed. Registered dental hygienists visually assessed denture use, number of natural teeth, teeth mobility, untreated caries, root fragments, gingivitis, need for care and treatment urgency among randomly selected active older adults living within New Hampshire communities. Altogether, 610 adults 60 years old and older attending 25 senior centers and congregate meal sites participated. Sixteen percent were edentulous and 42% reported having a removable upper or lower denture. Among edentulous adults, 5% had no dentures at all. Among 513 dentate participants, 22% had untreated caries, 14% had root fragments, 9% had gingivitis and 7% presented with obviously mobile teeth. Overall, 19% required early or urgent dental care. Differences were detected by sex, age group, urban versus rural location of the site and by the participation in a federal nutritional program for older adults. Baseline information about oral health needs of older adults in New Hampshire was gathered. Overall needs as well as existing oral health disparities will be addressed through the collaboration of public and private partners. Copyright © 2016 The American Dental Hygienists’ Association.

Effects of an orally active vasopressin V1 receptor antagonist.

PubMed

Burrell, L M; Phillips, P A; Stephenson, J; Risvanis, J; Hutchins, A M; Johnston, C I

1993-05-01

1. This paper reports on the in vitro and in vivo characteristics of a non-peptide vasopressin V1 receptor antagonist 1-(1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl)-3,4-dihydro-2( 1H)- quinolinone (OPC-21268). 2. OPC-21268 caused a concentration-dependent displacement of the selective V1 receptor antagonist radioligand, [125I]-[d(CH2)5, sarcosine7]AVP from vasopressin V1 receptors in rat liver and kidney membranes, inhibitory concentration of 50% (IC50) 4 x 10(-8), 0.3 mol/L liver and 1.5 x 10(-8), 0.2 mol/L kidney. OPC-21268 had little effect on the selective V2 antagonist radioligand [3H]desGly-NH2(9)-d(CH2)5[D-Ileu2, Ileu4]AVP binding to V2 receptors in renal membranes (IC50 > 10(-4) mol/L). 3. After oral administration to rats, OPC-21268 was an effective V1 antagonist to both liver and kidney V1 receptors, in a dose-dependent manner. 4. These studies confirm that OPC-21268 is a potent non-peptide, orally effective V1 vasopressin receptor antagonist.

The impact of preparatory activities on medical school selection outcomes: a cross-sectional survey of applicants to the university of Adelaide medical school in 2007

PubMed Central

2013-01-01

Background Selection into medical school is highly competitive with more applicants than places. Little is known about the preparation that applicants undertake for this high stakes process. The study aims to determine what preparatory activities applicants undertake and what difficulties they encounter for each stage of the application process to medical school and in particular what impact these have on the outcome. Methods A cross-sectional survey of 1097 applicants who applied for a place in the University of Adelaide Medical School in 2007 and participated in the UMAT (Undergraduate Medicine and Health Sciences Admission Test) and oral assessment components of the selection process. The main outcome measures were an offer of an interview and offer of a place in the medical school and were analysed using logistic regression. Results The odds of a successful outcome increased with each additional preparatory activity undertaken for the UMAT (odds ratio 1.22, 95% confidence interval 1.11 to 1.33; P < 0.001) and the oral assessment (1.36, 1.19 to 1.55; P < 0.001) stage of selection. The UMAT preparatory activities associated with the offer of an interview were attendance of a training course by a private organisation (1.75, 1.35 to 2.27: P < 0.001), use of online services of a private organisation (1.58, 1.23 to 2.04; P < 0.001), and familiarising oneself with the process (1.52, 1.15 to 2.00; p = 0.021). The oral assessment activities associated with an offer of a place included refining and learning a personal resume (9.73, 2.97 to 31.88; P < 0.001) and learning about the course structure (2.05, 1.29 to 3.26; P = 0.022). For the UMAT, applicants who found difficulties with learning for this type of test (0.47, 0.35 to 0.63: P < 0.001), with the timing of UMAT in terms of school exams (0.48, 0.5 to 0.66; P < 0.001) and with the inability to convey personal skills with the UMAT (0.67, 0.52 to 0.86; P = 0.026) were significantly less likely to be offered an interview. Conclusions Medical schools make an enormous effort to undertake a selection process that is fair and equitable and which selects students most appropriate for medical school and the course they provide. Our results indicate that performance in the selection processes can be improved by training. However, if these preparatory activities may be limited to those who can access them, the playing field is not even and increasing equity of access to medical schools will not be achieved. PMID:24289521

Oral choline supplementation for postoperative pain

PubMed Central

Sidhu, N.; Davies, S.; Nadarajah, A.; Rivera, J.; Whittington, R.; Mercier, R. J.; Virag, L.; Wang, S.; Flood, P.

2013-01-01

Background Activation of nicotinic receptors with nicotine has been shown to reduce post-surgical pain in clinical and preclinical studies. Choline is a selective agonist at α7-type nicotinic receptors that does not have addictive or sympathetic activating properties. It is anti-nociceptive in animal studies. We conducted a double-blind randomized trial of oral choline supplementation with lecithin to aid in the treatment of pain after gynaecological surgery. Methods Sixty women having open gynaecological surgery were randomly assigned to receive 20 g of lecithin before surgery or placebo. Plasma choline concentration and tumour necrosis factor (TNF) were measured. Pain report was the primary outcome measure. Results We achieved a small but statistically significant increase in choline after surgery with oral supplementation. Plasma TNF was not decreased and pain report was not different between groups at rest or with movement. There were no adverse effects of treatment. Conclusions Oral supplementation with lecithin during the perioperative period resulted in very slow absorption and thus only a small increase in plasma choline was achieved. This concentration was inadequate to reduce TNF as has been shown in other studies. The absence of an anti-inflammatory effect was likely related to our failure to demonstrate efficacy in pain reduction. PMID:23568851

Lactase persistence and augmented salivary alpha-amylase gene copy numbers might have been selected by the combined toxic effects of gluten and (food born) pathogens.

PubMed

Pruimboom, Leo; Fox, Tom; Muskiet, Frits A J

2014-03-01

Various positively selected adaptations to new nutrients have been identified. Lactase persistence is among the best known, conferring the ability for drinking milk at post weaning age. An augmented number of amylase gene (AMY1) copies, giving rise to higher salivary amylase activity, has been implicated in the consumption of starch-rich foods. Higher AMY1 copy numbers have been demonstrated in populations with recent histories of starchy-rich diets. It is however questionable whether the resulting polymorphisms have exerted positive selection only by providing easily available sources of macro and micronutrients. Humans have explored new environments more than any other animal. Novel environments challenge the host, but especially its immune system with new climatic conditions, food and especially pathogens. With the advent of the agricultural revolution and the concurrent domestication of cattle came new pathogens. We contend that specific new food ingredients (e.g., gluten) and novel pathogens drove selection for lactase persistence and higher AMY gene copy numbers. Both adaptations provide ample glucose for activating the sodium glucose-dependent co-transporter 1 (SGLT1), which is the principal glucose, sodium and water transporter in the gastro-intestinal tract. Their rapid uptake confers protection against potentially lethal dehydration, hyponatremia and ultimately multiple organ failure. Oral rehydration therapy aims at SGLT1 activity and is the current treatment of choice for chronic diarrhoea and vomiting. We hypothesize that lifelong lactase activity and rapid starch digestion should be looked at as the evolutionary covalent of oral rehydration therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Discovery of Aryl Aminoquinazoline Pyridones as Potent, Selective, and Orally Efficacious Inhibitors of Receptor Tyrosine Kinase c-Kit

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, Essa; Tasker, Andrew; White, Ryan D.

2008-12-09

Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation.

The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer .

PubMed

Folkes, Adrian J; Ahmadi, Khatereh; Alderton, Wendy K; Alix, Sonia; Baker, Stewart J; Box, Gary; Chuckowree, Irina S; Clarke, Paul A; Depledge, Paul; Eccles, Suzanne A; Friedman, Lori S; Hayes, Angela; Hancox, Timothy C; Kugendradas, Arumugam; Lensun, Letitia; Moore, Pauline; Olivero, Alan G; Pang, Jodie; Patel, Sonal; Pergl-Wilson, Giles H; Raynaud, Florence I; Robson, Anthony; Saghir, Nahid; Salphati, Laurent; Sohal, Sukhjit; Ultsch, Mark H; Valenti, Melanie; Wallweber, Heidi J A; Wan, Nan Chi; Wiesmann, Christian; Workman, Paul; Zhyvoloup, Alexander; Zvelebil, Marketa J; Shuttleworth, Stephen J

2008-09-25

Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.

Lack of effects of astemizole on vestibular ocular reflex, motion sickness, and cognitive performance in man

NASA Technical Reports Server (NTRS)

Kohl, Randall L.; Homick, Jerry L.; Cintron, Nitza; Calkins, Dick S.

1987-01-01

Astemizole was orally administered to 20 subjects in a randomized, double-blind design to assess the efficacy of this peripherally active antihistamine as an antimotion sickness drug possessing no central side-effects. Measures of vestibular ocular reflex (VOR) were made to evaluate the agent as a selective vestibular depressant. Following one week of orally administered astemizole (30 mg daily), a Staircase Profile Test, a VOR test, and a variety of tests of cognitive performance were administered. These tests revealed no statistically significant effects of astemizole. This leads to the conclusion that, although the drug probably reaches the peripheral vestibular apparatus in man by crossing the blood-vestibular barrier, a selective peripheral antihistamine (H1) action is inadequate to control motion sickness induced through cross-coupled accelerative semicircular canal stimulation in a rotating chair.

Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T-Type Calcium Channel Blocker, ABT-639

PubMed Central

2015-01-01

The discovery of a novel peripherally acting and selective Cav3.2 T-type calcium channel blocker, ABT-639, is described. HTS hits 1 and 2, which have poor metabolic stability, were optimized to obtain 4, which has improved stability and oral bioavailability. Modification of 4 to further improve ADME properties led to the discovery of ABT-639. Following oral administration, ABT-639 produces robust antinociceptive activity in experimental pain models at doses that do not significantly alter psychomotor or hemodynamic function in the rat. PMID:26101566

Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T-Type Calcium Channel Blocker, ABT-639.

PubMed

Zhang, Qingwei; Xia, Zhiren; Joshi, Shailen; Scott, Victoria E; Jarvis, Michael F

2015-06-11

The discovery of a novel peripherally acting and selective Cav3.2 T-type calcium channel blocker, ABT-639, is described. HTS hits 1 and 2, which have poor metabolic stability, were optimized to obtain 4, which has improved stability and oral bioavailability. Modification of 4 to further improve ADME properties led to the discovery of ABT-639. Following oral administration, ABT-639 produces robust antinociceptive activity in experimental pain models at doses that do not significantly alter psychomotor or hemodynamic function in the rat.

Perceived ejaculatory latency and pleasure in different outlets.

PubMed

Corty, Eric W

2008-11-01

Ejaculatory latencies have been studied in coitus and with masturbation, but not with oral or manual stimulation by a partner. The present study extended research on ejaculatory latency to these outlets, and investigated the effect of perceived pleasure on self-reported ejaculatory latency. A convenience sample of male college students, not selected for sexual dysfunction, completed questionnaires assessing the outcome measures. Self-report measures of latency to ejaculation in, and perceived pleasure associated with, four different outlets (vaginal intercourse, oral intercourse, manual stimulation by a partner, and masturbation). Ejaculatory latencies in partnered activities were predictive of each other. Masturbatory latencies were predictive of coital latencies but not oral or manual stimulation latencies; all the partnered activities were predictive of each other. There was no difference in time to ejaculation among any of the partnered outlets, although ejaculation occurred more quickly with masturbation than with coitus or manual stimulation. In terms of pleasure associated with the outlets, vaginal and oral intercourse were perceived as equally pleasurable, and both were rated as more pleasurable than manual stimulation or masturbation, which did not differ from each other. These results suggest that rapidity of ejaculation is consistent across outlets for the partnered sexual activities, and that there is little unique-in terms of ejaculatory latency--about vaginal intercourse compared with oral or manual stimulation by a partner. Masturbation, however, does differ from the partnered activities. Although the average correlation, for individuals, between latency and pleasure for the different outlets is near zero, there are subgroups of men who have (i) a negative relation, (ii) a positive relation, or (iii) no relation. Results show that men, for whom greater pleasure is associated with shorter latency, are more likely to be dissatisfied with their intravaginal ejaculatory latencies, regardless of actual latency.

Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy

PubMed Central

Faisal, Amir; Mak, Grace W Y; Gurden, Mark D; Xavier, Cristina P R; Anderhub, Simon J; Innocenti, Paolo; Westwood, Isaac M; Naud, Sébastien; Hayes, Angela; Box, Gary; Valenti, Melanie R; De Haven Brandon, Alexis K; O'Fee, Lisa; Schmitt, Jessica; Woodward, Hannah L; Burke, Rosemary; vanMontfort, Rob L M; Blagg, Julian; Raynaud, Florence I; Eccles, Suzanne A; Hoelder, Swen; Linardopoulos, Spiros

2017-01-01

Background: The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents anaphase onset until the appropriate attachment and tension across kinetochores is achieved. MPS1 kinase activity is essential for the activation of the spindle assembly checkpoint and has been shown to be deregulated in human tumours with chromosomal instability and aneuploidy. Therefore, MPS1 inhibition represents an attractive strategy to target cancers. Methods: To evaluate CCT271850 cellular potency, two specific antibodies that recognise the activation sites of MPS1 were used and its antiproliferative activity was determined in 91 human cancer cell lines. DLD1 cells with induced GFP-MPS1 and HCT116 cells were used in in vivo studies to directly measure MPS1 inhibition and efficacy of CCT271850 treatment. Results: CCT271850 selectively and potently inhibits MPS1 kinase activity in biochemical and cellular assays and in in vivo models. Mechanistically, tumour cells treated with CCT271850 acquire aberrant numbers of chromosomes and the majority of cells divide their chromosomes without proper alignment because of abrogation of the mitotic checkpoint, leading to cell death. We demonstrated a moderate level of efficacy of CCT271850 as a single agent in a human colorectal carcinoma xenograft model. Conclusions: CCT271850 is a potent, selective and orally bioavailable MPS1 kinase inhibitor. On the basis of in vivo pharmacodynamic vs efficacy relationships, we predict that more than 80% inhibition of MPS1 activity for at least 24 h is required to achieve tumour stasis or regression by CCT271850. PMID:28334731

Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy.

PubMed

Faisal, Amir; Mak, Grace W Y; Gurden, Mark D; Xavier, Cristina P R; Anderhub, Simon J; Innocenti, Paolo; Westwood, Isaac M; Naud, Sébastien; Hayes, Angela; Box, Gary; Valenti, Melanie R; De Haven Brandon, Alexis K; O'Fee, Lisa; Schmitt, Jessica; Woodward, Hannah L; Burke, Rosemary; vanMontfort, Rob L M; Blagg, Julian; Raynaud, Florence I; Eccles, Suzanne A; Hoelder, Swen; Linardopoulos, Spiros

2017-04-25

The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents anaphase onset until the appropriate attachment and tension across kinetochores is achieved. MPS1 kinase activity is essential for the activation of the spindle assembly checkpoint and has been shown to be deregulated in human tumours with chromosomal instability and aneuploidy. Therefore, MPS1 inhibition represents an attractive strategy to target cancers. To evaluate CCT271850 cellular potency, two specific antibodies that recognise the activation sites of MPS1 were used and its antiproliferative activity was determined in 91 human cancer cell lines. DLD1 cells with induced GFP-MPS1 and HCT116 cells were used in in vivo studies to directly measure MPS1 inhibition and efficacy of CCT271850 treatment. CCT271850 selectively and potently inhibits MPS1 kinase activity in biochemical and cellular assays and in in vivo models. Mechanistically, tumour cells treated with CCT271850 acquire aberrant numbers of chromosomes and the majority of cells divide their chromosomes without proper alignment because of abrogation of the mitotic checkpoint, leading to cell death. We demonstrated a moderate level of efficacy of CCT271850 as a single agent in a human colorectal carcinoma xenograft model. CCT271850 is a potent, selective and orally bioavailable MPS1 kinase inhibitor. On the basis of in vivo pharmacodynamic vs efficacy relationships, we predict that more than 80% inhibition of MPS1 activity for at least 24 h is required to achieve tumour stasis or regression by CCT271850.

An in vitro investigation of indigenous South African medicinal plants used to treat oral infections.

PubMed

Akhalwaya, S; van Vuuren, S; Patel, M

2018-01-10

Over a 120 South African medicinal plants are used for the treatment of oral diseases. Despite the vast collection of antimicrobial studies being done on South African plants, there is still limited research on pathogens associated with oral infections. In consultation with the available ethnobotanical literature, this study investigates the antimicrobial efficacy of some South African medicinal plants against oral pathogens. To provide a detailed account of the antimicrobial properties of selected South African medicinal plants used traditionally to treat oral infections. The effect on Streptococcus mutans biofilm formation and the toxicity profiles of these plants are also investigated. A total of 136 aqueous and organic extracts and six essential oils were prepared from 31 different plant species. These plant samples were screened for antimicrobial efficacy against nine oral pathogens using the micro-titre plate dilution assay. Plant extracts that were found to have noteworthy antimicrobial activity against S. mutans were further evaluated on the effect on S. mutans biofilm formation using the glass slide technique. The toxicity profiles of plant samples that were found to have noteworthy antimicrobial activity were evaluated using the brine shrimp lethality assay. The organic extract of Cissampelos torulosa stems displayed the lowest MIC value of 0.05mg/mL against both Lactobacillus spp. This high antimicrobial activity was also observed with the organic extract of Spirostachys africana leaves against Candida albicans. In some instances, a direct relationship was found between the traditional use of the plant and the antimicrobial activity observed. For example, noteworthy activity (MIC < 1.00mg/mL) was observed against all three Candida spp. when tested against Clematis brachiata (leaves), a plant traditionally used to treat oral thrush. Englerophytum magalismonatanum stems displayed notable activity against both Streptococcus spp. (MIC 0.83mg/mL against S. mutans and MIC 0.67mg/mL against S. sanguis). Spirostachys africana leaves displayed the greatest anti-adherent properties against S. mutans biofilm formation at both 24 and 48h, reducing the biofilm by 97.56% and 86.58% respectively. The majority of plant samples tested in the brine shrimp lethality assay (BSLA) were considered safe, however, 13 plant samples were considered toxic, at a concentration of 1mg/mL. Noteworthy antimicrobial activity for plants species such as C. brachiata and E. magalismonatnum provides validation for the traditional use of these plants. Spirostachys africana displayed the greatest reduction of adherent S. mutans cells. The BSLA results revealed that the majority of the plant samples were not toxic in nature. The findings from the results favour the potential use of these plants in treating oral diseases such as dental caries, periodontal diseases and oral thrush. Copyright © 2017 Elsevier B.V. All rights reserved.

Cytotoxic Components Against Human Oral Squamous Cell Carcinoma Isolated from Andrographis paniculata.

PubMed

Suzuki, Ryuichiro; Matsushima, Yasuaki; Okudaira, Noriyuki; Sakagami, Hiroshi; Shirataki, Yoshiaki

2016-11-01

The 5-year survival rate of patients with oral cancer has remained approximately 50% during the past 30 years, possibly due to the poor tumor selectivity of conventional anticancer drugs. This prompted us to search for new candidates for anticancer drugs that have higher cytotoxicity and tumor selectivity. Dried leaves of Andrographis paniculata were supplied from a market in Shanghai. The methanolic fraction of A. paniculata was further fractionated to identify cytotoxic principles by spectroscopic analysis and comparison with literature values. Viable cell number was determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide method, and tumor specificity was calculated by relative cytotoxicity against oral squamous cell carcinoma cell lines compared to that against normal oral cells. Apoptosis induction was detected by cleaved poly (ADP-ribose) polymerase and caspase-3 on western blot analysis. Major cytotoxicity in the methanol extract of a leaf of A. paniculata was recovered by partitioning with EtOAc, followed by silica gel chromatography. Further purification with reversed-phase high-performance liquid chromatography led to isolation of four known cytotoxic compounds, 14-deoxyandrographolide, andrographolide, neoandrographolide and deoxyandrographiside. Among them, andrographolide had the greatest cytotoxicity and tumor specificity, also inducing caspase-3 activation of HSC-2 oral squamous cell carcinoma cells. The present study identified andrographolide as a major antitumor principle in the methanolic extract of leaves of A. paniculata. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

The Application of Magnetic Bead Selection to Investigate Interactions between the Oral Microbiota and Salivary Immunoglobulins

PubMed Central

Madhwani, Tejal

2016-01-01

The effect of humoral immunity on the composition of the oral microbiota is less intensively investigated than hygiene and diet, in part due to a lack of simple and robust systems for investigating interactions between salivary immunoglobulins and oral bacteria. Here we report the application of an ex situ method to investigate the specificity of salivary immunoglobulins for salivary bacteria. Saliva collected from six volunteers was separated into immunoglobulin and microbial fractions, and the microbial fractions were then directly exposed to salivary immunoglobulins of “self” and “non-self” origin. Antibody-selected bacteria were separated from their congeners using a magnetic bead system, selective for IgA or IgG isotypes. The positively selected fractions were then characterized using gel-based eubacterial-specific DNA profiling. The eubacterial profiles of positively selected fractions diverged significantly from profiles of whole salivary consortia based on volunteer (P≤ 0.001%) and immunoglobulin origin (P≤ 0.001%), but not immunoglobulin isotype (P = 0.2). DNA profiles of separated microbial fractions were significantly (p≤ 0.05) less diverse than whole salivary consortia and included oral and environmental bacteria. Consortia selected using self immunoglobulins were generally less diverse than those selected with immunoglobulins of non-self origin. Magnetic bead separation facilitated the testing of interactions between salivary antibodies and oral bacteria, showing that these interactions are specific and may reflect differences in recognition by self and non-self immunoglobulins. Further development of this system could improve understanding of the relationship between the oral microbiota and the host immune system and of mechanisms underlying the compositional stability of the oral microbiota. PMID:27483159

Quantitative Structure-Cytotoxicity Relationship of Cinnamic Acid Phenetyl Esters.

PubMed

Uesawa, Yoshihiro; Sakagami, Hiroshi; Okudaira, Noriyuki; Toda, Kazuhiro; Takao, Koichi; Kagaya, Hajime; Sugita, Yoshiaki

2018-02-01

Many phenolic acid phenethyl esters possess diverse biological effects including antioxidant, cytoprotective, anti-inflammation and anti-tumor activities. However, most previous antitumor studies have not considered the cytotoxicity against normal cells. Ten cinnamic acid phenetyl esters were subjected to quantitative structure-activity relationship (QSAR) analysis, based on their cytotoxicity and tumor-specificity, in order to find their new biological activities. Cytotoxicity against four human oral squamous cell carcinoma cell lines and three oral normal mesenchymal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor specificity (TS) was evaluated by the ratio of the mean 50% cytotoxic concentration (CC 50 ) against normal oral cells to that against human oral squamous cell carcinoma cell lines. Potency-selectivity expression (PSE) value was calculated by dividing the TS value by CC 50 against tumor cells. Apoptosis markers were detected by western blot analysis. Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by force-field minimization. Western blot analysis demonstrated that [ 9 ] stimulated the cleavage of caspase-3, suggesting the induction of apoptosis. QSAR analysis demonstrated that TS values were correlated with shape, size and ionization potential. Chemical modification of the lead compound may be a potential choice for designing a new type of anticancer drugs. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Developing an Adaptive Tool to Select, Plan, and Scaffold Oral Assessment Tasks for Undergraduate Courses

ERIC Educational Resources Information Center

Demmans Epp, Carrie; Park, Gina; Plumb, Christopher

2015-01-01

The increased linguistic and cultural diversity of undergraduate classrooms at English language institutions has imposed additional pedagogical and assessment challenges on instructors, many of whom lack the knowledge necessary to design classroom activities and assessments that are fair to all students regardless of students' background and…

Engaging General Biology Students with Learning Contracts

ERIC Educational Resources Information Center

Litchfield, Brenda; Mata, Juan; Gray, Laura

2007-01-01

Students in a general biology class used a learning contract where they selected chapter-relevant activities they could complete through several formats: oral, written, or artistic. The majority of students felt they learned a lot with this method, the process was motivating, and that it should be used in future semesters. (Contains 6 figures.)

Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents.

PubMed

Sagnella, Sharon M; Gong, Xiaojuan; Moghaddam, Minoo J; Conn, Charlotte E; Kimpton, Kathleen; Waddington, Lynne J; Krodkiewska, Irena; Drummond, Calum J

2011-03-01

We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

A-C Estrogens as Potent and Selective Estrogen Receptor-Beta Agonists (SERBAs) to Enhance Memory Consolidation under Low-Estrogen Conditions.

PubMed

Hanson, Alicia M; Perera, K L Iresha Sampathi; Kim, Jaekyoon; Pandey, Rajesh K; Sweeney, Noreena; Lu, Xingyun; Imhoff, Andrea; Mackinnon, Alexander Craig; Wargolet, Adam J; Van Hart, Rochelle M; Frick, Karyn M; Donaldson, William A; Sem, Daniel S

2018-06-14

Estrogen receptor-beta (ERβ) is a drug target for memory consolidation in postmenopausal women. Herein is reported a series of potent and selective ERβ agonists (SERBAs) with in vivo efficacy that are A-C estrogens, lacking the B and D estrogen rings. The most potent and selective A-C estrogen is selective for activating ER relative to seven other nuclear hormone receptors, with a surprising 750-fold selectivity for the β over α isoform and with EC 50 s of 20-30 nM in cell-based and direct binding assays. Comparison of potency in different assays suggests that the ER isoform selectivity is related to the compound's ability to drive the productive conformational change needed to activate transcription. The compound also shows in vivo efficacy after microinfusion into the dorsal hippocampus and after intraperitoneal injection (0.5 mg/kg) or oral gavage (0.5 mg/kg). This simple yet novel A-C estrogen is selective, brain penetrant, and facilitates memory consolidation.

Differential prooxidative effects of the green tea polyphenol, (-)-epigallocatechin-3-gallate, in normal and oral cancer cells are related to differences in sirtuin 3 signaling.

PubMed

Tao, Ling; Park, Jong-Yung; Lambert, Joshua D

2015-02-01

We have previously reported that the green tea catechin, (-)-epigallocatechin-3-gallate (EGCG), can induce oxidative stress in oral cancer cells but exerts antioxidant effects in normal cells. Here, we report that these differential prooxidative effects are associated with sirtuin 3 (SIRT3), an important mitochondrial redox modulator. EGCG rapidly induced mitochondria-localized reactive oxygen species in human oral squamous carcinoma cells (SCC-25, SCC-9) and premalignant leukoplakia cells (MSK-Leuk1), but not in normal human gingival fibroblast cells (HGF-1). EGCG suppressed SIRT3 mRNA and protein expression, as well as, SIRT3 activity in SCC-25 cells, whereas it increased SIRT3 activity in HGF-1 cells. EGCG selectively decreased the nuclear localization of the estrogen-related receptor α (ERRα), the transcription factor regulating SIRT3 expression, in SCC-25 cells. This indicates that EGCG may regulate SIRT3 transcription in oral cancer cells via ERRα. EGCG also differentially modulated the mRNA expressions of SIRT3-associated downstream targets including glutathione peroxidase 1 and superoxide dismutase 2 in normal and oral cancer cells. SIRT3 represents a novel potential target through which EGCG exerts differential prooxidant effects in cancer and normal cells. Our results provide new biomarkers to be further explored in animal studies. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: selective targeting to diseased versus healthy tissue.

PubMed

Hua, Susan; Marks, Ellen; Schneider, Jennifer J; Keely, Simon

2015-07-01

Colon targeted drug delivery is an active area of research for local diseases affecting the colon, as it improves the efficacy of therapeutics and enables localized treatment, which reduces systemic toxicity. Targeted delivery of therapeutics to the colon is particularly advantageous for the treatment of inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease. Advances in oral drug delivery design have significantly improved the bioavailability of drugs to the colon; however in order for a drug to have therapeutic efficacy during disease, considerations must be made for the altered physiology of the gastrointestinal (GI) tract that is associated with GI inflammation. Nanotechnology has been used in oral dosage formulation design as strategies to further enhance uptake into diseased tissue within the colon. This review will describe some of the physiological challenges faced by orally administered delivery systems in IBD, the important developments in orally administered nano-delivery systems for colon targeting, and the future advances of this research. Inflammatory Bowel Disease (IBD) poses a significant problem for a large number of patients worldwide. Current medical therapy mostly aims at suppressing the active inflammatory episodes. In this review article, the authors described and discussed the various approaches current nano-delivery systems can offer in overcoming the limitations of conventional drug formulations. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Physiological and pathophysiological factors affecting the expression and activity of the drug transporter MRP2 in intestine. Impact on its function as membrane barrier.

PubMed

Arana, Maite R; Tocchetti, Guillermo N; Rigalli, Juan P; Mottino, Aldo D; Villanueva, Silvina S M

2016-07-01

The gastrointestinal epithelium functions as a selective barrier to absorb nutrients, electrolytes and water, but at the same time restricts the passage into the systemic circulation of intraluminal potentially toxic compounds. This epithelium maintains its selective barrier function through the presence of very selective and complex intercellular junctions and the ability of the absorptive cells to reject those compounds. Accordingly, the enterocytes metabolize orally incorporated xenobiotics and secrete the hydrophilic metabolites back into the intestinal lumen through specific transporters localized apically. In the recent decades, there has been increasing recognition of the existence of the intestinal cellular barrier. In the present review we focus on the role of the multidrug resistance-associated protein 2 (MRP2, ABCC2) in the apical membrane of the enterocytes, as an important component of this intestinal barrier, as well as on its regulation. We provide a detailed compilation of significant contributions demonstrating that MRP2 expression and function vary under relevant physiological and pathophysiological conditions. Because MRP2 activity modulates the availability and pharmacokinetics of many therapeutic drugs administered orally, their therapeutic efficacy and safety may vary as well. Copyright © 2016 Elsevier Ltd. All rights reserved.

Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3'-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor.

PubMed

Ye, Xiang-Yang; Chen, Stephanie Y; Wu, Shung; Yoon, David S; Wang, Haixia; Hong, Zhenqiu; O'Connor, Stephen P; Li, Jun; Li, James J; Kennedy, Lawrence J; Walker, Steven J; Nayeem, Akbar; Sheriff, Steven; Camac, Daniel M; Ramamurthy, Vidyhashankar; Morin, Paul E; Zebo, Rachel; Taylor, Joseph R; Morgan, Nathan N; Ponticiello, Randolph P; Harrity, Thomas; Apedo, Atsu; Golla, Rajasree; Seethala, Ramakrishna; Wang, Mengmeng; Harper, Timothy W; Sleczka, Bogdan G; He, Bin; Kirby, Mark; Leahy, David K; Li, Jianqing; Hanson, Ronald L; Guo, Zhiwei; Li, Yi-Xin; DiMarco, John D; Scaringe, Raymond; Maxwell, Brad; Moulin, Frederick; Barrish, Joel C; Gordon, David A; Robl, Jeffrey A

2017-06-22

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme (IC 50 3.0 nM) with >10000-fold selectivity over human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED 50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11β-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.

Discovery of Clinical Candidate 2-((2 S,6 S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3'-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ye, Xiang-Yang; Chen, Stephanie Y.; Wu, Shung

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme (IC 50 3.0 nM) with >10000-fold selectivity over human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED 50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition ofmore » 11β-HSD1 enzyme for the first 12 h period after dosing followed by an “inhibition holiday” so that the potential for hypothalamic–pituitary–adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.« less

Pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase.

PubMed Central

McMillan, R. M.; Spruce, K. E.; Crawley, G. C.; Walker, E. R.; Foster, S. J.

1992-01-01

1. This paper describes the pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase which is undergoing clinical evaluation. 2. ICI D2138 potently inhibited leukotriene synthesis in murine peritoneal macrophages (IC50 = 3 nM) and human blood (IC50 = 20 nM). In human and dog blood, ICI D2138 did not inhibit thromboxane B2 synthesis at a concentration of 500 microM, thus the selectivity ratio (cyclo-oxygenase: 5-lipoxygenase) was greater than 20,000. In contrast, zileuton (a 5-lipoxygenase inhibitor also undergoing clinical evaluation) exhibited a selectivity ratio of 15-100. 3. ICI D2138 potently and dose-dependently inhibited ex vivo leukotriene B4 (LTB4) synthesis by rat blood with ED50 values of 0.9, 4.0 and 80.0 mg kg-1 p.o. at 3, 10 and 20 h respectively after dosing. Similar activity was observed for inhibition of LTB4 production in a zymosan-inflamed rat air pouch model. Zileuton produced ED50 values of 5 and 20 mg kg-1 at 3 and 10 h respectively. 4. Oral administration of 1, 3 or 10 mg kg-1 ICI D2138 to dogs produced maximal inhibition of ex vivo LTB4 synthesis by blood for 5, 9 and 31 h respectively. A dose of 5 mg kg-1 p.o. of zileuton caused maximal inhibition of LTB4 for 24 h. 5. Oral administration of 10 mg kg-1 ICI D2138 caused total inhibition of LTB4 production in zymosan-inflamed rabbit knee joint. 6. Topical administration of ICI D2138 to rabbit skin caused a dose-related inhibition of arachidonic acid-induced plasma extravasation with an ID30 of 1.08 nmol per site.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1334748

In-Vitro Activity of Saponins of Bauhinia Purpurea, Madhuca Longifolia, Celastrus Paniculatus and Semecarpus Anacardium on Selected Oral Pathogens

PubMed Central

Jyothi, K. S.; Seshagiri, M.

2012-01-01

Objective: Dental caries, periodontitis and other mucosal diseases are caused by a complex community of microorganisms. This study aimed to investigate the antimicrobial properties of saponins of four important oil yielding medicinal plant extracts on selected oral pathogens that are involved in such diseases. Materials and Methods: Saponins were extracted from Bauhinia purpurea, Madhuca longifolia, Celastrus paniculatus and Semecarpus anacardium and purified. Antimicrobial properties of these saponins against Streptococcus mutans, Streptococcus mitis, Streptococcus salivarius, Staphylococcus aureus and Lactobacillus acidophilus were determined using well diffusion method. The minimum inhibitory concentration (MIC) was determined as the lowest concentration of saponins inhibiting bacterial growth after 14 h of incubation at 37°C. The bactericidal activity was evaluated using the viable cell count method. Results: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of Madhuca longifolia saponin on Streptococcus mutans MTCC 890, Streptococcus mitis and Staphylococcus aureus was 18.3 ± 0.15/34.4 ± 0.24 μg/ml, 19.0 ± 0.05/32.2 ± 0.0 μg/ml and 21.2 ± 0.35/39.0 ± 0.30 μg/ml, respectively and Bauhinia purpurea saponin on Streptococcus mutans MTCC 890, Staphylococcus aureus and Lactobacillus acidophilus was 26.4 ± 0.20/43.0 ± 0.40 μg/ml, 29.0 ± 0.30/39.6 ± 0.12 μg/ml and 20.2 ± 0.05/36.8 ± 0.23 μg/ml, respectively. Conclusion: The strong antimicrobial activity of Madhuca longifolia and Bauhinia purpurea may be due to the presence of complex triterpenoid saponins, oleanane type triterpenoid glycosides or atypical pentacyclic triterpenoid saponin. Hence, these extracted saponins may be used in food and oral products to prevent and control oral diseases. PMID:23323183

Design, synthesis, and in vivo SAR of a novel series of pyrazolines as potent selective androgen receptor modulators.

PubMed

Zhang, Xuqing; Li, Xiaojie; Allan, George F; Sbriscia, Tifanie; Linton, Olivia; Lundeen, Scott G; Sui, Zhihua

2007-08-09

A novel series of pyrazolines 2 have been designed, synthesized, and evaluated by in vivo screening as tissue-selective androgen receptor modulators (SARMs). Structure-activity relationships (SAR) were investigated at the R1 to R6 positions as well as the core pyrazoline ring and the anilide linker. Overall, strong electron-withdrawing groups at the R1 and R2 positions and a small group at the R5 and R6 position are optimal for AR agonist activity. The (S)-isomer of 7c exhibits more potent AR agonist activity than the corresponding (R)-isomer. (S)-7c exhibited an overall partial androgenic effect but full anabolic effect via oral administration in castrated rats. It demonstrated a noticeable antiandrogenic effect on prostate in intact rats with endogenous testosterone. Thus, (S)-7c is a tissue-selective nonsteroidal androgen receptor modulator with agonist activity on muscle and mixed agonist and antagonist activity on prostate.

Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection.

PubMed

Tran, Thien-Duc; Pryde, David C; Jones, Peter; Adam, Fiona M; Benson, Neil; Bish, Gerwyn; Calo, Frederick; Ciaramella, Guiseppe; Dixon, Rachel; Duckworth, Jonathan; Fox, David N A; Hay, Duncan A; Hitchin, James; Horscroft, Nigel; Howard, Martin; Gardner, Iain; Jones, Hannah M; Laxton, Carl; Parkinson, Tanya; Parsons, Gemma; Proctor, Katie; Smith, Mya C; Smith, Nicholas; Thomas, Amy

2011-04-15

The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model. Copyright © 2011 Elsevier Ltd. All rights reserved.

Evaluation of cytotoxic and antitumoral properties of Tessaria absinthioides (Hook & Arn) DC, "pájaro bobo", aqueous extract.

PubMed

Persia, Fabio A; Rinaldini, Estefanía; Carrión, Adriana; Hapon, María Belén; Gamarra-Luques, Carlos

2017-01-01

Higher plants have provided various natural derived drugs used currently in western medicine. Tessaria absinthioides (Hook. & Arn.) DC, Asteraceae, is a native plant from South-America with reported ethnopharmacological and culinary uses. Despite recent scientific reports about plants properties, there is not a well conducted research about its anticancer and potential toxic effects. The current work demonstrates the plant aqueous extract composition; the in vitro induced cytotoxicity, and explores, in vivo, its oral toxicity and antitumoral effects. Composition of aqueous extract was determined by phytochemical reactions. Cytotoxicity was tested in tumoral (Hela, Gli-37, HCT-116 and MCF-7) and non-tumoral (HBL-100) cells, using MTT assay. Oral toxicity and the antitumor activity against colorectal carcinoma were studied in rodents. The chemical analysis revealed the presence of flavonoids, carbohydrates, sterols, terpenes and tannins. Cytotoxicity towards tumoral cells was observed (CV50: 3.0 to 14.8 υg/ml); while in non-tumoral cells, extracts evidenced a selective reduced toxicity (CV50: 29.5 υg/ml). Oral administration of the extract does not induce acute nor dose-repeated toxicity at doses up to 2000 mg/kg and 1000 mg/kg/day, respectively. The antitumoral effect was confirmed by a significant increase in a median survival from 24 weeks (non-treated) to 30 weeks (T. absinthioides treated). The present data indicate that T. absinthioides extract exhibits cytotoxicity against cancer cell lines, with no-toxic effects and significant antitumoral effects in colorectal cancer when is orally administrated. In conclusion, T. absinthioides possesses selective cytotoxicity and antitumoral activities, making its plant derivatives products promising for cancer research and treatment.

Chemosensory responsiveness to ethanol and its individual sensory components in alcohol-preferring, -nonpreferring and genetically heterogeneous rats

PubMed Central

Brasser, Susan M.; Silbaugh, Bryant C.; Ketchum, Myles J.; Olney, Jeffrey J.; Lemon, Christian H.

2011-01-01

Alcohol activates orosensory circuits that project to motivationally relevant limbic forebrain areas that control appetite, feeding and drinking. To date, limited data exists regarding the contribution of chemosensory-derived ethanol reinforcement to ethanol preference and consumption. Measures of taste reactivity to intra-orally infused ethanol have not found differences in initial orofacial responses to alcohol between alcohol-preferring (P) and – nonpreferring (NP) genetically selected rat lines. Yet, in voluntary intake tests P rats prefer highly-concentrated ethanol upon initial exposure, suggesting an early sensory-mediated attraction. Here, we directly compared self-initiated chemosensory responding for alcohol and prototypic sweet, bitter, and oral trigeminal stimuli among selectively bred P, NP, and non-selected Wistar (WI) outbred lines to determine whether differential sensory responsiveness to ethanol and its putative sensory components are phenotypically associated with genetically-influenced alcohol preference. Rats were tested for immediate short-term lick responses to alcohol (3–40%), sucrose (0.01–1 M), quinine (0.01–3 mM) and capsaicin (0.003–1 mM) in a brief-access assay designed to index orosensory-guided behavior. P rats exhibited elevated short-term lick responses to both alcohol and sucrose relative to NP and WI lines across a broad range of concentrations of each stimulus and in the absence of blood alcohol levels that would produce significant postabsorptive effects. There was no consistent relationship between genetically-mediated alcohol preference and orosensory avoidance of quinine or capsaicin. These data indicate that enhanced initial chemosensory attraction to ethanol and sweet stimuli are phenotypes associated with genetic alcohol preference and are considered within the framework of downstream activation of oral appetitive reward circuits. PMID:22129513

Chemosensory responsiveness to ethanol and its individual sensory components in alcohol-preferring, alcohol-nonpreferring and genetically heterogeneous rats.

PubMed

Brasser, Susan M; Silbaugh, Bryant C; Ketchum, Myles J; Olney, Jeffrey J; Lemon, Christian H

2012-03-01

Alcohol activates orosensory circuits that project to motivationally relevant limbic forebrain areas that control appetite, feeding and drinking. To date, limited data exists regarding the contribution of chemosensory-derived ethanol reinforcement to ethanol preference and consumption. Measures of taste reactivity to intra-orally infused ethanol have not found differences in initial orofacial responses to alcohol between alcohol-preferring (P) and alcohol-non-preferring (NP) genetically selected rat lines. Yet, in voluntary intake tests, P rats prefer highly concentrated ethanol upon initial exposure, suggesting an early sensory-mediated attraction. Here, we directly compared self-initiated chemosensory responding for alcohol and prototypic sweet, bitter and oral trigeminal stimuli among selectively bred P, NP and non-selected Wistar (WI) outbred lines to determine whether differential sensory responsiveness to ethanol and its putative sensory components are phenotypically associated with genetically influenced alcohol preference. Rats were tested for immediate short-term lick responses to alcohol (3-40%), sucrose (0.01-1 M), quinine (0.01-3 mM) and capsaicin (0.003-1 mM) in a brief-access assay designed to index orosensory-guided behavior. P rats exhibited elevated short-term lick responses to both alcohol and sucrose relative to NP and WI lines across a broad range of concentrations of each stimulus and in the absence of blood alcohol levels that would produce significant post-absorptive effects. There was no consistent relationship between genetically mediated alcohol preference and orosensory avoidance of quinine or capsaicin. These data indicate that enhanced initial chemosensory attraction to ethanol and sweet stimuli are phenotypes associated with genetic alcohol preference and are considered within the framework of downstream activation of oral appetitive reward circuits. © 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.

Evaluation of oral keratinocyte progenitor and T-lymphocite cells response during early healing after augmentation of keratinized gingiva with a 3D collagen matrix - a pilot study.

PubMed

Rusu, Darian; Calenic, Bogdan; Greabu, Maria; Kralev, Alexander; Boariu, Marius; Bojin, Florina; Anghel, Simona; Paunescu, Virgil; Vela, Octavia; Calniceanu, Horia; Stratul, Stefan-Ioan

2016-07-07

The aim of the present study is to analyze the behavior of selected populations of oral keratinocytes and T-lymphocytes, responsible for re-constructing and maintaining the oral epithelial tissue architecture, following augmentation of the keratinized oral mucosa using a 3D-collagen matrix. Different groups of oral keratinocytes were isolated from biopsies harvested from 3 patients before the surgical procedure, as well as 7 and 14 days after the augmentation procedure. T-lymphocytes were isolated from peripheral blood at same timepoints. Keratinocytes were characterized for stem and differentiation markers, such as p63, cytokeratin 10 and 14, and in vitro parameters, such as cell viability, cell size and colony-forming efficiency. T-lymphocytes were analyzed for viability and the expression of various cluster of differentiation markers. The methods included magnetic separation of cell populations, immunofluorescence, flow cytometry, and histology of oral biopsies. Both at 7 and 14 days, the majority of cells that repopulate the matrix were actively proliferating/progenitor oral keratinocytes with the phenotype integrin alfa6beta4 + CD71+. These cells display in vitro characteristics similar to the progenitor cells analyzed before the matrix placement. T-lymphocytes expressed CD8 and CD69 markers, while CD25 was absent. The study shows that two weeks after the collagen membrane placement, the healing process appeared to be histologically complete, with no abnormal immune response induced by the matrix, however, with a higher than usual content of active proliferating cells, the majority of keratinocytes being characterized as transit amplifying cells.

Selective Killing Effects of Cold Atmospheric Pressure Plasma with NO Induced Dysfunction of Epidermal Growth Factor Receptor in Oral Squamous Cell Carcinoma.

PubMed

Lee, Jung-Hwan; Om, Ji-Yeon; Kim, Yong-Hee; Kim, Kwang-Mahn; Choi, Eun-Ha; Kim, Kyoung-Nam

2016-01-01

The aim of this study is to investigate the effects of cold atmospheric pressure plasma (CAP)-induced radicals on the epidermal growth factor receptor (EGFR), which is overexpressed by oral squamous cell carcinoma, to determine the underlying mechanism of selective killing. CAP-induced highly reactive radicals were observed in both plasma plume and cell culture media. The selective killing effect was observed in oral squamous cell carcinoma compared with normal human gingival fibroblast. Degradation and dysfunction of EGFRs were observed only in the EGFR-overexpressing oral squamous cell carcinoma and not in the normal cell. Nitric oxide scavenger pretreatment in cell culture media before CAP treatment rescued above degradation and dysfunction of the EGFR as well as the killing effect in oral squamous cell carcinoma. CAP may be a promising cancer treatment method by inducing EGFR dysfunction in EGFR-overexpressing oral squamous cell carcinoma via nitric oxide radicals.

Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis.

PubMed

Shailubhai, Kunwar; Palejwala, Vaseem; Arjunan, Krishna Priya; Saykhedkar, Sayali; Nefsky, Bradley; Foss, John A; Comiskey, Stephen; Jacob, Gary S; Plevy, Scott E

2015-11-06

To evaluate the effect of orally administered plecanatide or dolcanatide, analogs of uroguanylin, on amelioration of colitis in murine models. The cyclic guanosine monophosphate (cGMP) stimulatory potency of plecanatide and dolcanatide was measured using a human colon carcinoma T84 cell-based assay. For animal studies all test agents were formulated in phosphate buffered saline. Sulfasalazine or 5-amino salicylic acid (5-ASA) served as positive controls. Effect of oral treatment with test agents on amelioration of acute colitis induced either by dextran sulfate sodium (DSS) in drinking water or by rectal instillation of trinitrobenzene sulfonic (TNBS) acid, was examined in BALB/c and/or BDF1 mice. Additionally, the effect of orally administered plecanatide on the spontaneous colitis in T-cell receptor alpha knockout (TCRα(-/-)) mice was also examined. Amelioration of colitis was assessed by monitoring severity of colitis, disease activity index and by histopathology. Frozen colon tissues were used to measure myeloperoxidase activity. Plecanatide and dolcanatide are structurally related analogs of uroguanylin, which is an endogenous ligand of guanylate cyclase-C (GC-C). As expected from the agonists of GC-C, both plecanatide and dolcanatide exhibited potent cGMP-stimulatory activity in T84 cells. Once-daily treatment by oral gavage with either of these analogs (0.05-0.5 mg/kg) ameliorated colitis in both DSS and TNBS-induced models of acute colitis, as assessed by body weight, reduction in colitis severity (P < 0.05) and disease activity index (P < 0.05). Amelioration of colitis by either of the drug candidates was comparable to that achieved by orally administered sulfasalazine or 5-ASA. Plecanatide also effectively ameliorated colitis in TCRα(-/-) mice, a model of spontaneous colitis. As dolcanatide exhibited higher resistance to proteolysis in simulated gastric and intestinal juices, it was selected for further studies. This is the first-ever study reporting the therapeutic utility of GC-C agonists as a new class of orally delivered and mucosally active drug candidates for the treatment of inflammatory bowel diseases.

Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis

PubMed Central

Shailubhai, Kunwar; Palejwala, Vaseem; Arjunan, Krishna Priya; Saykhedkar, Sayali; Nefsky, Bradley; Foss, John A; Comiskey, Stephen; Jacob, Gary S; Plevy, Scott E

2015-01-01

AIM: To evaluate the effect of orally administered plecanatide or dolcanatide, analogs of uroguanylin, on amelioration of colitis in murine models. METHODS: The cyclic guanosine monophosphate (cGMP) stimulatory potency of plecanatide and dolcanatide was measured using a human colon carcinoma T84 cell-based assay. For animal studies all test agents were formulated in phosphate buffered saline. Sulfasalazine or 5-amino salicylic acid (5-ASA) served as positive controls. Effect of oral treatment with test agents on amelioration of acute colitis induced either by dextran sulfate sodium (DSS) in drinking water or by rectal instillation of trinitrobenzene sulfonic (TNBS) acid, was examined in BALB/c and/or BDF1 mice. Additionally, the effect of orally administered plecanatide on the spontaneous colitis in T-cell receptor alpha knockout (TCRα-/-) mice was also examined. Amelioration of colitis was assessed by monitoring severity of colitis, disease activity index and by histopathology. Frozen colon tissues were used to measure myeloperoxidase activity. RESULTS: Plecanatide and dolcanatide are structurally related analogs of uroguanylin, which is an endogenous ligand of guanylate cyclase-C (GC-C). As expected from the agonists of GC-C, both plecanatide and dolcanatide exhibited potent cGMP-stimulatory activity in T84 cells. Once-daily treatment by oral gavage with either of these analogs (0.05-0.5 mg/kg) ameliorated colitis in both DSS and TNBS-induced models of acute colitis, as assessed by body weight, reduction in colitis severity (P < 0.05) and disease activity index (P < 0.05). Amelioration of colitis by either of the drug candidates was comparable to that achieved by orally administered sulfasalazine or 5-ASA. Plecanatide also effectively ameliorated colitis in TCRα-/- mice, a model of spontaneous colitis. As dolcanatide exhibited higher resistance to proteolysis in simulated gastric and intestinal juices, it was selected for further studies. CONCLUSION: This is the first-ever study reporting the therapeutic utility of GC-C agonists as a new class of orally delivered and mucosally active drug candidates for the treatment of inflammatory bowel diseases. PMID:26558155

Integrating fluoroquinolones into the hospital formulary.

PubMed

Bertino, J S

2001-10-01

With the increasing availability of new agents, selection of fluoroquinolones for formulary inclusion can be difficult. Appropriate evaluation of the important characteristics (pharmacokinetic and pharmacodynamic properties, antimicrobial activity, efficacy, tolerability, cost) of these agents should allow selection of the most cost-effective ones. Evidence from in vitro studies and clinical trials indicates differences exist among fluoroquinolones, especially in terms of activity against gram-positive, aerobic organisms. For selected clinical situations, it may be important to choose an agent that is available in both intravenous and oral formulations. Comparative drug costs, as well as costs associated with potential clinical failure and adverse events, should be evaluated carefully. Dosage regimens should be considered, as shorter durations of therapy and less frequent dose administration may lead to reduced labor costs and increased patient compliance, thereby improving effectiveness and economic efficiency.

Characterization of SB-271046: A potent, selective and orally active 5-HT6 receptor antagonist

PubMed Central

Routledge, Carol; Bromidge, Steven M; Moss, Stephen F; Price, Gary W; Hirst, Warren; Newman, Helen; Riley, Graham; Gager, Tracey; Stean, Tania; Upton, Neil; Clarke, Stephen E; Brown, Anthony M; Middlemiss, Derek N

2000-01-01

SB-271046, potently displaced [3H]-LSD and [125I]-SB-258585 from human 5-HT6 receptors recombinantly expressed in HeLa cells in vitro (pKi 8.92 and 9.09 respectively). SB-271046 also displaced [125I]-SB-258585 from human caudate putamen and rat and pig striatum membranes (pKi 8.81, 9.02 and 8.55 respectively). SB-271046 was over 200 fold selective for the 5-HT6 receptor vs 55 other receptors, binding sites and ion channels. In functional studies on human 5-HT6 receptors SB-271046 competitively antagonized 5-HT-induced stimulation of adenylyl cyclase activity with a pA2 of 8.71. SB-271046 produced an increase in seizure threshold over a wide-dose range in the rat maximal electroshock seizure threshold (MEST) test, with a minimum effective dose of ⩽0.1 mg kg−1 p.o. and maximum effect at 4 h post-dose. The level of anticonvulsant activity achieved correlated well with the blood concentrations of SB-271046 (EC50 of 0.16 μM) and brain concentrations of 0.01–0.04 μM at Cmax. These data, together with the observed anticonvulsant activity of other selective 5-HT6 receptor antagonists, SB-258510 (10 mg kg−1, 2–6 h pre-test) and Ro 04-6790 (1–30 mg kg−1, 1 h pre-test), in the rat MEST test, suggest that the anticonvulsant properties of SB-271046 are likely to be mediated by 5-HT6 receptors. Overall, these studies demonstrate that SB-271046 is a potent and selective 5-HT6 receptor antagonist and is orally active in the rat MEST test. SB-271046 represents a valuable tool for evaluating the in vivo central function of 5-HT6 receptors. PMID:10928964

Assessment of oral bioavailability enhancing approaches for SB-247083 using flow-through cell dissolution testing as one of the screens.

PubMed

Perng, Cherng-Yih; Kearney, Albert S; Palepu, Nagesh R; Smith, Brian R; Azzarano, Leonard M

2003-01-02

SB-247083 is a potent, nonpeptidic, orally active, ETA-selective, endothelin receptor antagonist. The diacid form and three salts (monoarginine, diarginine and disodium) of SB-247083 were evaluated during the pre-clinical phase of development. The developability attributes (i.e. hygroscopicity, thermal behavior, aqueous solubility, and drug-excipient compatibility) of these compounds were evaluated. In addition to these attributes, the flow-through cell (FTC) dissolution testing (using USP Apparatus 4) was used as a screening technique to evaluate several SB-247083 formulations of the diacid and its salts. FTC dissolution testing offers two distinct advantages over the more traditional static-condition dissolution testing: (1) maintenance of sink conditions; and (2) the ability to change the dissolution medium during a dissolution run. The former advantage is especially important for poorly aqueous soluble drugs having associated dissolution-rate-limitations, and the latter advantage allows one to more closely simulate the pH gradient associated with transit through the GI tract. Based on the comparative dissolution data, three formulations were chosen for oral dosing in dogs. The reasonable correlation found between the FTC dissolution results and the oral bioavailability data demonstrate that FTC dissolution testing can be a valuable tool for aiding in salt (solid-state form) and formulation selection in the early stages of development of drug candidates.

Analysis of a unique global public-private partnership to promote oral health.

PubMed

Pine, Cynthia M; Dugdill, Lindsey

2011-08-01

Partnerships for health promotion are between two or more partners to work co-operatively towards a set of shared health outcomes; few public-private partnerships in oral health promotion have been established. To undertake a detailed analysis of a unique global public-private partnership to promote oral health between a global company, Unilever and the Féderation Dentaire International (FDI), a membership organisation representing more than one million dentists worldwide. Qualitative and quantitative, including: collating and analysing a wide range of partnership documents (n =164); reviewing film and pictorial records; undertaking structured interviews (n=34) with people who had a critical role in establishing and delivering the aims of the partnership, and external experts; and site visits to selected global projects active at the time of the evaluation. Over 1 million people have been reached directly through their engagement with 39 projects in 36 countries; an oral health message about the benefits of twice daily tooth brushing has appeared with the authority of the FDI logo on billions of packs of Unilever Oral Care's toothpastes worldwide; many individual members of National Dental Associations have participated in health promotion activities within their communities for the first time; some organisational challenges during the development and delivery of the partnership were recognised by both partners. The first phase of this unique global partnership has been successful in making major progress towards achieving its goals; lessons learned have ensured that the next phase of the partnership has significant potential to contribute to improving oral health globally. © 2011 FDI World Dental Federation.

Discovery of orally efficacious RORγt inverse agonists, part 1: Identification of novel phenylglycinamides as lead scaffolds.

PubMed

Shirai, Junya; Tomata, Yoshihide; Kono, Mitsunori; Ochida, Atsuko; Fukase, Yoshiyuki; Sato, Ayumu; Masada, Shinichi; Kawamoto, Tetsuji; Yonemori, Kazuko; Koyama, Ryoukichi; Nakagawa, Hideyuki; Nakayama, Masaharu; Uga, Keiko; Shibata, Akira; Koga, Keiko; Okui, Toshitake; Shirasaki, Mikio; Skene, Robert; Sang, BiChing; Hoffman, Isaac; Lane, Wes; Fujitani, Yasushi; Yamasaki, Masashi; Yamamoto, Satoshi

2018-01-15

A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evaluation and Management of Dehydration in Children.

PubMed

Santillanes, Genevieve; Rose, Emily

2018-05-01

The article discusses the evaluation of dehydration in children and reviews the literature on physical findings of dehydration. Pediatric dehydration is a common problem in emergency departments and wide practice variation in treatment exists. Dehydration can be treated with oral, nasogastric, subcutaneous, or intravenous fluids. Although oral rehydration is underutilized in the United States, most children with dehydration can be successfully rehydrated via the oral route. Selection of oral rehydration solution and techniques for successful oral rehydration are presented. Appropriate selection and rate of administration of intravenous fluids are also discussed for isonatremic, hyponatremic, and hypernatremic dehydration. Copyright © 2017 Elsevier Inc. All rights reserved.

Oral mucosal lesions and risk habits among men in an Italian study population.

PubMed

Campisi, G; Margiotta, V

2001-01-01

A randomly selected study population of 118 male subjects (> or = 40 years) living on the Mediterranean island of Pantelleria (southwest of Sicily, Italy) was examined for the presence of oral mucosal lesions, with particular emphasis on the early diagnosis of oral precancerous and cancerous lesions. The study population was interviewed for socioeconomic and behavioural information, and clinically examined using WHO criteria. The prevalence of oral mucosal lesions observed, and data obtained about oral hygiene, tobacco smoking, alcohol drinking and exposure to actinic radiation, were analysed. Alcohol drinking was the most common habit in the study population (73%), followed by tobacco smoking (58.5%, of whom 96% were cigarette smokers). Only 3% showed good oral hygiene and 25% were edentate. Oral lesions were observed in 81.3% of the study group, mainly coated tongue (51.4%), leukoplakia (13.8%), traumatic oral lesions (traumatic ulcers and frictional white lesions) in 9.2%, actinic cheilitis (4.6%), and squamous cell carcinoma in one case (0.9%). Statistically significant associations were found between the prevalence of coated tongue and tobacco smoking (P<0.0001), and between the prevalence of actinic cheilitis and tobacco smoking/alcohol drinking (P<0.05). Analysis of clinical and anamnestic data underlined the effective presence, in the population examined, of the behavioural risk factors for oral precancerous and cancerous lesions, and the lack of cultural motivation towards primary prevention activities, such as the elimination of risk habits.

Pharmacokinetics of the Antiviral Lectin Griffithsin Administered by Different Routes Indicates Multiple Potential Uses.

PubMed

Barton, Christopher; Kouokam, J Calvin; Hurst, Harrell; Palmer, Kenneth E

2016-12-17

Griffithsin (GRFT) is a red alga-derived lectin with demonstrated broad spectrum antiviral activity against enveloped viruses, including severe acute respiratory syndrome-Coronavirus (SARS-CoV), Japanese encephalitis virus (JEV), hepatitis C virus (HCV), and herpes simplex virus-2 (HSV-2). However, its pharmacokinetic profile remains largely undefined. Here, Sprague Dawley rats were administered a single dose of GRFT at 10 or 20 mg/kg by intravenous, oral, and subcutaneous routes, respectively, and serum GRFT levels were measured at select time points. In addition, the potential for systemic accumulation after oral dosing was assessed in rats after 10 daily treatments with GRFT (20 or 40 mg/kg). We found that parenterally-administered GRFT in rats displayed a complex elimination profile, which varied according to administration routes. However, GRFT was not orally bioavailable, even after chronic treatment. Nonetheless, active GRFT capable of neutralizing HIV-Env pseudoviruses was detected in rat fecal extracts after chronic oral dosing. These findings support further evaluation of GRFT for pre-exposure prophylaxis against emerging epidemics for which specific therapeutics are not available, including systemic and enteric infections caused by susceptible enveloped viruses. In addition, GRFT should be considered for antiviral therapy and the prevention of rectal transmission of HIV-1 and other susceptible viruses.

JB-9322, a new selective histamine H2-receptor antagonist with potent gastric mucosal protective properties.

PubMed

Palacios, B; Montero, M J; Sevilla, M A; Román, L S

1995-05-01

1. JB-9322 is a selective histamine H2-receptor antagonist with gastric antisecretory activity and mucosal protective properties. 2. The affinity of JB-9322 for the guinea-pig atria histamine H2-receptor was approximately 2 times greater than that of ranitidine. 3. In vivo, the ID50 value for the inhibition of gastric acid secretion in pylorus-ligated rats was 5.28 mg kg-1 intraperitoneally. JB-9322 also dose-dependently inhibited gastric juice volume and pepsin secretion. In gastric lumen-perfused rats, intravenous injection of JB-9322 dose-dependently reduced histamine-, pentagastrin- and carbachol-stimulated gastric acid secretion. 4. JB-9322 showed antiulcer activity against aspirin and indomethacin-induced gastric lesions and was more potent than ranitidine. 5. JB-9322 effectively inhibited macroscopic gastric haemorrhagic lesions induced by ethanol. Intraperitoneal injection was effective in preventing the lesions as well as oral treatment. The oral ID50 value for these lesions was 1.33 mg kg-1. By contrast, ranitidine (50 mg kg-1) failed to reduce these lesions. In addition, the protective effect of JB-9322 was independent of prostaglandin synthesis. 6. These results indicate that JB-9322 is a new antiulcer drug that exerts a potent cytoprotective effect in addition to its gastric antisecretory activity.

Bioavailability of curcumin and curcumin glucuronide in the central nervous system of mice after oral delivery of nano-curcumin.

PubMed

Szymusiak, Magdalena; Hu, Xiaoyu; Leon Plata, Paola A; Ciupinski, Paulina; Wang, Zaijie Jim; Liu, Ying

2016-09-10

Curcumin is a bioactive molecule extracted from Turmeric roots that has been recognized to possess a wide variety of important biological activities. Despite its great pharmacological activities, curcumin is highly hydrophobic, which results in poor bioavailability. We have formulated this hydrophobic compound into stable polymeric nanoparticles (nano-curcumin) to enhance its oral absorption. Pharmacokinetic analysis after oral delivery of nano-curcumin in mice demonstrated approximately 20-fold reduction in dose requirement when compared to unformulated curcumin to achieve comparable plasma and central nervous system (CNS) tissue concentrations. This investigation corroborated our previous study of curcumin functionality of attenuating opioid tolerance and dependence, which shows equivalent efficacy of low-dose (20mg/kg) nano-curcumin and high-dose (400mg/kg) pure curcumin in mice. Furthermore, the highly selective and validated liquid chromatography-mass spectrometry (LC-MS) method was developed to quantify curcumin glucuronide, the major metabolite of curcumin. The results suggest that the presence of curcumin in the CNS is essential for prevention and reversal of opioid tolerance and dependence. Copyright © 2016 Elsevier B.V. All rights reserved.

Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid: an orally active, selective very late antigen-4 antagonist.

PubMed

Muro, Fumihito; Iimura, Shin; Sugimoto, Yuuichi; Yoneda, Yoshiyuki; Chiba, Jun; Watanabe, Toshiyuki; Setoguchi, Masaki; Iigou, Yutaka; Matsumoto, Keiko; Satoh, Atsushi; Takayama, Gensuke; Taira, Tomoe; Yokoyama, Mika; Takashi, Tohru; Nakayama, Atsushi; Machinaga, Nobuo

2009-12-24

We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.

Association of stress, depression, and suicidal ideation with subjective oral health status and oral functions in Korean adults aged 35 years or more.

PubMed

Kim, Young Sun; Kim, Han-Na; Lee, Jung-Ha; Kim, Se-Yeon; Jun, Eun-Joo; Kim, Jin-Bom

2017-06-23

Oral health greatly affects well-being throughout the different stages of life from childhood to late adulthood. Loss of teeth due to poor oral health hinders mastication, leading to poor nutrition absorption, and affects pronunciation and aesthetics, leading to interpersonal difficulties. As social activities become limited, a sense of isolation and loneliness, stress, and depression grows while happiness decreases. This study aimed to examine the association of stress, depression, and suicidal ideation with oral health status and oral functions in a large nationwide sample of Korean adults aged 35 years or more. The sample comprised 15,716 adults, selected using a rolling survey sampling method and data were extracted from the Fifth Korea National Health and Nutrition Examination Survey (KNHANES) (2010-2012). Participants were interviewed about their self-evaluation of health including oral health status and mental health, such as stress, depression, and suicidal ideation. Data from 11,347 adults were finally selected after excluding participants with missing answers. The dependent variables were stress, depression, and suicidal ideation. The independent variables were gender, age, household income, education, smoking, drinking, oral health perception, chewing, and speaking. Complex samples logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Participants met the criteria for stress (25.4%), depression (13.0%), and suicidal ideation (13.9%). Subjective oral health status was not significantly associated with stress, depression, and suicidal ideation. However, the presence of very uncomfortable chewing problems was significantly associated with stress (OR = 2.294, 95% CI = 1.41, 3.72), depression (OR = 3.232, 95% CI = 1.97, 5.31), and suicidal ideation (OR = 2.727, 95% CI = 1.58, 4.72). The presence of very uncomfortable speaking problems was significantly associated with stress (OR = 1.592, 95% CI = 1.13, 2.24) but not significantly associated with depression and suicidal ideation. Oral functional problems including chewing and speaking difficulties can be associated with mental health. It is necessary to develop oral health promotion programs for adults and help them maintain a good quality of life and mental health.

Pressor response to intravenous tyramine in healthy subjects after safinamide, a novel neuroprotectant with selective, reversible monoamine oxidase B inhibition.

PubMed

Cattaneo, Carlo; Caccia, Carla; Marzo, Antonio; Maj, Roberto; Fariello, Ruggero G

2003-01-01

Safinamide is a novel neuroprotectant combining sodium and calcium channel blocking properties with selective, reversible monoamine oxidase type B (MAO B) inhibition. Phase 1 studies have demonstrated that in healthy volunteers, the ED50 (a dose that inhibits enzyme activity by 50% in 50% of treated subjects) for MAO B inhibition is 87.5 microg/kg/day orally, and that no MAO A inhibition occurs after 10-mg/kg oral dosing. To assess the risk of inducing the "cheese effect," the effect of safinamide and placebo on the pressor response to tyramine was investigated in a group of healthy male volunteers. The study was an open, single-dose placebo-controlled trial with the 2 treatments in sequence. An increase of 30 mm Hg systolic blood pressure was obtained by intravenous tyramine administered by 0.5-mg incremental boluses injected at 15-minute intervals. The amount of tyramine necessary to achieve such a blood pressure increase was the same after the safinamide 2-mg/kg oral load compared with placebo. These results suggest that dietary restrictions for food with high tyramine content should not be required under safinamide treatment.

Endogenous concentrations, pharmacokinetics, and selected pharmacodynamic effects of a single dose of exogenous GABA in horses.

PubMed

Knych, H K; Steinmetz, S J; McKemie, D S

2015-04-01

The anti-anxiety and calming effects following activation of the GABA receptor have been exploited in performance horses by administering products containing GABA. The primary goal of the study reported here was to describe endogenous concentrations of GABA in horses and the pharmacokinetics, selected pharmacodynamic effects, and CSF concentrations following administration of a GABA-containing product. The mean (±SD) endogenous GABA level was 36.4 ± 12.5 ng/mL (n = 147). Sixteen of these horses received a single intravenous and oral dose of GABA (1650 mg). Blood, urine, and cerebrospinal fluid (n = 2) samples were collected at time 0 and at various times for up to 48 h and analyzed using LC-MS. Plasma clearance and volume of distribution was 155.6 and 147.6 L/h and 0.154 and 7.39 L for the central and peripheral compartments, respectively. Terminal elimination half-life was 22.1 (intravenous) and 25.1 (oral) min. Oral bioavailability was 9.81%. Urine GABA concentrations peaked rapidly returning to baseline levels by 3 h. Horses appeared behaviorally unaffected following oral administration, while sedative-like changes following intravenous administration were transient. Heart rate was increased for 1 h postintravenous administration, and gastrointestinal sounds decreased for approximately 30 min following both intravenous and oral administration. Based on a limited number of horses and time points, exogenously administered GABA does not appear to enter the CSF to an appreciable extent. © 2014 John Wiley & Sons Ltd.

Flavonoids of Cynara scolymus possess potent xanthinoxidase inhibitory activity in vitro but are devoid of hypouricemic effects in rats after oral application.

PubMed

Sarawek, Sasiporn; Feistel, Bjoern; Pischel, Ivo; Butterweck, Veronika

2008-02-01

Artichoke (Cynara scolymus L.) leaves have been historically used for the treatment of hyperuricemia and gout, however whether artichoke is truly efficacious for this indication, is still a matter of debate. Thus, the goal of the present study was first to examine the xanthine oxidase (XO) inhibitory activity of an artichoke leaf extract (ALE) and some of its main compounds in vitro and then further test potentially active substances for possible hypouricemic effects using an in vivo rat model. The in vitro study showed that ALE inhibited XO with only minimal inhibitory action (< 5 %) at 100 microg/mL. However, when selected compounds were tested, the caffeic acid derivatives revealed a weak XO inhibitory effect with IC (50) > 100 microM. From the tested flavones the aglycone luteolin potently inhibited XO with an IC (50) value of 1.49 microM. Luteolin 7-O-glucoside and luteolin 7-O-glucuronide showed lower XO inhibition activities with IC (50) values of 19.90 microM and 20.24 microM, respectively. However, oral administration of an aqueous ALE, luteolin, and luteolin 7-O-glucoside did not produce any observable hypouricemic effects after acute oral treatment in potassium oxonate-treated rats. After intraperitoneal injection of luteolin a decrease in uric acid levels was detected suggesting that the hypouricemic effects of luteolin are due to its original form rather than its metabolites produced by the gut flora. In conclusion, an aqueous ALE, caffeic acid derivatives and flavones exerted XO inhibitory effects in vitro but a hypouricemic activity could not be confirmed after oral administration.

Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABAA Receptor Modulators.

PubMed

Forkuo, Gloria S; Nieman, Amanda N; Yuan, Nina Y; Kodali, Revathi; Yu, Olivia B; Zahn, Nicolas M; Jahan, Rajwana; Li, Guanguan; Stephen, Michael Rajesh; Guthrie, Margaret L; Poe, Michael M; Hartzler, Benjamin D; Harris, Ted W; Yocum, Gene T; Emala, Charles W; Steeber, Douglas A; Stafford, Douglas C; Cook, James M; Arnold, Leggy A

2017-06-05

We describe pharmacokinetic and pharmacodynamic properties of two novel oral drug candidates for asthma. Phenolic α 4 β 3 γ 2 GABA A R selective compound 1 and acidic α 5 β 3 γ 2 selective GABA A R positive allosteric modulator compound 2 relaxed airway smooth muscle ex vivo and attenuated airway hyperresponsiveness (AHR) in a murine model of asthma. Importantly, compound 2 relaxed acetylcholine contracted human tracheal airway smooth muscle strips. Oral treatment of compounds 1 and 2 decreased eosinophils in bronchoalveolar lavage fluid in ovalbumin sensitized and challenged mice, thus exhibiting anti-inflammatory properties. Additionally, compound 1 reduced the number of lung CD4 + T lymphocytes and directly modulated their transmembrane currents by acting on GABA A Rs. Excellent pharmacokinetic properties were observed, including long plasma half-life (up to 15 h), oral availability, and extremely low brain distribution. In conclusion, we report the selective targeting of GABA A Rs expressed outside the brain and demonstrate reduction of AHR and airway inflammation with two novel orally available GABA A R ligands.

Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis.

PubMed

Camps, Montserrat; Rückle, Thomas; Ji, Hong; Ardissone, Vittoria; Rintelen, Felix; Shaw, Jeffrey; Ferrandi, Chiara; Chabert, Christian; Gillieron, Corine; Françon, Bernard; Martin, Thierry; Gretener, Denise; Perrin, Dominique; Leroy, Didier; Vitte, Pierre-Alain; Hirsch, Emilio; Wymann, Matthias P; Cirillo, Rocco; Schwarz, Matthias K; Rommel, Christian

2005-09-01

Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg). We show that Pik3cg(-/-) mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kgamma as a therapeutic target. We also describe that oral treatment with a PI3Kgamma inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg(-/-) mice. Our results identify selective PI3Kgamma inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.

Vasopressin and a nonpeptide antidiuretic hormone receptor antagonist (OPC-31260).

PubMed

Burrell, L M; Phillips, P A; Stephenson, J M; Risvanis, J; Johnston, C I

1994-03-01

The development of nonpeptide orally active AVP analogues has provided a new tool with which to assess the physiological and pathophysiological role of vasopressin (AVP). We have previously characterised the nonpeptide vasopressin V1 receptor antagonist OPC-21268, and now report the in vitro characterisation of the nonpeptide V2 receptor antagonist OPC-31260 in the rat. OPC-31260 caused a concentration-dependent displacement of the selective AVP V2 receptor antagonist radioligand, [3H]desGly-NH2(9)[d(CH2)5, D-Ile2,Ile4]AVP from V2 receptors in rat kidney medulla membranes. The concentration of OPC-31260 that displaced 50% of specific AVP binding (IC50) was 20 +/- 2 nmol/l for renal V2 receptors. OPC-31260 also caused a concentration-dependent displacement of the selective AVP V1 receptor antagonist radioligand, [125I]-[d(CH2)5,sarcosine7]AVP from V1 receptors in both rat liver and kidney medulla membranes. The IC50 was 500 +/- 30 nmol/l for both renal and liver V1 receptors. After oral administration to rats, OPC-31260 was an effective inhibitor of AVP at renal V2 and liver V1 receptors in a time-dependent manner. In vitro binding kinetic studies showed that OPC-31260 was a competitive antagonist at both the renal V2 receptor and the hepatic V1 receptor. OPC-31260 is a nonpeptide, orally effective competitive inhibitor of AVP with a V2:V1 receptor selectivity ratio of 25:1 indicating relative V2 receptor selectivity.

Treatment of oral malodour. Medium-term efficacy of mechanical and/or chemical agents: a systematic review.

PubMed

Slot, Dagmar E; De Geest, Sophie; van der Weijden, Fridus A; Quirynen, Marc

2015-04-01

What is the effect of a dentifrice (DF), a mouthwash (MW), tongue cleaning (TC), or any combination of these as adjunct to toothbrushing on intra-oral malodour and tongue coating as compared to toothbrushing alone in systemically healthy patients, when used for a minimum follow-up period of 2 weeks? The MEDLINE-PubMed, Cochrane-CENTRAL and EMBASE databases were searched up to August 2014. Measurements of Volatile Sulphur Compounds and organoleptic scores of oral malodour were selected as outcome variables. Data were extracted and a descriptive analysis was performed. Independent screening of 1054 unique papers resulted in 12 eligible clinical trials with a medium-term (≥2 weeks) duration. The majority of studies provided a significant reduction in oral malodour when evaluating products with an active ingredient (incorporated into a DF or a MW) used adjunctively to toothbrushing. The added value of tongue cleaning over a MW was evaluated in one study. Due to very limited evidence, the potential effect of a specifically formulated dentifrice, a mouthwash or a tongue scraper for treating oral malodour is, in general, unclear. For mouthwashes containing the active ingredients chlorhexidine + cetylpyridinium chloride + zinc (CHX + CPC + Zn) and zinc chloride + cetylpyridinium chloride (ZnCl + CPC) most evidence was available. The strength of a recommendation to use these products was graded to be 'weak'. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture.

PubMed

Joshi, Hemant N; Tejwani, Ravindra W; Davidovich, Martha; Sahasrabudhe, Vaishali P; Jemal, Mohammed; Bathala, Mohinder S; Varia, Sailesh A; Serajuddin, Abu T M

2004-01-09

Oral bioavailability of a poorly water-soluble drug was greatly enhanced by using its solid dispersion in a surface-active carrier. The weakly basic drug (pK(a) approximately 5.5) had the highest solubility of 0.1mg/ml at pH 1.5, < 1 microg/ml aqueous solubility between pH 3.5 and 5.5 at 24+/-1 degrees C, and no detectable solubility (< 0.02 microg/ml) at pH greater than 5.5. Two solid dispersion formulations of the drug, one in Gelucire 44/14 and another one in a mixture of polyethylene glycol 3350 (PEG 3350) with polysorbate 80, were prepared by dissolving the drug in the molten carrier (65 degrees C) and filling the melt in hard gelatin capsules. From the two solid dispersion formulations, the PEG 3350-polysorbate 80 was selected for further development. The oral bioavailability of this formulation in dogs was compared with that of a capsule containing micronized drug blended with lactose and microcrystalline cellulose and a liquid solution in a mixture of PEG 400, polysorbate 80 and water. For intravenous administration, a solution in a mixture of propylene glycol, polysorbate 80 and water was used. Absolute oral bioavailability values from the capsule containing micronized drug, the capsule containing solid dispersion and the oral liquid were 1.7+/-1.0%, 35.8+/-5.2% and 59.6+/-21.4%, respectively. Thus, the solid dispersion provided a 21-fold increase in bioavailability of the drug as compared to the capsule containing micronized drug. A capsule formulation containing 25 mg of drug with a total fill weight of 600 mg was subsequently selected for further development. The selected solid dispersion formulation was physically and chemically stable under accelerated storage conditions for at least 6 months. It is hypothesized that polysorbate 80 ensures complete release of drug in a metastable finely dispersed state having a large surface area, which facilitates further solubilization by bile acids in the GI tract and the absorption into the enterocytes. Thus, the bioavailability of this poorly water-soluble drug was greatly enhanced by formulation as a solid dispersion in a surface-active carrier.

Progress of Oral Insulin and Related Drug Delivery Systems and their Pharmacokinetics.

PubMed

Chen, Jingjing; Liu, Rui; Liu, Changxiao; Jin, Xin; Zhang, Qinghua; Wang, Jialu; Zhao, Fang; Wang, Ze; Qiu, Haiyan; Li, Yazhuo; Yi, Xiulin

2018-05-22

As society has developed and living standards have improved, diabetes has become a severe public health issue. Insulin plays a crucial role in managing hyperglycemia caused by type I diabetes and particular type II diabetes. Many researchers are seeking alternative, more acceptable methods of insulin delivery, such as oral insulin. An oral formulation has become a new goal for insulin delivery in recent years. The PubMed and CNKI databases were searched for "oral insulin, " "drug delivery systems, " and "pharmacokinetics, " and 85 relevant articles were selected from the results as material for this review. These papers were authoritative and had a higher number of citations. Oral insulin would be highly advantageous but is poorly absorbed. The main reason for low absorptivity is the hydrolysis of insulin by enzymes in the gastrointestinal tract. Lack of active transport vectors that pass through the intestinal epithelium is also a non-negligible problem. Additional issues need to be considered to facilitate appropriate research, such as long-term efficacy and safety, clinical data, and toxicological characteristics. This review summarized recent advances in oral insulin and the pharmacokinetic profile of the suitable delivery system, providing valuable reference material for future research. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Vesiculo-erosive oral mucosal disease--management with topical corticosteroids: (1) Fundamental principles and specific agents available.

PubMed

González-Moles, M A; Scully, C

2005-04-01

Vesiculo-erosive diseases of the oral mucosa pose a major challenge in oral medicine, because they are chronic, painful, and interfere with the daily activities and quality of life of the patients, including disturbing eating, drinking, talking, and personal relationships. Many are autoimmune diseases, and corticosteroid therapy is currently central to their treatment. These diseases present with inflammation and alterations to epithelial integrity, through cell and/or humoral immunity-mediated attack on epithelial-connective tissue targets. Until recently, despite their serious adverse effects, it was necessary to prescribe systemic corticosteroids to control severe erosive oral diseases. Now, however, many of these diseases can be controlled by high-potency topical corticosteroids, which have proved to be highly efficacious and to cause fewer adverse effects compared with systemic corticosteroids. Nevertheless, although topical corticosteroids are still the most widely used drugs in the practice of oral medicine, the scientific body of evidence for their use in the oral cavity is virtually non-existent, and therefore many of the protocols followed are, of necessity, drawn from experience of their use in a dermatological setting. This review aims to set out the key aspects of the use of topical corticosteroids in oral medicine. The issues covered include the indications and basic rules for their use, the types of corticosteroids, the drug selection, and the specific formulations.

Discovery, synthesis, selectivity modulation and DMPK characterization of 5-azaspiro[2.4]heptanes as potent orexin receptor antagonists.

PubMed

Stasi, Luigi Piero; Artusi, Roberto; Bovino, Clara; Buzzi, Benedetta; Canciani, Luca; Caselli, Gianfranco; Colace, Fabrizio; Garofalo, Paolo; Giambuzzi, Silvia; Larger, Patrice; Letari, Ornella; Mandelli, Stefano; Perugini, Lorenzo; Pucci, Sabrina; Salvi, Matteo; Toro, PierLuigi

2013-05-01

Starting from a orexin 1 receptor selective antagonist 4,4-disubstituted piperidine series a novel potent 5-azaspiro[2.4]heptane dual orexin 1 and orexin 2 receptor antagonist class has been discovered. SAR and Pharmacokinetic optimization of this series is herein disclosed. Lead compound 15 exhibits potent activity against orexin 1 and orexin 2 receptors along with low cytochrome P450 inhibition potential, good brain penetration and oral bioavailability in rats. Copyright © 2013 Elsevier Ltd. All rights reserved.

Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.

PubMed

Schnute, Mark E; O'Brien, Patrick M; Nahra, Joe; Morris, Mark; Howard Roark, W; Hanau, Cathleen E; Ruminski, Peter G; Scholten, Jeffrey A; Fletcher, Theresa R; Hamper, Bruce C; Carroll, Jeffery N; Patt, William C; Shieh, Huey S; Collins, Brandon; Pavlovsky, Alexander G; Palmquist, Katherine E; Aston, Karl W; Hitchcock, Jeffrey; Rogers, Michael D; McDonald, Joseph; Johnson, Adam R; Munie, Grace E; Wittwer, Arthur J; Man, Chiu-Fai; Settle, Steven L; Nemirovskiy, Olga; Vickery, Lillian E; Agawal, Arun; Dyer, Richard D; Sunyer, Teresa

2010-01-15

Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model. Copyright 2009 Elsevier Ltd. All rights reserved.

Optimizing Ligand Efficiency of Selective Androgen Receptor Modulators (SARMs)

PubMed Central

2015-01-01

A series of selective androgen receptor modulators (SARMs) containing the 1-(trifluoromethyl)benzyl alcohol core have been optimized for androgen receptor (AR) potency and drug-like properties. We have taken advantage of the lipophilic ligand efficiency (LLE) parameter as a guide to interpret the effect of structural changes on AR activity. Over the course of optimization efforts the LLE increased over 3 log units leading to a SARM 43 with nanomolar potency, good aqueous kinetic solubility (>700 μM), and high oral bioavailability in rats (83%). PMID:26819671

Graduates' Self-Assessment of Their Oral Presentations of Group Projects: An EFL Case Study in Romania

ERIC Educational Resources Information Center

Macari, Ileana Oana

2017-01-01

This study investigated tourism graduate students' perceptions of academic achievement as revealed in the end of term self-assessment grids for the course English for tourism. Data were collected from 59 first year Romanian Master of Arts students by examining their personal portfolios after the in-class and follow-up activities. The selection of…

R-268712, an orally active transforming growth factor-β type I receptor inhibitor, prevents glomerular sclerosis in a Thy1 nephritis model.

PubMed

Terashima, Hideki; Kato, Mikio; Ebisawa, Masayuki; Kobayashi, Hideki; Suzuki, Kanae; Nezu, Yoshikazu; Sada, Toshio

2014-07-05

R-268712 is a novel and specific inhibitor of activin receptor-like kinase 5 (ALK5), a transforming growth factor β (TGF-β) type I receptor. Evaluation of in vitro inhibition indicated that R-268712 is a potent and selective inhibitor of ALK5 with an IC50 of 2.5nM, an approximately 5000-fold more selectivity for ALK5 than p38 mitogen-activated protein kinase (MAPK). Oral administration of R-268712 at doses of 1, 3 and 10mg/kg also inhibited the development of renal fibrosis in a dose-dependent manner in a unilateral ureteral obstruction (UUO) model. Additionally, we evaluated the efficacy of R-268712 in a heminephrectomized anti-Thy1 glomerulonephritis model at doses of 0.3 and 1mg/kg. R-268712 reduced proteinuria and glomerulosclerosis significantly with improvement of renal function. Collectively, these results suggested that R-268712 and other ALK5 inhibitors could suppress glomerulonephritis as well as glomerulosclerosis by an inhibitory mechanism that involves suppression of TGF-β signaling. Copyright © 2014 Elsevier B.V. All rights reserved.

A long-lasting oral preformulation of the angiotensin II AT1 receptor antagonist losartan.

PubMed

De Paula, Washington X; Denadai, Ângelo M L; Braga, Aline N G; Shastri, V Prasad; Pinheiro, Sérgio V B; Frezard, Frederic; Santos, Robson A S; Sinisterra, Ruben D

2018-05-10

Losartan (Los), a non-peptidic orally active agent, reduces arterial pressure through specific and selective blockade of angiotensin II receptor AT1. However, this widely used AT1 antagonist presents low bioavailability and needs once or twice a day dosage. In order to improve its bioavailability, we used the host: guest strategy based on β-cyclodextrin (βCD). The results suggest that Los included in βCD showed a typical pulsatile release pattern after oral administration to rats, with increasing the levels of plasma of Los. In addition, the inclusion compound presented oral efficacy for 72 h, in contrast to Los alone, which shows antagonist effect for only 6 h. In transgenic (mREN2)L27 rats, the Los/βCD complex reduced blood pressure for about 6 d, whereas Los alone reduced blood pressure for only 2 d. More importantly, using this host: guest strategy, sustained release of Los for over a week via the oral route can be achieved without the need for encapsulation in a polymeric carrier. The proposed preformulation increased the efficacy reducing the dose or spacing between each dose intake.

5-Fluorouracil sensitivity varies among oral micro-organisms.

PubMed

Vanlancker, Eline; Vanhoecke, Barbara; Smet, Rozel; Props, Ruben; Van de Wiele, Tom

2016-08-01

5-Fluorouracil (5-FU), a commonly used chemotherapeutic agent, often causes oral mucositis, an inflammation and ulceration of the oral mucosa. Micro-organisms in the oral cavity are thought to play an important role in the aggravation and severity of mucositis, but the mechanisms behind this remain unclear. Although 5-FU has been shown to elicit antibacterial effects at high concentrations (>100 µM), its antibacterial effect at physiologically relevant concentrations in the oral cavity is unknown. This study reports the effect of different concentrations of 5-FU (range 0.1-50 µM) on the growth and viability of bacterial monocultures that are present in the oral cavity and the possible role in the activity of dihydropyrimidine dehydrogenase (DPD), an enzyme involved in 5-FU resistance. Our data showed a differential sensitivity among the tested oral species towards physiological concentrations of 5-FU. Klebsiellaoxytoca, Streptococcus salivarius, Streptococcus mitis, Streptococcus oralis, Pseudomonas aeruginosa and Lactobacillus salivarius appeared to be highly resistant to all tested concentrations. In contrast, Lactobacillusoris, Lactobacillus plantarum, Streptococcus pyogenes, Fusobacterium nucleatum and Neisseria mucosa showed a significant reduction in growth and viability starting from very low concentrations (0.2-3.1 µM). We can also provide evidence that DPD is not involved in the 5-FU resistance of the selected species. The observed variability in response to physiological 5-FU concentrations may explain why certain microbiota lead to a community dysbiosis and/or an overgrowth of certain resistant micro-organisms in the oral cavity following cancer treatment.

Comparing the efficacy of hyper-pure chlorine-dioxide with other oral antiseptics on oral pathogen microorganisms and biofilm in vitro.

PubMed

Herczegh, Anna; Gyurkovics, Milán; Agababyan, Hayk; Ghidán, Agoston; Lohinai, Zsolt

2013-09-01

This study examines the antibacterial properties of sodium hypochlorite (NaOCl), chlorhexidine gluconate (CHX), Listerine®, and high purity chlorine dioxide (Solumium, ClO2) on selected common oral pathogen microorganisms and on dental biofilm in vitro. Antimicrobial activity of oral antiseptics was compared to the gold standard phenol. We investigated Streptococcus mutans, Lactobacillus acidophilus, Enterococcus faecalis, Veillonella alcalescens, Eikenella corrodens, Actinobacillus actinomycetemcomitans and Candida albicans as some important representatives of the oral pathogens. Furthermore, we collected dental plaque from the upper first molars of healthy young students. Massive biofilm was formed in vitro and its reduction was measured after treating it with mouthrinses: CHX, Listerine® or hyper pure ClO2. Their biofilm disrupting effect was measured after dissolving the crystal violet stain from biofilm by photometer. The results have showed that hyper pure ClO2 solution is more effective than other currently used disinfectants in case of aerobic bacteria and Candida yeast. In case of anaerobes its efficiency is similar to CHX solution. The biofilm dissolving effect of hyper pure ClO2 is significantly stronger compared to CHX and Listerine® after 5 min treatment. In conclusion, hyper pure ClO2 has a potent disinfectant efficacy on oral pathogenic microorganisms and a powerful biofilm dissolving effect compared to the current antiseptics, therefore high purity ClO2 may be a new promising preventive and therapeutic adjuvant in home oral care and in dental or oral surgery practice.

Differences between Angus and Holstein cattle in the Lupinus leucophyllus induced inhibition of fetal activity.

PubMed

Green, Benedict T; Panter, Kip E; Lee, Stephen T; Welch, Kevin D; Pfister, James A; Gardner, Dale R; Stegelmeier, Bryan L; Davis, T Zane

2015-11-01

Calves with congenital defects born to cows that have grazed teratogenic Lupinus spp. during pregnancy can suffer from what is termed crooked calf syndrome. Crooked calf syndrome defects include cleft palate, spinal column defects and limb malformations formed by alkaloid-induced inhibition of fetal movement. In this study, we tested the hypothesis that there are differences in fetal activity of fetuses carried by Holstein verses Angus heifers orally dosed with 1.1 g/kg dried ground Lupinus leucophyllus. Fetal activity was monitored via transrectal ultrasonography and maternal serum was analyzed for specific lupine alkaloids. There were more (P < 0.05) movements in fetuses of Holstein heifers than those in Angus heifers at eight and 12 h after oral dosing. In addition to serum alkaloid toxicokinetic differences, the Holstein heifers had significantly lower serum concentrations of anagyrine at 2, 4, and 8 h after oral dosing than Angus heifers. Holstein heifers also had significantly greater serum concentrations of lupanine at 12, 18 and 24 h after dosing than the Angus heifers. These results suggest that there are breed differences in susceptibility to lupine-induced crooked calf syndrome. These differences may also be used to discover genetic markers that identify resistant animals, thus facilitating selective breeding of resistant herds. Published by Elsevier Ltd.

Oral versus intravenous antibiotic treatment for bone and joint infections (OVIVA): study protocol for a randomised controlled trial.

PubMed

Li, Ho Kwong; Scarborough, Matthew; Zambellas, Rhea; Cooper, Cushla; Rombach, Ines; Walker, A Sarah; Lipsky, Benjamin A; Briggs, Andrew; Seaton, Andrew; Atkins, Bridget; Woodhouse, Andrew; Berendt, Anthony; Byren, Ivor; Angus, Brian; Pandit, Hemant; Stubbs, David; McNally, Martin; Thwaites, Guy; Bejon, Philip

2015-12-21

Bone and joint infection in adults arises most commonly as a complication of joint replacement surgery, fracture fixation and diabetic foot infection. The associated morbidity can be devastating to patients and costs the National Health Service an estimated £20,000 to £40,000 per patient. Current standard of care in most UK centres includes a prolonged course (4-6 weeks) of intravenous antibiotics supported, if available, by an outpatient parenteral antibiotic therapy service. Intravenous therapy carries with it substantial risks and inconvenience to patients, and the antibiotic-related costs are approximately ten times that of oral therapy. Despite this, there is no evidence to suggest that oral therapy results in inferior outcomes. We hypothesise that, by selecting oral agents with high bioavailability, good tissue penetration and activity against the known or likely pathogens, key outcomes in patients managed primarily with oral therapy are non-inferior to those in patients treated by intravenous therapy. The OVIVA trial is a parallel group, randomised (1:1), un-blinded, non-inferiority trial conducted in thirty hospitals across the UK. Eligible participants are adults (>18 years) with a clinical syndrome consistent with a bone, joint or metalware-associated infection who have received ≤7 days of intravenous antibiotic therapy from the date of definitive surgery (or the start of planned curative therapy in patients treated without surgical intervention). Participants are randomised to receive either oral or intravenous antibiotics, selected by a specialist infection physician, for the first 6 weeks of therapy. The primary outcome measure is definite treatment failure within one year of randomisation, as assessed by a blinded endpoint committee, according to pre-defined microbiological, histological and clinical criteria. Enrolling 1,050 subjects will provide 90 % power to demonstrate non-inferiority, defined as less than 7.5 % absolute increase in treatment failure rate in patients randomised to oral therapy as compared to intravenous therapy (one-sided alpha of 0.05). If our results demonstrate non-inferiority of orally administered antibiotic therapy, this trial is likely to facilitate a dramatically improved patient experience and alleviate a substantial financial burden on healthcare services. ISRCTN91566927 - 14/02/2013.

Missing Oral Health-Related Data in the interRAI-HC - Associations with Selected Variables of General Health and the Effect of Multiple Imputation on the Relationship between Oral and General Health.

PubMed

Krausch-Hofmann, Stefanie; Bogaerts, Kris; Hofmann, Michael; de Almeida Mello, Johanna; Fávaro Moreira, Nádia Cristina; Lesaffre, Emmanuel; Declerck, Dominique; Declercq, Anja; Duyck, Joke

2015-01-01

Missing data within the comprehensive geriatric assessment of the interRAI suite of assessment instruments potentially imply the under-detection of conditions that require care as well as the risk of biased statistical results. Impaired oral health in older individuals has to be registered accurately as it causes pain and discomfort and is related to the general health status. This study was based on interRAI-Home Care (HC) baseline data from 7590 subjects (mean age 81.2 years, SD 6.9) in Belgium. It was investigated if missingness of the oral health-related items was associated with selected variables of general health. It was also determined if multiple imputation of missing data affected the associations between oral and general health. Multivariable logistic regression was used to determine if the prevalence of missingness in the oral health-related variables was associated with activities of daily life (ADLH), cognitive performance (CPS2) and depression (DRS). Associations between oral health and ADLH, CPS2 and DRS were determined, with missing data treated by 1. the complete-case technique and 2. by multiple imputation, and results were compared. The individual oral health-related variables had a similar proportion of missing values, ranging from 16.3% to 17.2%. The prevalence of missing data in all oral health-related variables was significantly associated with symptoms of depression (dental prosthesis use OR 1.66, CI 1.41-1.95; damaged teeth OR 1.74, CI 1.48-2.04; chewing problems OR 1.74, CI 1.47-2.05; dry mouth OR 1.65, CI 1.40-1.94). Missingness in damaged teeth (OR 1.27, CI 1.08-1.48), chewing problems (OR 1.22, CI 1.04-1.44) and dry mouth (OR 1.23, CI 1.05-1.44) occurred more frequently in cognitively impaired subjects. ADLH was not associated with the prevalence of missing data. When comparing the complete-case technique with the multiple imputation approach, nearly identical odds ratios characterized the associations between oral and general health. Cognitively impaired and depressive individuals had a higher risk of missing oral health-related information. Associations between oral health and ADLH, CPS2 and DRS were not influenced by multiple imputation of missing data. Further research should concentrate on the mechanisms that mediate the occurrence of missingness to develop preventative strategies.

The Indicating Factors of Oral Reading Fluency of Monolingual and Bilingual Children in Egypt

ERIC Educational Resources Information Center

Hussien, Abdelaziz M.

2014-01-01

This study examined oral reading fluency (ORF) of bilingual and monolingual students. The author selected a sample of 510 (258 males and 252 females) native Arabic-speaking sixth-graders (62 bilinguals and 448 monolinguals) in Egypt. The purposes were; (a) to examine oral reading rate, oral reading accuracy, prosody, and oral reading comprehension…

Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.

2014-09-24

We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipidmore » prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.« less

Thoracic and respirable particle definitions for human health risk assessment.

PubMed

Brown, James S; Gordon, Terry; Price, Owen; Asgharian, Bahman

2013-04-10

Particle size-selective sampling refers to the collection of particles of varying sizes that potentially reach and adversely affect specific regions of the respiratory tract. Thoracic and respirable fractions are defined as the fraction of inhaled particles capable of passing beyond the larynx and ciliated airways, respectively, during inhalation. In an attempt to afford greater protection to exposed individuals, current size-selective sampling criteria overestimate the population means of particle penetration into regions of the lower respiratory tract. The purpose of our analyses was to provide estimates of the thoracic and respirable fractions for adults and children during typical activities with both nasal and oral inhalation, that may be used in the design of experimental studies and interpretation of health effects evidence. We estimated the fraction of inhaled particles (0.5-20 μm aerodynamic diameter) penetrating beyond the larynx (based on experimental data) and ciliated airways (based on a mathematical model) for an adult male, adult female, and a 10 yr old child during typical daily activities and breathing patterns. Our estimates show less penetration of coarse particulate matter into the thoracic and gas exchange regions of the respiratory tract than current size-selective criteria. Of the parameters we evaluated, particle penetration into the lower respiratory tract was most dependent on route of breathing. For typical activity levels and breathing habits, we estimated a 50% cut-size for the thoracic fraction at an aerodynamic diameter of around 3 μm in adults and 5 μm in children, whereas current ambient and occupational criteria suggest a 50% cut-size of 10 μm. By design, current size-selective sample criteria overestimate the mass of particles generally expected to penetrate into the lower respiratory tract to provide protection for individuals who may breathe orally. We provide estimates of thoracic and respirable fractions for a variety of breathing habits and activities that may benefit the design of experimental studies and interpretation of particle size-specific health effects.

Thoracic and respirable particle definitions for human health risk assessment

PubMed Central

2013-01-01

Background Particle size-selective sampling refers to the collection of particles of varying sizes that potentially reach and adversely affect specific regions of the respiratory tract. Thoracic and respirable fractions are defined as the fraction of inhaled particles capable of passing beyond the larynx and ciliated airways, respectively, during inhalation. In an attempt to afford greater protection to exposed individuals, current size-selective sampling criteria overestimate the population means of particle penetration into regions of the lower respiratory tract. The purpose of our analyses was to provide estimates of the thoracic and respirable fractions for adults and children during typical activities with both nasal and oral inhalation, that may be used in the design of experimental studies and interpretation of health effects evidence. Methods We estimated the fraction of inhaled particles (0.5-20 μm aerodynamic diameter) penetrating beyond the larynx (based on experimental data) and ciliated airways (based on a mathematical model) for an adult male, adult female, and a 10 yr old child during typical daily activities and breathing patterns. Results Our estimates show less penetration of coarse particulate matter into the thoracic and gas exchange regions of the respiratory tract than current size-selective criteria. Of the parameters we evaluated, particle penetration into the lower respiratory tract was most dependent on route of breathing. For typical activity levels and breathing habits, we estimated a 50% cut-size for the thoracic fraction at an aerodynamic diameter of around 3 μm in adults and 5 μm in children, whereas current ambient and occupational criteria suggest a 50% cut-size of 10 μm. Conclusions By design, current size-selective sample criteria overestimate the mass of particles generally expected to penetrate into the lower respiratory tract to provide protection for individuals who may breathe orally. We provide estimates of thoracic and respirable fractions for a variety of breathing habits and activities that may benefit the design of experimental studies and interpretation of particle size-specific health effects. PMID:23575443

Enhanced anticancer activity and oral bioavailability of ellagic acid through encapsulation in biodegradable polymeric nanoparticles.

PubMed

Mady, Fatma M; Shaker, Mohamed A

2017-01-01

Despite the fact that various studies have investigated the clinical relevance of ellagic acid (EA) as a naturally existing bioactive substance in cancer therapy, little has been reported regarding the efficient strategy for improving its oral bioavailability. In this study, we report the formulation of EA-loaded nanoparticles (EA-NPs) to find a way to enhance its bioactivity as well as bioavailability after oral administration. Poly(ε-caprolactone) (PCL) was selected as the biodegradable polymer for the formulation of EA-NPs through the emulsion-diffusion-evaporation technique. The obtained NPs have been characterized by measuring particle size, zeta potential, Fourier transform infrared, differential scanning calorimetry, and X-ray diffraction. The entrapment efficiency and the release profile of EA was also determined. In vitro cellular uptake and cytotoxicity of the obtained NPs were evaluated using Caco-2 and HCT-116 cell lines, respectively. Moreover, in vivo study has been performed to measure the oral bioavailability of EA-NPs compared to free EA, using New Zealand white rabbits. NPs with distinct shape were obtained with high entrapment and loading efficiencies. Diffusion-driven release profile of EA from the prepared NPs was determined. EA-NP-treated HCT-116 cells showed relatively lower cell viability compared to free EA-treated cells. Fluorometric imaging revealed the cellular uptake and efficient localization of EA-NPs in the nuclear region of Caco-2 cells. In vivo testing revealed that the oral administration of EA-NPs produced a 3.6 times increase in the area under the curve compared to that of EA. From these results, it can be concluded that incorporation of EA into PCL as NPs enhances its oral bioavailability and activity.

Enhanced anticancer activity and oral bioavailability of ellagic acid through encapsulation in biodegradable polymeric nanoparticles

PubMed Central

Mady, Fatma M; Shaker, Mohamed A

2017-01-01

Despite the fact that various studies have investigated the clinical relevance of ellagic acid (EA) as a naturally existing bioactive substance in cancer therapy, little has been reported regarding the efficient strategy for improving its oral bioavailability. In this study, we report the formulation of EA-loaded nanoparticles (EA-NPs) to find a way to enhance its bioactivity as well as bioavailability after oral administration. Poly(ε-caprolactone) (PCL) was selected as the biodegradable polymer for the formulation of EA-NPs through the emulsion–diffusion–evaporation technique. The obtained NPs have been characterized by measuring particle size, zeta potential, Fourier transform infrared, differential scanning calorimetry, and X-ray diffraction. The entrapment efficiency and the release profile of EA was also determined. In vitro cellular uptake and cytotoxicity of the obtained NPs were evaluated using Caco-2 and HCT-116 cell lines, respectively. Moreover, in vivo study has been performed to measure the oral bioavailability of EA-NPs compared to free EA, using New Zealand white rabbits. NPs with distinct shape were obtained with high entrapment and loading efficiencies. Diffusion-driven release profile of EA from the prepared NPs was determined. EA-NP-treated HCT-116 cells showed relatively lower cell viability compared to free EA-treated cells. Fluorometric imaging revealed the cellular uptake and efficient localization of EA-NPs in the nuclear region of Caco-2 cells. In vivo testing revealed that the oral administration of EA-NPs produced a 3.6 times increase in the area under the curve compared to that of EA. From these results, it can be concluded that incorporation of EA into PCL as NPs enhances its oral bioavailability and activity. PMID:29066891

Single oral doses of netazepide (YF476), a gastrin receptor antagonist, cause dose-dependent, sustained increases in gastric pH compared with placebo and ranitidine in healthy subjects.

PubMed

Boyce, M; David, O; Darwin, K; Mitchell, T; Johnston, A; Warrington, S

2012-07-01

Nonclinical studies have shown netazepide (YF476) to be a potent, selective, competitive and orally active gastrin receptor antagonist. To administer to humans for the first time single oral doses of netazepide, to assess their tolerability, safety, pharmacokinetics and effect on 24-h gastric pH. We did two randomised double-blind single-dose studies in healthy subjects. The first (n = 12) was a six-way incomplete crossover pilot study of rising doses of netazepide (range 0.5-100 mg) and placebo. The second (n = 20) was a five-way complete crossover study of netazepide 5, 25 and 100 mg, ranitidine 150 mg and placebo. In both trials we collected frequent blood samples, measured plasma netazepide and calculated pharmacokinetic parameters. In the comparative trial we measured gastric pH continuously for 24 h and compared treatments by percentage time gastric pH ≥4. Netazepide was well tolerated. Median t (max) and t (½) for the 100 mg dose were about 1 and 7 h, respectively, and the pharmacokinetics were dose-proportional. Netazepide and ranitidine each increased gastric pH. Onset of activity was similarly rapid for both. All netazepide doses were more effective than placebo (P ≤ 0.023). Compared with ranitidine, netazepide 5 mg was as effective, and netazepide 25 and 100 mg were much more effective (P ≤ 0.010), over the 24 h after dosing. Activity of ranitidine lasted about 12 h, whereas that of netazepide exceeded 24 h. In human: netazepide is an orally active gastrin antagonist, and gastrin has a major role in controlling gastric acidity. Repeated-dose studies are justified. NCT01538784 and NCT01538797. © 2012 Blackwell Publishing Ltd.

Efficacy of a new sealant to prevent white spot lesions during fixed orthodontic treatment : A 12-month, single-center, randomized controlled clinical trial.

PubMed

Hammad, Shaza M; Knösel, Michael

2016-11-01

White spot lesions (WSLs) are an undesirable side effect of fixed orthodontic appliance therapy and are reported to occur in 2-96 % of orthodontic patients. In this study, the efficacy of a new sealant to prevent WSLs during fixed orthodontic treatment was compared to a control group that did not receive sealant. For this 2-arm parallel-group randomized trial, 50 subjects aged 12-18 years (mean age 14.57 ± 2.04 years) were recruited from the orthodontics department at Mansoura University, Egypt. Eligibility criteria were no restorations, no active WSLs or caries, and adequate oral hygiene. Subjects were randomized in a 1:1 ratio to one of the two arms prior to undergoing fixed orthodontic treatment, namely a single application of SeLECT Defense™ sealant during the bracketing appointment or no sealant (control arm). Instructions and dentifrices for local home fluoridation regimen were identical in both groups. Oral hygiene was assessed using the Approximal Plaque Index (API) at specified time intervals. Dental photographs were taken for blinded WSLs assessment; inter- and intra-operator error were also calculated. Categorical data were tested using the χ 2 test, and a logistic regression model was adopted to detect associations between decalcification (WSLs), sealant application, and oral hygiene status. Only excellent or good oral hygiene were independent prognostic factors for preventing severe WSLs (p = 0.035). No significant effect on caries incidence was observed for the sealant. In combination with adequate oral hygiene SeLECT Defense™ helps to reduced the frequency of WSLs. However, the sealat showed no significant effect as sole preventive strategy.

Discovery of a novel class of potent coumarin monoamine oxidase B inhibitors: development and biopharmacological profiling of 7-[(3-chlorobenzyl)oxy]-4-[(methylamino)methyl]-2H-chromen-2-one methanesulfonate (NW-1772) as a highly potent, selective, reversible, and orally active monoamine oxidase B inhibitor.

PubMed

Pisani, Leonardo; Muncipinto, Giovanni; Miscioscia, Teresa Fabiola; Nicolotti, Orazio; Leonetti, Francesco; Catto, Marco; Caccia, Carla; Salvati, Patricia; Soto-Otero, Ramon; Mendez-Alvarez, Estefania; Passeleu, Celine; Carotti, Angelo

2009-11-12

In an effort to discover novel selective monoamine oxidase (MAO) B inhibitors with favorable physicochemical and pharmacokinetic profiles, 7-[(m-halogeno)benzyloxy]coumarins bearing properly selected polar substituents at position 4 were designed, synthesized, and evaluated as MAO inhibitors. Several compounds with MAO-B inhibitory activity in the nanomolar range and excellent MAO-B selectivity (selectivity index SI > 400) were identified. Structure-affinity relationships and docking simulations provided valuable insights into the enzyme-inhibitor binding interactions at position 4, which has been poorly explored. Furthermore, computational and experimental studies led to the identification and biopharmacological characterization of 7-[(3-chlorobenzyl)oxy]-4-[(methylamino)methyl]-2H-chromen-2-one methanesulfonate 22b (NW-1772) as an in vitro and in vivo potent and selective MAO-B inhibitor, with rapid blood-brain barrier penetration, short-acting and reversible inhibitory activity, slight inhibition of selected cytochrome P450s, and low in vitro toxicity. On the basis of this preliminary preclinical profile, inhibitor 22b might be viewed as a promising clinical candidate for the treatment of neurodegenerative diseases.

Integration of active pharmaceutical ingredient solid form selection and particle engineering into drug product design.

PubMed

Ticehurst, Martyn David; Marziano, Ivan

2015-06-01

This review seeks to offer a broad perspective that encompasses an understanding of the drug product attributes affected by active pharmaceutical ingredient (API) physical properties, their link to solid form selection and the role of particle engineering. While the crucial role of active pharmaceutical ingredient (API) solid form selection is universally acknowledged in the pharmaceutical industry, the value of increasing effort to understanding the link between solid form, API physical properties and drug product formulation and manufacture is now also being recognised. A truly holistic strategy for drug product development should focus on connecting solid form selection, particle engineering and formulation design to both exploit opportunities to access simpler manufacturing operations and prevent failures. Modelling and predictive tools that assist in establishing these links early in product development are discussed. In addition, the potential for differences between the ingoing API physical properties and those in the final product caused by drug product processing is considered. The focus of this review is on oral solid dosage forms and dry powder inhaler products for lung delivery. © 2015 Royal Pharmaceutical Society.

Tivantinib (ARQ-197) exhibits anti-tumor activity with down-regulation of FAK in oral squamous cell carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xi, Wei-Hong; Yang, Li-Yun; Cao, Zhong-Yi, E-mail: m18070383032@163.com

Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide and the 5 years survival rate of the patients is about 60% in the USA, due to acquired chemotherapeutic resistance and metastasis of the disease. In this study, we found that tivantinib, a selective MET inhibitor, suppresses OCSS cell proliferation and colony formation, however, anti-tumor activities induced by tivantinib are independent of the inhibition of MET signaling pathway. In addition, tivantinib cause G2/M cell cycle arrest and caspases-dependent apoptosis in OSCC cell lines. We also found that tivantinib dose-dependently suppressed the activation and expression of FAK. Inmore » all, these data suggested that tivantinib may be developed as a chemotherapeutic agent to effectively treat certain cancers including OSCC. - Highlights: • Tivantinib suppresses OSCC cell growth independent of the inhibition of HGF/MET signaling pathway. • Tivantinib blocks cell cycle and induces caspases-mediated apoptosis. • Tivantinib elicits its anti-tumor activity with the inhibition of FAK signaling pathway.« less

The ultrastructural surface morphology of oral cancer cells and keratinocytes after exposure to chitosan

NASA Astrophysics Data System (ADS)

Fatimah; Sarsito, A. S.; Wimardhani, Y. S.

2017-08-01

Low-molecular-weight chitosan (LMWC) has the same selective cytotoxic effects on oral cancer cells as cisplatin. The cell deaths caused by the anticancer characteristics of chitosan show that apoptosis is not the death pathway of the primary cells involved. The interactions between LMWC and the cells need to be explored. The objective of this study was to compare the ultrastructural morphology of oral Squamous Cell Carcinoma (SCC Ca)-922 and noncancer keratinocyte HaCaT cell lines after exposure to LMWC and cisplatin. The cells were treated with LMWC and cisplatin, and their ultrastructural morphology was analyzed using scanning electron micrographs. Features of early apoptosis, seen as the loss of microvilli, were detected in the LMWC-exposed Ca9-22 cells, and there was a material surrounding the cells. In contrast, the LMWC-exposed HaCaT cells showed no changes related to apoptosis. The results were the opposite when cisplatin was used. This study confirms that there are differences in the ultrastructural surface morphology of LMWC-exposed and cisplatin-exposed oral cancer cells and keratinocytes that could be correlated with their biological activity.

Pre-cancer risk assessment in habitual smokers from DIC images of oral exfoliative cells using active contour and SVM analysis.

PubMed

Dey, Susmita; Sarkar, Ripon; Chatterjee, Kabita; Datta, Pallab; Barui, Ananya; Maity, Santi P

2017-04-01

Habitual smokers are known to be at higher risk for developing oral cancer, which is increasing at an alarming rate globally. Conventionally, oral cancer is associated with high mortality rates, although recent reports show the improved survival outcomes by early diagnosis of disease. An effective prediction system which will enable to identify the probability of cancer development amongst the habitual smokers, is thus expected to benefit sizable number of populations. Present work describes a non-invasive, integrated method for early detection of cellular abnormalities based on analysis of different cyto-morphological features of exfoliative oral epithelial cells. Differential interference contrast (DIC) microscopy provides a potential optical tool as this mode provides a pseudo three dimensional (3-D) image with detailed morphological and textural features obtained from noninvasive, label free epithelial cells. For segmentation of DIC images, gradient vector flow snake model active contour process has been adopted. To evaluate cellular abnormalities amongst habitual smokers, the selected morphological and textural features of epithelial cells are compared with the non-smoker (-ve control group) group and clinically diagnosed pre-cancer patients (+ve control group) using support vector machine (SVM) classifier. Accuracy of the developed SVM based classification has been found to be 86% with 80% sensitivity and 89% specificity in classifying the features from the volunteers having smoking habit. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthesis, antifungal activity of caffeic acid derivative esters, and their synergism with fluconazole and nystatin against Candida spp.

PubMed

Sardi, Janaína de Cássia Orlandi; Gullo, Fernanda Patrícia; Freires, Irlan Almeida; Pitangui, Nayla de Souza; Segalla, Maicon Petrônio; Fusco-Almeida, Ana Marisa; Rosalen, Pedro Luiz; Regasini, Luís Octávio; Mendes-Giannini, Maria José Soares

2016-12-01

We tested the antifungal potential of caffeic acid and 8 of its derivative esters against Candidaalbicans ATCC 90028 and 9 clinical isolatesand carried out a synergism assay with fluconazole and nystatin. Propyl caffeate (C3) showed the best antifungal activity against the tested strains. When in combination, C3 markedly reduced the MIC of fluconazole and nystatin with synergistic effect up to 64-fold. Finally, C3 showed a high IC 50 value and selective indexagainst oral keratinocytes, demonstrating low toxicity against this cell type and selectivity for yeast cells. Further research should confirm its antifungal potential for development of combined therapy to treat C. albicans infections. Copyright © 2016 Elsevier Inc. All rights reserved.

Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis.

PubMed

De Savi, Chris; Pape, Andrew; Sawyer, Yvonne; Milne, David; Davies, Chris; Cumming, John G; Ting, Attilla; Lamont, Scott; Smith, Peter D; Tart, Jonathon; Page, Ken; Moore, Peter

2011-06-01

A new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure-activity and structure-property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics. Copyright © 2011 Elsevier Ltd. All rights reserved.

Oral Supplementation with Non-Absorbable Antibiotics or Curcumin Attenuates Western Diet-Induced Atherosclerosis and Glucose Intolerance in LDLR−/− Mice – Role of Intestinal Permeability and Macrophage Activation

PubMed Central

Ghosh, Siddhartha S.; Bie, Jinghua; Wang, Jing; Ghosh, Shobha

2014-01-01

Association between circulating lipopolysaccharide (LPS) and metabolic diseases (such as Type 2 Diabetes and atherosclerosis) has shifted the focus from Western diet-induced changes in gut microbiota per se to release of gut bacteria-derived products into circulation as the possible mechanism for the chronic inflammatory state underlying the development of these diseases. Under physiological conditions, an intact intestinal barrier prevents this release of LPS underscoring the importance of examining and modulating the direct effects of Western diet on intestinal barrier function. In the present study we evaluated two strategies, namely selective gut decontamination and supplementation with oral curcumin, to modulate Western-diet (WD) induced changes in intestinal barrier function and subsequent development of glucose intolerance and atherosclerosis. LDLR−/− mice were fed WD for 16 weeks and either received non-absorbable antibiotics (Neomycin and polymyxin) in drinking water for selective gut decontamination or gavaged daily with curcumin. WD significantly increased intestinal permeability as assessed by in vivo translocation of FITC-dextran and plasma LPS levels. Selective gut decontamination and supplementation with curcumin significantly attenuated the WD-induced increase in plasma LPS levels (3.32 vs 1.90 or 1.51 EU/ml, respectively) and improved intestinal barrier function at multiple levels (restoring intestinal alkaline phosphatase activity and expression of tight junction proteins, ZO-1 and Claudin-1). Consequently, both these interventions significantly reduced WD-induced glucose intolerance and atherosclerosis in LDLR−/− mice. Activation of macrophages by low levels of LPS (50 ng/ml) and its exacerbation by fatty acids is likely the mechanism by which release of trace amounts of LPS into circulation due to disruption of intestinal barrier function induces the development of these diseases. These studies not only establish the important role of intestinal barrier function, but also identify oral supplementation with curcumin as a potential therapeutic strategy to improve intestinal barrier function and prevent the development of metabolic diseases. PMID:25251395

Preparation of mucoadhesive oral patches containing tetracycline hydrochloride and carvacrol for treatment of local mouth bacterial infections and candidiasis.

PubMed

Obaidat, Rana M; Bader, Ammar; Al-Rajab, Wafa; Abu Sheikha, Ghassan; Obaidat, Aiman A

2011-01-01

The specific aim of this work was to prepare mucoadhesive patches containing tetracycline hydrochloride and carvacrol in an attempt to develop a novel oral drug delivery system for the treatment of mouth infections. The bilayered patches were prepared using ethyl cellulose as a backing layer and carbopol 934 as a matrix mucoadhesive layer. Patches were prepared with different loading amounts of tetracycline hydrochloride and carvacrol. The antimicrobial activity was assessed for the prepared patches using the disc-diffusion method against the yeast Candida albicans and five bacterial strains, including Pseudomonas aeruginosa, Escherichia coli, Bacillus cereus, Staphylococcus aureus, and Bacillus bronchispti. In this work, we highlighted the possibility of occurrence of a synergistic action between carvacrol and tetracycline. The best formulation was selected based on microbiological tests, drug release, ex-vivo mucoadhesive performance, and swelling index. Physical characteristics of the selected formulations were determined. These included pH, patch thickness, weight uniformity, content uniformity, folding endurance, and patch stability.

Sex steroids, sexual behavior, and selection attention for erotic stimuli in women using oral contraceptives.

PubMed

Alexander, G M; Sherwin, B B

1993-01-01

The relationship between sex steroids and sexual behavior was examined in 19 oral contraceptive users. Retrospective assessment of sexual attitudes were obtained and women completed daily ratings of sexual behavior and well-being for 28 days. Plasma levels of free testosterone (T), estradiol, and progesterone were measured at weekly intervals. In addition, women performed a novel selective attention task designed to measure the strength of the tendency to be distracted by sexual stimuli. Multiple regression analyses using average sexual behavior variables as dependent variables, and hormone levels sexual attitudes and well-being as predictor variables, showed that free T was strongly and positively associated with sexual desire, sexual thoughts, and anticipation of sexual activity. A role for T in attention to sexual stimuli was also supported by the positive correlation between free T and the bias for sexual stimuli in a subgroup of women. These results are consistent with the hypothesis that T may enhance cognitive aspects of women's sexual behavior.

Coordinate induction of both cytochrome P4503A and MDR1 by St John's wort in healthy subjects.

PubMed

Dresser, George K; Schwarz, Ute I; Wilkinson, Grant R; Kim, Richard B

2003-01-01

Many drugs are cosubstrates of cytochrome P450 (CYP) 3A and MDR1; furthermore, their disposition is markedly affected by pretreatment with inducing agents, including St John's wort. Such drug interactions reflect induction of both proteins through a common mechanism involving the steroid X receptor/pregnane X receptor. However, the relative contributions of enhanced metabolism and efflux transport to the overall induction process are unknown. The effects of 12 days' pretreatment with St John's wort on the disposition of selected in vivo probe drugs were determined in 21 young healthy subjects. Midazolam after oral and intravenous administration was used to assess CYP3A activity in both the intestinal epithelium and the liver, whereas the disposition of fexofenadine after an oral dose was assumed to be a measure of MDR1 function, and the oral plasma concentration-time profile of cyclosporine (INN, ciclosporin) was considered to reflect both CYP3A and MDR1 activities. St John's wort markedly affected the plasma concentration-time profiles of all of the drugs, with associated increases in their clearance. With midazolam, the enhancement was considerably less after intravenous administration (approximately 1.5-fold) than after oral administration (approximately 2.7-fold), and estimated intestinal and hepatic extraction ratios were higher by approximately 1.2- to 1.4-fold. By contrast, the oral clearances of fexofenadine and cyclosporine were equally increased by approximately 1.6-fold and 1.9-fold, respectively; these changes were both statistically less than for midazolam's oral clearance and greater than its estimated intestinal extraction. Although the disposition of all 3 drugs was altered by St John's wort, the extent of induction measured by oral clearance was different with CYP3A activity (midazolam), apparently increasing more than MDR1 function (fexofenadine), whereas with cyclosporine the change in oral clearance appeared to be more closely associated with the increase in MDR1 rather than CYP3A, despite the fact that both proteins are importantly involved in its disposition. These discordances indicate that, although a common molecular mechanism may be involved, the quantitative aspects of induction are complex and depend on the particular drug and the relative contributions of CYP3A and MDR1 in its disposition.

Introducing Cytology-Based Theranostics in Oral Squamous Cell Carcinoma: A Pilot Program.

PubMed

Patrikidou, Anna; Valeri, Rosalia Maria; Kitikidou, Kyriaki; Destouni, Charikleia; Vahtsevanos, Konstantinos

2016-04-01

We aimed to evaluate the feasibility and reliability of brush cytology in the biomarker expression profiling of oral squamous cell carcinomas within the concept of theranostics, and to correlate this biomarker profile with patient measurable outcomes. Markers representative of prognostic gene expression changes in oral squamous cell carcinoma was selected. These markers were also selected to involve pathways for which commercially available or investigational agents exist for clinical application. A set of 7 markers were analysed by immunocytochemistry on the archival primary tumour material of 99 oral squamous cell carcinoma patients. We confirmed the feasibility of the technique for the expression profiling of oral squamous cell carcinomas. Furthermore, our results affirm the prognostic significance of the epidermal growth factor receptor (EGFR) family and the angiogenic pathway in oral squamous cell carcinoma, confirming their interest for targeted therapy. Brush cytology appears feasible and applicable for the expression profiling of oral squamous cell carcinoma within the concept of theranostics, according to sample availability.

Lysophosphatidic acid induces expression of genes in human oral keratinocytes involved in wound healing.

PubMed

Thorlakson, Hong Huynh; Engen, Stian Andre; Schreurs, Olav; Schenck, Karl; Blix, Inger Johanne Schytte

2017-08-01

Epithelial cells participate in wound healing by covering wounds, but also as important mediators of wound healing processes. Topical application of the phospholipid growth factor lysophosphatidic acid (LPA) accelerates dermal wound healing and we hypothesized that LPA can play a role in human oral wound healing through its effects on human oral keratinocytes (HOK). HOK were isolated from gingival biopsies and exposed to LPA. The LPA receptor profile, signal transduction pathways, gene expression and secretion of selected cytokines were analyzed. HOK expressed the receptors LPA 1 , LPA 5 and LPA 6 and LPA activated the ERK1/2, JNK and p38 intracellular pathways, substantiated by secretion of IL-6 and IL-8. The early (2h) and intermediate (6h) gene expression profiles of HOK after LPA treatment showed a wide array of regulated genes. The majority of the strongest upregulated genes were related to chemotaxis and inflammation, and became downregulated after 6h. At 6h, genes coding for factors involved in extracellular matrix remodeling and re-epithelialization became highly expressed. IL-36γ, not earlier known to be regulated by LPA, was strongly transcribed and translated but not secreted. After stimulation with LPA, HOK responded by regulating factors and genes that are essential in wound healing processes. As LPA is found in saliva and is released by activated cells after wounding, our results indicate that LPA has a favorable physiological role in oral wound healing. This may further point towards a beneficial role for application of LPA on oral surgical or chronic wounds. Copyright © 2017 Elsevier Ltd. All rights reserved.

Host Immune Selection of Rumen Bacteria through Salivary Secretory IgA

PubMed Central

Fouhse, Janelle M.; Smiegielski, Luke; Tuplin, Melanie; Guan, Le Luo; Willing, Benjamin P.

2017-01-01

The rumen microbiome is integral to efficient production in cattle and shows strong host specificity, yet little is known about what host factors shape rumen microbial composition. Secretory immunoglobulin A (SIgA) is produced in large amounts in the saliva, can coat both commensal and pathogenic microbes within the gut, and presents a plausible mechanism of host specificity. However, the role salivary SIgA plays in commensal bacteria selection in ruminants remains elusive. The main objectives of this study were to develop an immuno-affinity benchtop method to isolate SIgA-tagged microbiota and to determine if salivary SIgA preferentially binds selected bacteria. We hypothesized that SIgA-tagged bacteria would differ from total bacteria, thus supporting a potential host-derived mechanism in commensal bacterial selection. Whole rumen (n = 9) and oral secretion samples (n = 10) were incubated with magnetic beads conjugated with anti-secretory IgA antibodies to enrich SIgA-tagged microbiota. Microbial DNA from the oral secretion, whole rumen, SIgA-tagged oral secretion, and SIgA-tagged rumen was isolated for amplicon sequencing of V1–V3 region of 16S rDNA genes. Whole rumen and oral secretion had distinctive (P < 0.05) bacterial compositions indicated by the non-parametric multidimensional scaling plot using Euclidean distance metrics. The SIgA-tagged microbiota from rumen and oral secretion had similar abundance of Bacteroidetes, Actinobacteria, Fibrobacter, candidate phyla TM7, and Tenericutes and are clustered tightly. Composition of SIgA-tagged oral secretion microbiota was more similar to whole rumen microbiota than whole oral secretion due to enrichment of rumen bacteria (Lachnospiraceae) and depletion of oral taxa (Streptococcus, Rothia, Neisseriaceae, and Lactobacillales). In conclusion, SIgA-tagged oral secretion microbiota had an increased resemblance to whole rumen microbiota, suggesting salivary SIgA-coating may be one host-derived mechanism impacting commensal colonization. Further studies, to explore the variations in antibody affinity between different animals as a driver of microbial composition are warranted. PMID:28553275

Oral health activities of early head start teachers directed toward children and parents.

PubMed

Kranz, Ashley M; Rozier, R Gary; Zeldin, Leslie P; Preisser, John S

2011-01-01

This cross-sectional study examined Early Head Start (EHS) teachers' oral health program activities and their association with teacher and program characteristics. Self-completed questionnaires were distributed to the staff in all EHS programs in North Carolina. Variables for dental health activities for parents (four items) and children (four items) were constructed as the sum of responses to a 0-4 Likert-type scale (never to very frequently). Ordinary least squares regression models examined the association between teachers' oral health program activities and modifiable teacher (oral health knowledge, values, self-efficacy, dental health training, perceived barriers to dental activities) and program (director and health coordinator knowledge and perceived barriers to dental activities) characteristics. Teachers in the parent (n=260) and child (n=231) analyses were a subset of the 485 staff respondents (98 percent response rate). Teachers engaged in child oral health activities (range = 0-16; mean = 9.0) more frequently than parent activities (range = 0-16; mean = 6.9). Teachers' oral health values, perceived oral health self-efficacy, dental training, and director and health coordinator knowledge were positively associated with oral health activities (P < 0.05). Perceived barriers were negatively associated with child activities (P < 0.05). The level of oral health activity in EHS programs is less than optimal. Several characteristics of EHS staff were identified that can be targeted with education interventions. Evidence for effectiveness of EHS interventions needs to be strengthened, but results of this survey provide encouraging findings about the potential effects of teacher training on their oral health practices.

Efficacy, tolerability, and pharmacokinetics of oxcarbazepine oral loading in patients with epilepsy.

PubMed

Kim, Dong Wook; Gu, Nami; Jang, In-Jin; Chu, Kon; Yu, Kyung-Sang; Cho, Joo-Youn; Yoon, Seo Hyun; Kim, Hwa Suk; Oh, Jeeyoung; Lee, Sang Kun

2012-01-01

The rapid achievement of effective levels of antiepileptic drugs (AEDs) is required in patients with epilepsy who have a higher risk of seizures, and oral loading of AEDs may be an important consideration in these patients. We performed the present study to investigate the efficacy and tolerability of oral loading of oxcarbazepine in patients with recurrent seizures, or after temporary discontinuation of AEDs for diagnostic or presurgical evaluation of epilepsy. Forty adult patients were studied and oxcarbazepine was administered orally at a single loading dosage of 30 mg/kg. The plasma levels of oxcarbazepine and its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD), were measured, and clinical assessment of adverse events was performed at 2, 4, 6, 8, 10, 12, 16, and 24 h after oral loading of oxcarbazepine. Approximately two-thirds of patients reached effective levels of MHD 2 h after receiving the oral loading, and all patients reached effective levels 4 h after oxcarbazepine administration. Most patients maintained therapeutic MHD levels for at least 16 h. Almost half of the patients experienced adverse events, but all were mild to moderate in severity and resolved spontaneously within 24 h. Our study shows that oral loading of oxcarbazepine is an effective and well-tolerated method for rapidly achieving therapeutic levels of MHD in patients with epilepsy, and is a useful option in selected patients with recurrent seizures, or after temporary discontinuation of AEDs. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

Impact of oral health education on oral hygiene knowledge, practices, plaque control and gingival health of 13- to 15-year-old school children in Bangalore city.

PubMed

D'Cruz, A M; Aradhya, S

2013-05-01

To assess effectiveness of an oral health education (OHE) programme on oral hygiene knowledge, practices, plaque control and gingival health of 13- to 15-year-old school children in Bangalore city. Three schools were randomly selected and assigned to experimental I, experimental II and control groups. At baseline, a 20-item questionnaire was used to assess the oral hygiene knowledge and practices. Clinical examinations (Turesky-Gilmore-Glickman modification of Quigley Hein plaque index; Loe-Silness gingival index) were performed by 2 examiners. OHE was provided by the investigator for experimental groups I (lecture using a PowerPoint presentation) and II (lecture using a PowerPoint presentation with toothbrushing demonstration). Control group did not receive any intervention. Reinforcement was provided for experimental groups at 3 and 6 months. At end of 9 months, questionnaire was administered and clinical examinations were performed. Data were analysed using chi-square, anova and post hoc Tukey's tests. Nine months post-intervention, there was significant improvement in oral hygiene knowledge and practices in experimental groups. There were significant reductions in mean plaque index and gingival index scores in the experimental groups. The control group did not show any significant improvement. Active involvement of school children with reinforcement of OHE can improve oral hygiene knowledge, practices and gingival health and decrease plaque levels. © 2012 John Wiley & Sons A/S.

Selective Estrogen Receptor Modulation Increases Hippocampal Activity during Probabilistic Association Learning in Schizophrenia

PubMed Central

Kindler, Jochen; Weickert, Cynthia Shannon; Skilleter, Ashley J; Catts, Stanley V; Lenroot, Rhoshel; Weickert, Thomas W

2015-01-01

People with schizophrenia show probabilistic association learning impairment in conjunction with abnormal neural activity. The selective estrogen receptor modulator (SERM) raloxifene preserves neural activity during memory in healthy older men and improves memory in schizophrenia. Here, we tested the extent to which raloxifene modifies neural activity during learning in schizophrenia. Nineteen people with schizophrenia participated in a twelve-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of the SERM raloxifene administered orally at 120 mg daily to assess brain activity during probabilistic association learning using functional magnetic resonance imaging (fMRI). Raloxifene improved probabilistic association learning and significantly increased fMRI BOLD activity in the hippocampus and parahippocampal gyrus relative to placebo. A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls. Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia. These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia. PMID:25829142

Guide for health professionals addressing oral care for individuals in oncological treatment based on scientific evidence.

PubMed

Carvalho, Caroline Gomes; Medeiros-Filho, João Batista; Ferreira, Meire Coelho

2018-02-22

Oncological treatment can cause changes in the oral cavity compromising oral functions. The aim of the study was, based on a systematic review, to draft a guide directed at the team of health professionals involved in the oral care of oncological patients. A systematic search of the literature was performed for articles published between 2000 and April 2017. Searches were made of electronic databases and hand search. The inclusion criteria were systematic reviews of randomized clinical trials (RCTs) and RCTs published in English, involving pediatric and adult oncological patients and focused on the prevention and treatment of oral complications as well as studies addressing the maintenance of oral health. Among the 1237 studies identified, 129 were pre-selected and 54 were selected to form the basis for the clinical guide. The studies analyzed stress the need for oral assessments as well as preventive and curative actions prior to oncological treatment. To minimize the severity of oral problems, the studies emphasize daily oral care, the treatment of xerostomia with saliva substitute and hydration, and low-level laser therapy, nystatin, acyclovir, respectively, for the prevention and treatment of oral mucositis, oral candidiasis, and infection by herpes simplex virus. Thus, the guide produced addresses oral assessments and professional and home care before, during, and after oncological treatment. The guide drafted has the function of assisting health professionals involved in the oral care of patients with cancer, enabling the prevention or treatment of oral complications stemming from oncological treatment.

On prilled Nanotubes-in-Microgel Oral Systems for protein delivery.

PubMed

de Kruif, Jan Kendall; Ledergerber, Gisela; Garofalo, Carla; Fasler-Kan, Elizaveta; Kuentz, Martin

2016-04-01

Newly discovered active macromolecules are highly promising for therapy, but poor bioavailability hinders their oral use. Microencapsulation approaches, such as protein prilling into microspheres, may enable protection from gastrointestinal (GI) enzymatic degradation. This would increase bioavailability mainly for local delivery to GI lumen or mucosa. This work's purpose was to design a novel architecture, namely a Nanotubes-in-Microgel Oral System, by prilling for protein delivery. Halloysite nanotubes (HNT) were selected as orally acceptable clay particles and their lumen was enlarged by alkaline etching. This chemical modification increased the luminal volume to a mean of 216.3 μL g(-1) (+40.8%). After loading albumin as model drug, the HNT were entrapped in microgels by prilling. The formation of Nanoparticles-in-Microsphere Oral System (NiMOS) yielded entrapment efficiencies up to 63.2%. NiMOS shape was spherical to toroidal, with a diameter smaller than 320 μm. Release profiles depended largely on the employed system and HNT type. Protein stability was determined throughout prilling and after in vitro enzymatic degradation. Prilling did not harm protein structure, and NiMOS demonstrated higher enzymatic protection than pure nanotubes or microgels, since up to 82% of BSA remained unscathed after in vitro digestion. Therefore, prilled NiMOS was shown to be a promising and flexible multi-compartment system for oral (local) macromolecular delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Non-oral gram-negative facultative rods in chronic periodontitis microbiota.

PubMed

van Winkelhoff, Arie J; Rurenga, Patrick; Wekema-Mulder, Gepke J; Singadji, Zadrach M; Rams, Thomas E

2016-05-01

The subgingival prevalence of gram-negative facultative rods not usually inhabiting or indigenous to the oral cavity (non-oral GNFR), as well as selected periodontal bacterial pathogens, were evaluated by culture in untreated and treated chronic periodontitis patients. Subgingival biofilm specimens from 102 untreated and 101 recently treated adults with chronic periodontitis in the Netherlands were plated onto MacConkey III and Dentaid selective media with air-5% CO2 incubation for isolation of non-oral GNFR, and onto enriched Oxoid blood agar with anaerobic incubation for recovery of selected periodontal bacterial pathogens. Suspected non-oral GNFR clinical isolates were identified to a species level with the VITEK 2 automated system. A total of 87 (42.9%) out of 203 patients yielded subgingival non-oral GNFR. Patients recently treated with periodontal mechanical debridement therapy demonstrated a greater prevalence of non-oral GNFR (57.4% vs 28.4%, P < 0.0001), and a greater number of different non-oral GNFR species (23 vs 14 different species), than untreated patients. Sphingomonas paucimobilis was the most frequently isolated subgingival non-oral GNFR species. Several GNFR species normally found in animals and human zoonotic infections, and not previously detected in human subgingival biofilms, were recovered from some patients, including Bordetella bronchispetica, Pasteurella canis, Pasteurella pneumotropica and Neisseria zoodegmatis. Porphyromonas gingivalis and Tannerella forsythia were significantly associated with the presence of subgingival non-oral GNFR. A surprisingly high proportion of Dutch chronic periodontitis patients yielded cultivable non-oral GNFR in periodontal pockets, particularly among those recently treated with periodontal mechanical debridement therapy. Since non-oral GNFR species may resist mechanical debridement from periodontal pockets, and are often not susceptible to many antibiotics frequently used in periodontal practice, their subgingival presence may complicate periodontal treatment in species-positive patients and increase risk of potentially dangerous GNFR infections developing at other body sites. Copyright © 2016 Elsevier Ltd. All rights reserved.

Specific Selection of Essential Oil Compounds for Treatment of Children’s Infection Diseases

PubMed Central

Pauli, Alexander; Schilcher, Heinz

2004-01-01

Preparations with essential oils and their dosages applied in the therapy of children’s infectious diseases are well documented. In contrast, information is only sparingly available about uses of isolated pure essential oil compounds for the treatment of such infections. To find out safe antimicrobials from essential oils, microbiological inhibitory data of children pathogens were combined with oral and dermal acute toxicity data to calculate oral and dermal therapeutical indices (TI). The superiority of antibiotic drugs became obvious following calculating oral TIs of antimicrobials from higher plants, which suggests that oral administrations of essential oil compounds are not suitable to cure severe infections. A few selected compounds from higher plants show moderate effectiveness against gram-positive bacteria, yeast and fungi, but not gram-negative bacteria. Topical application or inhalation of selected compounds for the treatment or additional treatment of mild infections is reasonable.

Discovery of a Selective S1P1 Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate.

PubMed

Demont, Emmanuel H; Andrews, Benjamin I; Bit, Rino A; Campbell, Colin A; Cooke, Jason W B; Deeks, Nigel; Desai, Sapna; Dowell, Simon J; Gaskin, Pam; Gray, James R J; Haynes, Andrea; Holmes, Duncan S; Kumar, Umesh; Morse, Mary A; Osborne, Greg J; Panchal, Terry; Patel, Bela; Perboni, Alcide; Taylor, Simon; Watson, Robert; Witherington, Jason; Willis, Robert

2011-06-09

Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P1 and S1P3-5). It has been postulated that fingolimod's efficacy is due to S1P1 agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P3 agonism. We have discovered a series of selective S1P1 agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate, 20, a potent, S1P3-sparing, orally active S1P1 agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P3 is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.

Discovery of a Selective S1P1 Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate

PubMed Central

2011-01-01

Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P1 and S1P3−5). It has been postulated that fingolimod's efficacy is due to S1P1 agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P3 agonism. We have discovered a series of selective S1P1 agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate, 20, a potent, S1P3-sparing, orally active S1P1 agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P3 is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels. PMID:24900328

Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases.

PubMed

Sandham, David A; Arnold, Nicola; Aschauer, Heinrich; Bala, Kamlesh; Barker, Lucy; Brown, Lyndon; Brown, Zarin; Budd, David; Cox, Brian; Docx, Cerys; Dubois, Gerald; Duggan, Nicholas; England, Karen; Everatt, Brian; Furegati, Marcus; Hall, Edward; Kalthoff, Frank; King, Anna; Leblanc, Catherine J; Manini, Jodie; Meingassner, Josef; Profit, Rachael; Schmidt, Alfred; Simmons, Jennifer; Sohal, Bindi; Stringer, Rowan; Thomas, Matthew; Turner, Katharine L; Walker, Christoph; Watson, Simon J; Westwick, John; Willis, Jennifer; Williams, Gareth; Wilson, Caroline

2013-11-01

Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development. Copyright © 2013 Elsevier Ltd. All rights reserved.

48 CFR 15.102 - Oral presentations.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Oral presentations. 15.102 Section 15.102 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION CONTRACTING METHODS AND CONTRACT TYPES CONTRACTING BY NEGOTIATION Source Selection Processes and Techniques 15.102 Oral...

Antidepressant-like responses to the combined sigma and 5-HT1A receptor agonist OPC-14523.

PubMed

Tottori, K; Miwa, T; Uwahodo, Y; Yamada, S; Nakai, M; Oshiro, Y; Kikuchi, T; Altar, C A

2001-12-01

The antidepressant-like activity of a novel compound, OPC-14523, was investigated in comparison with the conventional antidepressants, fluoxetine and imipramine. OPC-14523 bound with nanomolar affinities to sigma receptors (IC(50)=47-56 nM), the 5-HT(1A) receptor (IC(50)=2.3 nM), and the 5-HT transporter (IC(50)=80 nM). OPC-14523 inhibited the in vitro reuptake of 3H-5-HT (IC(50)=27 nM), but it showed very weak inhibitory activity on 3H-NE and 3H-DA reuptake. OPC-14523 did not inhibit MAO A or B activities or muscarinic receptors. A single oral administration of OPC-14523 produced a marked antidepressant-like effect in the forced swimming test (FST) with rats (ED(50)=27 mg/kg) and mice (ED(50)=20mg/kg) without affecting the general locomotor activity. In contrast, fluoxetine and imipramine each required at least four days of repeated dosing to show this activity. The acute activity of OPC-14523 was blocked by pretreatment with the sigma receptor antagonist NE-100 or the selective 5-HT(1A) receptor antagonist WAY-100635. The induction of flat body posture by OPC-14523 was blocked by the selective 5-HT(1A) receptor antagonist NAN-190, and forebrain 5-HT biosynthesis was attenuated by OPC-14523 at behaviorally effective doses. In contrast, OPC-14523, unlike fluoxetine, failed to inhibit 5-HT reuptake at oral doses below 100mg/kg. Thus, the acute antidepressant-like action of OPC-14523 is achieved by the combined stimulation of sigma and 5-HT(1A) receptors without inhibition of 5-HT reuptake in vivo.

In-vitro evaluation and comparison of the anti-microbial potency of commercially available oral hygiene products against Streptococcus mutans.

PubMed

Sentila, R; Gandhimathi, A; Karthika, S; Suryalakshmi, R; Michael, A

2011-06-01

Dental caries is the destruction of enamel, dentin, or cementum of teeth due to bacterial activities, which if left untreated can cause considerable pain, discomfort, and treatment costs are very high. Of the oral bacteria, Streptococcus mutans is considered to be causative agent of dental caries in humans. This study aims at screening the antibacterial potential of available oral hygiene products against S. mutans, the primary etiological agent. A selective number of toothpaste and mouth rinse available in the nearby local market was subjected to the study. The experiments were designed in a way to determine which one of these products had the greatest anti-S.mutans activity. Antibiotic sensitivity tests against the pathogenic strains were also conducted. Pathogenic strains of S.mutans were isolated from clinical dental specimen and identified using MTCC standard strain No. 890. Of the 86.66% samples which showed positive for S.mutans growth, almost 96% conferred sensitivity to 0.08 mg/ml of penicillin. Among the toothpastes used, A showed the maximum inhibitory activity against S.mutans inhibiting its growth even at a very low concentration of 0.0156 g/ml. Similar results were seen in the case of the mouth rinses used for the study, which showed that N had the most effective activity against S.mutans even at 1:8 dilution. The oral hygiene products containing triclosan proved to be the most effective followed by those containing fluoride. Herbal products showed comparatively lesser activity in inhibiting the growth of S. mutans. Even though there are so many products available to curb the progression of dental caries in the population targeted, there is still an undoubted prevalence and incidence of caries among the general public. The need for a better alternative to help control dental caries is on the rise even today.

Sensory Sensitivity and Food Selectivity in Children with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Chistol, Liem T.; Bandini, Linda G.; Must, Aviva; Phillips, Sarah; Cermak, Sharon A.; Curtin, Carol

2018-01-01

Few studies have compared atypical sensory characteristics and food selectivity between children with and without autism spectrum disorder (ASD). We compared oral sensory processing between children with (n = 53) and without ASD (n = 58), ages 3-11 years. We also examined the relationships between atypical oral sensory processing, food…

Oral Exam System at Teacher Appointments in Turkey

ERIC Educational Resources Information Center

Colak, Ismail; Demir, Selcuk Besir

2017-01-01

Many systems have been developed on teacher selection and appointments procedures throughout history in Turkey. Latest teacher appointments and selection systems in Turkey is Oral Exam Evaluation. This new system is discussed in detail in this study. Basically, the study is to analysis what the positive and negative reflections of the system might…

Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist.

PubMed

Arai, Kiyoshi; Homma, Tsuyoshi; Morikawa, Yuka; Ubukata, Naoko; Tsuruoka, Hiyoyuki; Aoki, Kazumasa; Ishikawa, Hirokazu; Mizuno, Makoto; Sada, Toshio

2015-08-15

The present study was designed to characterize the pharmacological profile of CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist. In the radioligand-binding assay, CS-3150 inhibited (3)H-aldosterone binding to mineralocorticoid receptor with an IC50 value of 9.4nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 36 and 713nM, respectively. CS-3150 also showed at least 1000-fold higher selectivity for mineralocorticoid receptor over other steroid hormone receptors, glucocorticoid receptor, androgen receptor and progesterone receptor. In the reporter gene assay, CS-3150 inhibited aldosterone-induced transcriptional activation of human mineralocorticoid receptor with an IC50 value of 3.7nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 66 and 970nM, respectively. CS-3150 had no agonistic effect on mineralocorticoid receptor and did not show any antagonistic or agonistic effect on glucocorticoid receptor, androgen receptor and progesterone receptor even at the high concentration of 5μM. In adrenalectomized rats, single oral administration of CS-3150 suppressed aldosterone-induced decrease in urinary Na(+)/K(+) ratio, an index of in vivo mineralocorticoid receptor activation, and this suppressive effect was more potent and longer-lasting than that of spironolactone and eplerenone. Chronic treatment with CS-3150 inhibited blood pressure elevation induced by deoxycorticosterone acetate (DOCA)/salt-loading to rats, and this antihypertensive effect was more potent than that of spironolactone and eplerenone. These findings indicate that CS-3150 is a selective and highly potent mineralocorticoid receptor antagonist with long-lasting oral activity. This agent could be useful for the treatment of hypertension, cardiovascular and renal disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

A novel antagonist of the prostaglandin E(2) EP(4) receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models.

PubMed

Chen, Q; Muramoto, K; Masaaki, N; Ding, Y; Yang, H; Mackey, M; Li, W; Inoue, Y; Ackermann, K; Shirota, H; Matsumoto, I; Spyvee, M; Schiller, S; Sumida, T; Gusovsky, F; Lamphier, M

2010-05-01

Rheumatoid arthritis (RA) is an autoimmune disorder involving subsets of activated T cells, in particular T helper (Th) 1 and Th17 cells, which infiltrate and damage tissues and induce inflammation. Prostaglandin E(2) (PGE(2)) enhances the Th17 response, exacerbates collagen-induced arthritis (CIA) and promotes inflammatory pain. The current study investigated whether selective antagonism of the PGE(2) EP(4) receptor would suppress Th1/Th17 cell development and inflammatory arthritis in animal models of RA. Effects of PGE(2) and a novel EP(4) receptor antagonist ER-819762 on Th1 differentiation, interleukin-23 (IL-23) production by dendritic cells (DCs), and Th17 development were assessed in vitro. The effect of ER-819762 was evaluated in CIA and glucose-6-phosphate isomerase (GPI)-induced arthritis models. In addition, the effects of ER-819762 on pain were evaluated in a model of chronic inflammatory pain induced by complete Freund's adjuvant (CFA) in the rat. Stimulation of the EP(4) receptor enhanced Th1 differentiation via phosphatidylinositol 3 kinase signalling, selectively promoted Th17 cell expansion, and induced IL-23 secretion by activated DCs, effects suppressed by ER-819762 or anti-PGE(2) antibody. Oral administration of ER-19762 suppressed Th1 and Th17 cytokine production, suppressed disease in collagen- and GPI-induced arthritis in mice, and suppressed CFA-induced inflammatory pain in rats. PGE(2) stimulates EP(4) receptors to promote Th1 differentiation and Th17 expansion and is critically involved in development of arthritis in two animal models. Selective suppression of EP(4) receptor signalling may have therapeutic value in RA both by modifying inflammatory arthritis and by relieving pain.

Hit-to-lead optimization of 2-(1H-pyrazol-1-yl)-thiazole derivatives as a novel class of EP1 receptor antagonists.

PubMed

Atobe, Masakazu; Naganuma, Kenji; Kawanishi, Masashi; Morimoto, Akifumi; Kasahara, Ken-ichi; Ohashi, Shigeki; Suzuki, Hiroko; Hayashi, Takahiko; Miyoshi, Shiro

2013-11-15

We describe a medicinal chemistry approach to generate a series of 2-(1H-pyrazol-1-yl)thiazole compounds that act as selective EP1 receptor antagonists. The obtained results suggest that compound 12 provides the best EP1 receptor antagonist activity and demonstrates good oral pharmacokinetics. Copyright © 2013 Elsevier Ltd. All rights reserved.

The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men

PubMed Central

Basaria, Shehzad; Collins, Lauren; Dillon, E. Lichar; Orwoll, Katie; Storer, Thomas W.; Miciek, Renee; Ulloor, Jagadish; Zhang, Anqi; Eder, Richard; Zientek, Heather; Gordon, Gilad; Kazmi, Syed; Sheffield-Moore, Melinda

2013-01-01

Background. Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity. Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones. Methods. In this placebo-controlled study, 76 healthy men (21–50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention. Results. LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone–binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation. Conclusions. LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should evaluate its efficacy in improving physical function and health outcomes in select populations. PMID:22459616

A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebral disc degeneration and associated pain.

PubMed

Makino, Hiroto; Seki, Shoji; Yahara, Yasuhito; Shiozawa, Shunichi; Aikawa, Yukihiko; Motomura, Hiraku; Nogami, Makiko; Watanabe, Kenta; Sainoh, Takeshi; Ito, Hisakatsu; Tsumaki, Noriyuki; Kawaguchi, Yoshiharu; Yamazaki, Mitsuaki; Kimura, Tomoatsu

2017-12-05

Intervertebral disc (IVD) degeneration is a major cause of low back pain. The transcription factor c-Fos/Activator Protein-1 (AP-1) controls the expression of inflammatory cytokines and matrix metalloproteinases (MMPs) that contribute to the pathogenesis IVD degeneration. We investigated the effects of inhibition of c-Fos/AP-1 on IVD degeneration and associated pain. A selective inhibitor, T-5224, significantly suppressed the interleukin-1β-induced up-regulation of Mmp-3, Mmp-13 and Adamts-5 transcription in human nucleus pulposus cells and in a mouse explant culture model of IVD degeneration. We used a tail disc percutaneous needle puncture method to further assess the effects of oral administration of T-5224 on IVD degeneration. Analysis of disc height, T2-magnetic resonance imaging (MRI) findings, and histology revealed that IVD degeneration was significantly mitigated by T-5224. Further, oral administration of T-5224 ameliorated pain as indicated by the extended tail-flick latency in response to heat stimulation of rats with needle-puncture-induced IVD degeneration. These findings suggest that the inhibition of c-Fos/AP-1 prevents disc degeneration and its associated pain and that T-5224 may serve as a drug for the prevention of IVD degeneration.

Preclinical development of a non-toxic oral formulation of monoethanolamine, a lipid precursor, for prostate cancer treatment

PubMed Central

Saxena, Roopali; Yang, Chunhua; Rao, Mukkavilli; Turaga, Ravi Chakra; Garlapati, Chakravarthy; Gundala, Sushma Reddy; Myers, Kimberly; Ghareeb, Ahmed; Bhattarai, Shristi; Kamilinia, Golnaz; Bristi, Sangina; Su, Dan; Gadda, Giovanni; Rida, Padmashree C. G.; Cantuaria, Guilherme H.; Aneja, Ritu

2018-01-01

Purpose Most currently-available chemotherapeutic agents target rampant cell division in cancer cells, thereby affecting rapidly-dividing normal cells resulting in toxic side-effects. This non-specificity necessitates identification of novel cellular pathways that are reprogrammed selectively in cancer cells and can be exploited to develop pharmacologically superior and less-toxic therapeutics. Despite growing awareness on dysregulation of lipid metabolism in cancer cells, targeting lipid biosynthesis is still largely uncharted territory. Herein, we report development of a novel non-toxic orally-deliverable anticancer formulation of monoethanolamine (Etn), for prostate cancer by targeting the Kennedy pathway of phosphatidylethanolamine (PE) lipid biosynthesis. Experimental Design We first evaluated GI-tract stability, drug-drug interaction liability, pharmacokinetic and toxicokinetic properties of Etn to evaluate its suitability as a non-toxic orally-deliverable agent. We next performed in vitro and in vivo experiments to investigate efficacy and mechanism of action. Results Our data demonstrate that Etn exhibits excellent bioavailability, GI-tract stability, and no drug-drug interaction liability. Remarkably, orally-fed Etn inhibited tumor growth in four weeks by ~67% in mice bearing human prostate cancer PC-3 xenografts without any apparent toxicity. Mechanistically, Etn exploits selective overexpression of choline kinase in cancer cells, resulting in accumulation of phosphoethanolamine (PhosE), accompanied by downregulation of HIF-1α that induces metabolic stress culminating into cell death. Conclusions Our study provides first evidence for the superior anticancer activity of Etn, a simple lipid precursor formulation, whose non-toxicity conforms to FDA-approved standards, compelling its clinical development for prostate cancer management. PMID:28167510

Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms

PubMed Central

Quintás-Cardama, Alfonso; Vaddi, Kris; Liu, Phillip; Manshouri, Taghi; Li, Jun; Scherle, Peggy A.; Caulder, Eian; Wen, Xiaoming; Li, Yanlong; Waeltz, Paul; Rupar, Mark; Burn, Timothy; Lo, Yvonne; Kelley, Jennifer; Covington, Maryanne; Shepard, Stacey; Rodgers, James D.; Haley, Patrick; Kantarjian, Hagop

2010-01-01

Constitutive JAK2 activation in hematopoietic cells by the JAK2V617F mutation recapitulates myeloproliferative neoplasm (MPN) phenotypes in mice, establishing JAK2 inhibition as a potential therapeutic strategy. Although most polycythemia vera patients carry the JAK2V617F mutation, half of those with essential thrombocythemia or primary myelofibrosis do not, suggesting alternative mechanisms for constitutive JAK-STAT signaling in MPNs. Most patients with primary myelofibrosis have elevated levels of JAK-dependent proinflammatory cytokines (eg, interleukin-6) consistent with our observation of JAK1 hyperactivation. Accordingly, we evaluated the effectiveness of selective JAK1/2 inhibition in experimental models relevant to MPNs and report on the effects of INCB018424, the first potent, selective, oral JAK1/JAK2 inhibitor to enter the clinic. INCB018424 inhibited interleukin-6 signaling (50% inhibitory concentration [IC50] = 281nM), and proliferation of JAK2V617F+ Ba/F3 cells (IC50 = 127nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F+ polycythemia vera patients (IC50 = 67nM) versus healthy donors (IC50 > 400nM). In a mouse model of JAK2V617F+ MPN, oral INCB018424 markedly reduced splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects. Preliminary clinical results support these preclinical data and establish INCB018424 as a promising oral agent for the treatment of MPNs. PMID:20130243

Correlations between the enantio- and regio-selective metabolisms of warfarin.

PubMed

Takahashi, Harumi; Ohara, Minami; Shibata, Soichi; Lee, Ming Ta Michael; Cavallari, Larisa H; Nutescu, Edith A; Scordo, Maria G; Pengo, Vittorio; Padrini, Roberto; Atsuda, Koichiro; Matsubara, Hajime; Chen, Yuan Tsong; Echizen, Hirotoshi

2017-01-01

To clarify whether the activities of multiple CYPs associated with warfarin metabolism would be correlated with each other. Oral clearances (CLpo) of warfarin enantiomers were estimated in 378 Chinese, Caucasians and African-Americans. The partial metabolic clearances (CLm) for 7-hydroxywarfarin enantiomers were also measured. In addition, CLpo and CLm were determined in a patient on warfarin and rifampicin. Correlations between CLpo for warfarin enantiomers existed across the three populations. In addition, there was a significant correlation between the CLm for 7-hydroxylation of warfarin enantiomers. Under induced conditions by rifampicin, there were significant correlations between the enantio- and regio-selective metabolisms of warfarin. Metabolic activities of CYP2C9, CYP1A2 and CYP3A4 may be regulated by common transcriptional mechanism(s).

Oral Efficacy of Apigenin against Cutaneous Leishmaniasis: Involvement of Reactive Oxygen Species and Autophagy as a Mechanism of Action

PubMed Central

Fonseca-Silva, Fernanda; Inacio, Job D. F.; Canto-Cavalheiro, Marilene M.; Menna-Barreto, Rubem F. S.; Almeida-Amaral, Elmo E.

2016-01-01

Background The treatment for leishmaniasis is currently based on pentavalent antimonials and amphotericin B; however, these drugs result in numerous adverse side effects. The lack of affordable therapy has necessitated the urgent development of new drugs that are efficacious, safe, and more accessible to patients. Natural products are a major source for the discovery of new and selective molecules for neglected diseases. In this paper, we evaluated the effect of apigenin on Leishmania amazonensis in vitro and in vivo and described the mechanism of action against intracellular amastigotes of L. amazonensis. Methodology/Principal Finding Apigenin reduced the infection index in a dose-dependent manner, with IC50 values of 4.3 μM and a selectivity index of 18.2. Apigenin induced ROS production in the L. amazonensis-infected macrophage, and the effects were reversed by NAC and GSH. Additionally, apigenin induced an increase in the number of macrophages autophagosomes after the infection, surrounding the parasitophorous vacuole, suggestive of the involvement of host autophagy probably due to ROS generation induced by apigenin. Furthermore, apigenin treatment was also effective in vivo, demonstrating oral bioavailability and reduced parasitic loads without altering serological toxicity markers. Conclusions/Significance In conclusion, our study suggests that apigenin exhibits leishmanicidal effects against L. amazonensis-infected macrophages. ROS production, as part of the mechanism of action, could occur through the increase in host autophagy and thereby promoting parasite death. Furthermore, our data suggest that apigenin is effective in the treatment of L. amazonensis-infected BALB/c mice by oral administration, without altering serological toxicity markers. The selective in vitro activity of apigenin, together with excellent theoretical predictions of oral availability, clear decreases in parasite load and lesion size, and no observed compromises to the overall health of the infected mice encourage us to supports further studies of apigenin as a candidate for the chemotherapeutic treatment of leishmaniasis. PMID:26862901

Bruxism and oral parafunctional hyperactivity in social phobia outpatients.

PubMed

Hermesh, H; Schapir, L; Marom, S; Skopski, R; Barnea, E; Weizman, A; Winocur, E

2015-02-01

Anxiety and selective serotonin reuptake inhibitors (SSRIs) are considered aggravating factors for bruxism. We examined the influence of anxiety, depression and SSRI on bruxism in social phobia (SP). Twenty-three drug naïve, 17 SSRI-treated SP patients and 33 healthy controls underwent a psychiatric assessment and completed Leibowitz Social Anxiety Scale and Beck Depression Inventory. Oral parafunctional activity (PF) was evaluated by TM-dental examination and by a questionnaire. Drug- naïve and SSRI-treated SP patients did not differ on demographic and clinical measures. Awake bruxism, 'JAW PLAY' and at least one PF were more prevalent in SP than in controls. Severity of SP predicted the presence of PF. SP, but not depression, was associated with higher risk of oral PF and awake bruxism. Chronic SSRI treatment of SP did not affect sleep and awake bruxism. Dental and anxiety screening may improve the prognosis psychiatric and dental patients. Effective treatment of SP may mitigate bruxism. © 2014 John Wiley & Sons Ltd.

Percutaneous Occlusion of the Left Atrial Appendage with the Watchman Device in an Active Duty Sailor with Atrial Fibrillation and Recurrent Thromboembolism Despite Appropriate Use of Oral Anticoagulation.

PubMed

Cox, Justin M; Choi, Anthony J; Oakley, Luke S; Francisco, Gregory M; Nayak, Keshav R

2018-05-23

Atrial fibrillation is the most common significant cardiac arrhythmia and is associated with a five-fold increased risk of stroke from thromboembolism. Over 94% of these emboli arise from the left atrial appendage. Systemic embolic phenomena are rare, accounting for less than 1 out of 10 of all embolic events, but have a similar prevention strategy. Anticoagulation significantly reduces the risk of these events, and thus forms the cornerstone of therapy for most patients with atrial fibrillation. Left atrial appendage occlusion with the Watchman device is a recently approved alternative for stroke prevention in selected patients. We present a case of an active duty U.S. Navy sailor at low risk for thromboembolism who nonetheless suffered recurrent thromboembolic events despite appropriate anticoagulation, and thus underwent Watchman implantation. The therapy in this case will ideally provide a lifetime of protection from recurrent systemic embolization while allowing the patient to continue his active duty military career without restriction due to oral anticoagulation.

Prevalence of oral candidiasis in HIV/AIDS children in highly active antiretroviral therapy era. A literature analysis.

PubMed

Gaitán-Cepeda, Luis Alberto; Sánchez-Vargas, Octavio; Castillo, Nydia

2015-08-01

SummaryHighly active antiretroviral therapy has decreased the morbidity and mortality related to HIV infection, including oral opportunistic infections. This paper offers an analysis of the scientific literature on the epidemiological aspects of oral candidiasis in HIV-positive children in the combination antiretroviral therapy era. An electronic databases search was made covering the highly active antiretroviral therapy era (1998 onwards). The terms used were oral lesions, oral candidiasis and their combination with highly active antiretroviral therapy and HIV/AIDS children. The following data were collected from each paper: year and country in which the investigation was conducted, antiretroviral treatment, oral candidiasis prevalence and diagnostic parameters (clinical or microbiological). Prevalence of oral candidiasis varied from 2.9% in American HIV-positive children undergoing highly active antiretroviral therapy to 88% in Chilean HIV-positive children without antiretroviral therapy. With respect to geographical location and antiretroviral treatment, higher oral candidiasis prevalence in HIV-positive children on combination antiretroviral therapy/antiretroviral therapy was reported in African children (79.1%) followed by 45.9% reported in Hindu children. In HIV-positive Chilean children on no antiretroviral therapy, high oral candidiasis prevalence was reported (88%) followed by Nigerian children (80%). Oral candidiasis is still frequent in HIV-positive children in the highly active antiretroviral therapy era irrespective of geographical location, race and use of antiretroviral therapy. © The Author(s) 2014.

Protease-activated receptor 2 modulates proliferation and invasion of oral squamous cell carcinoma cells.

PubMed

Al-Eryani, Kamal; Cheng, Jun; Abé, Tatsuya; Maruyama, Satoshi; Yamazaki, Manabu; Babkair, Hamzah; Essa, Ahmed; Saku, Takashi

2015-07-01

Based on our previous finding that protease-activated receptor 2 (PAR-2) regulates hemophagocytosis of oral squamous cell carcinoma (SCC) cells, which induces their heme oxygenase 1-dependent keratinization, we have formulated a hypothesis that PAR-2 functions in wider activities of SCC cells. To confirm this hypothesis, we investigated immunohistochemical profiles of PAR-2 in oral SCC tissues and its functional roles in cell proliferation and invasion in SCC cells in culture. The PAR-2 expression modes were determined in 48 surgical tissue specimens of oral SCC. Using oral SCC-derived cell systems, we determined both gene and protein expression levels of PAR-2. SCC cell proliferation and invasive properties were also examined in conditions in which PAR-2 was activated by the synthetic peptide SLIGRL. PAR-2 was immunolocalized in oral SCC and carcinoma in situ cells, especially in those on the periphery of carcinoma cell foci (100% of cases), but not in normal oral epithelia. Its expression at both gene and protein levels was confirmed in 3 oral SCC cell lines including ZK-1. Activation of PAR-2 induced ZK-1 cell proliferation in a dose-dependent manner. PAR-2-activated ZK-1 cells invaded faster than nonactivated ones. The expression of PAR-2 is specific to oral malignancies, and PAR-2 regulates the growth and invasion of oral SCC cells. Copyright © 2015 Elsevier Inc. All rights reserved.

Changes in the oral ecosystem induced by the use of 8% arginine toothpaste.

PubMed

Koopman, Jessica E; Hoogenkamp, Michel A; Buijs, Mark J; Brandt, Bernd W; Keijser, Bart J F; Crielaard, Wim; Ten Cate, Jacob M; Zaura, Egija

2017-01-01

Bacterial metabolism of arginine in the oral cavity has a pH-raising and thus, potential anti-caries effect. However, the influence of arginine on the oral microbial ecosystem remains largely unresolved. In this pilot study, nine healthy individuals used toothpaste containing 8% arginine for eight weeks. Saliva was collected to determine arginolytic potential and sucrose metabolic activity at the Baseline, Week 4, Week 8 and after a two weeks Wash-out period. To follow the effects on microbial ecology, 16S rDNA sequencing on saliva and plaque samples at Baseline and Week 8 and metagenome sequencing on selected saliva samples of the same time-points was performed. During the study period, the arginolytic potential of saliva increased, while the sucrose metabolism in saliva decreased. These effects were reversed during the Wash-out period. Although a few operational taxonomic units (OTUs) in plaque changed in abundance during the study period, there was no real shift in the plaque microbiome. In the saliva microbiome there was a significant compositional shift, specifically the genus Veillonella had increased significantly in abundance at Week 8. Indeed, the presence of arginine in toothpaste affects the arginolytic capacity of saliva and reduces its sucrose metabolic activity. Additionally, it leads to a shift in the salivary microbiome composition towards a healthy ecology from a caries point of view. Therefore, arginine can be regarded as a genuine oral prebiotic. Copyright © 2016 Elsevier Ltd. All rights reserved.

Oral rice-based vaccine induces passive and active immunity against enterotoxigenic E. coli-mediated diarrhea in pigs.

PubMed

Takeyama, Natsumi; Yuki, Yoshikazu; Tokuhara, Daisuke; Oroku, Kazuki; Mejima, Mio; Kurokawa, Shiho; Kuroda, Masaharu; Kodama, Toshiaki; Nagai, Shinya; Ueda, Susumu; Kiyono, Hiroshi

2015-09-22

Enterotoxigenic Escherichia coli (ETEC) causes severe diarrhea in both neonatal and weaned pigs. Because the cholera toxin B subunit (CTB) has a high level of amino acid identity to the ETEC heat-labile toxin (LT) B-subunit (LTB), we selected MucoRice-CTB as a vaccine candidate against ETEC-induced pig diarrhea. When pregnant sows were orally immunized with MucoRice-CTB, increased amounts of antigen-specific IgG and IgA were produced in their sera. CTB-specific IgG was secreted in the colostrum and transferred passively to the sera of suckling piglets. IgA antibodies in the colostrum and milk remained high with a booster dose after farrowing. Additionally, when weaned minipigs were orally immunized with MucoRice-CTB, production of CTB-specific intestinal SIgA, as well as systemic IgG and IgA, was induced. To evaluate the cross-protective effect of MucoRice-CTB against ETEC diarrhea, intestinal loop assay with ETEC was conducted. The fluid volume accumulated in the loops of minipigs immunized with MucoRice-CTB was significantly lower than that in control minipigs, indicating that MucoRice-CTB-induced cross-reactive immunity could protect weaned pigs from diarrhea caused by ETEC. MucoRice-CTB could be a candidate oral vaccine for inducing both passive and active immunity to protect both suckling and weaned piglets from ETEC diarrhea. Copyright © 2015 Elsevier Ltd. All rights reserved.

Highly Tissue Substructure-Specific Effects of Human Papilloma Virus in Mucosa of HIV-Infected Patients Revealed by Laser-Dissection Microscopy-Assisted Gene Expression Profiling

PubMed Central

Baumgarth, Nicole; Szubin, Richard; Dolganov, Greg M.; Watnik, Mitchell R.; Greenspan, Deborah; Da Costa, Maria; Palefsky, Joel M.; Jordan, Richard; Roederer, Mario; Greenspan, John S.

2004-01-01

Human papilloma virus (HPV) causes focal infections of epithelial layers in skin and mucosa. HIV-infected patients on highly active antiretroviral therapy (HAART) appear to be at increased risk of developing HPV-induced oral warts. To identify the mechanisms that allow long-term infection of oral epithelial cells in these patients, we used a combination of laser-dissection microscopy (LDM) and highly sensitive and quantitative, non-biased, two-step multiplex real-time RT-PCR to study pathogen-induced alterations of specific tissue subcompartments. Expression of 166 genes was compared in three distinct epithelial and subepithelial compartments isolated from biopsies of normal mucosa from HIV-infected and non-infected patients and of HPV32-induced oral warts from HIV-infected patients. In contrast to the underlying HIV infection and/or HAART, which did not significantly elaborate tissue substructure-specific effects, changes in oral warts were strongly tissue substructure-specific. HPV 32 seems to establish infection by selectively enhancing epithelial cell growth and differentiation in the stratum spinosum and to evade the immune system by actively suppressing inflammatory responses in adjacent underlying tissues. With this highly sensitive and quantitative method tissue-specific expression of hundreds of genes can be studied simultaneously in a few cells. Because of its large dynamic measurement range it could also become a method of choice to confirm and better quantify results obtained by microarray analysis. PMID:15331396

A Novel Self-Microemulsifying System for the Simultaneous Delivery and Enhanced Oral Absorption of Curcumin and Resveratrol.

PubMed

Jaisamut, Patcharawalai; Wiwattanawongsa, Kamonthip; Wiwattanapatapee, Ruedeekorn

2017-03-01

The use of curcumin and resveratrol in combination has now become increasingly of interest because of their synergistic effects as therapeutic agents for various diseases, especially cancer. To overcome the poor oral bioavailability of both compounds and improve patient compliance, a novel self-microemulsifying formulation containing curcumin together with resveratrol was developed. Capryol 90, Cremophor EL, and Labrasol were selected as the oil, surfactant, and co-surfactant in the formulation, respectively, based on the solubility study of both compounds. More than 70 % and 80 % of curcumin and resveratrol, respectively, were released in 20 min. The formulation formed a fine oil in water microemulsion with droplet sizes in aqueous media of 15-20 nm. In addition, the formulation containing curcumin and resveratrol showed greater antioxidant activity than that of the formulations with individual compounds, while the cytotoxic activity against HT-29 of the co-formulation (IC 50  = 18.25 µM; curcumin and resveratrol in the ratio 1 : 1) was less than the formulation with only curcumin (IC 50  = 30.1 µM) and only resveratrol (IC 50  = 25.4 µM). After oral administration to rabbits, the self-microemulsifying formulation containing curcumin together with resveratrol increased the total plasma concentrations of curcumin and resveratrol by 10-fold and 6-fold, respectively, compared to the unformulated combination. This study clearly demonstrated the potential use of the self-microemulsifying formulation for co-delivery, and enhanced oral absorption of poorly water-soluble natural compounds. In addition, the combination was found to produce synergistic antioxidant activity and cytotoxicity against HT-29 cells. Georg Thieme Verlag KG Stuttgart · New York.

Development, characterization, and in vivo assessment of mucoadhesive nanoparticles containing fluconazole for the local treatment of oral candidiasis.

PubMed

Rençber, Seda; Karavana, Sinem Yaprak; Yılmaz, Fethiye Ferda; Eraç, Bayri; Nenni, Merve; Özbal, Seda; Pekçetin, Çetin; Gurer-Orhan, Hande; Hoşgör-Limoncu, Mine; Güneri, Pelin; Ertan, Gökhan

2016-01-01

This study aimed to develop a suitable buccal mucoadhesive nanoparticle (NP) formulation containing fluconazole for the local treatment of oral candidiasis. The suitability of the prepared formulations was assessed by means of particle size (PS), polydispersity index, and zeta potential measurements, morphology analysis, mucoadhesion studies, drug entrapment efficiency (EE), in vitro drug release, and stability studies. Based on the optimum NP formulation, ex vivo drug diffusion and in vitro cytotoxicity studies were performed. Besides, evaluation of the antifungal effect of the optimum formulation was evaluated using agar diffusion method, fungicidal activity-related in vitro release study, and time-dependent fungicidal activity. The effect of the optimum NP formulation on the healing of oral candidiasis was investigated in an animal model, which was employed for the first time in this study. The zeta potential, mucoadhesion, and in vitro drug release studies of various NP formulations revealed that chitosan-coated NP formulation containing EUDRAGIT(®) RS 2.5% had superior properties than other formulations. Concerning the stability study of the selected formulation, the formulation was found to be stable for 6 months. During the ex vivo drug diffusion study, no drug was found in receptor phase, and this is an indication of local effect. The in vitro antifungal activity studies showed the in vitro efficacy of the NP against Candida albicans for an extended period. Also, the formulation had no cytotoxic effect at the tested concentration. For the in vivo experiments, infected rabbits were successfully treated with local administration of the optimum NP formulation once a day. This study has shown that the mucoadhesive NP formulation containing fluconazole is a promising candidate with once-a-day application for the local treatment of oral candidiasis.

Analysis of subsequent publication of scientific orally presented abstracts of the French National Congress of Radiology. Part II: Focus on the French abstracts.

PubMed

Dangouloff-Ros, V; Ronot, M; Lagadec, M; Vilgrain, V

2015-05-01

To evaluate the publication rate of scientific abstracts that were presented orally at the 2008, 2009, and 2010 annual meetings of the French Society of Radiology by French radiologists, and to perform a French regional analysis. Orally presented abstracts were identified by examining online abstract books of the 2008, 2009, and 2010 annual meetings of the French Society of Radiology, and cross-checked by reviewing the paper version of abstracts for the same period. Only abstracts from French teams were selected. The administrative region of submission was noted for each abstract and for each region the total population, the number of active radiologists, the number of active members of the French Society of Radiology and the number of academic radiologists were noted. Imaging subspecialties were also noted. 625 abstracts were identified resulting in 268 publications (publication rate: 43%). The median number of presentations and publications per region was 18 (range: 1-255) and 7 (range: 0-101), respectively. The ratio per million inhabitants was 7.5 and 3 respectively. The median number of presentations and publications per 100 active radiologists (respectively members of the FSR) was 7 and 3 (respectively 10 and 4). The median number of presentations and publications per academic radiologist were 2.6, and 1.2, respectively. The regional variations for each indicator were high (40-180%). Three subspecialties had a publication rate of more than 50%: thoracic imaging (58%), abdominal imaging (52%), and genitourinary imaging (51%). The publication rate of orally presented French scientific abstracts was high, with important variations according to the regions of origin and imaging subspecialties. Copyright © 2015 Éditions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

Design, synthesis, and pharmacological evaluation of a novel series of hormone sensitive lipase inhibitor.

PubMed

Ogiyama, Tomoko; Yamaguchi, Mitsuhiro; Kurikawa, Nobuya; Honzumi, Shoko; Terayama, Koji; Nagaoka, Nobumi; Yamamoto, Yuka; Kimura, Takako; Sugiyama, Daisuke; Inoue, Shin-Ichi

2017-09-01

HSL inhibition is a promising approach to the treatment of dyslipidemia. As a result of re-optimization of lead compound 2, we identified novel compound 25a exhibiting potent inhibitory activity against HSL enzyme and cell with high selectivity for cholinesterases (AChE and BuChE). Reflecting its potent in vitro activity, compound 25a exhibited antilipolytic effect in rats at 1mg/kg p.o., which indicated that this novel compound is the most potent orally active HSL inhibitor. Moreover, compound 25a did not show bioactivation liability. Copyright © 2017 Elsevier Ltd. All rights reserved.

The turnover of estrogen receptor α by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy

PubMed Central

Wardell, Suzanne E.; Marks, Jeffrey R.; McDonnell, Donald P.

2011-01-01

It has become apparent of late that even in tamoxifen and/or aromatase resistant breast cancers, ERα remains a bona fide therapeutic target. Not surprisingly, therefore, there has been considerable interest in developing Selective ER Degraders (SERDs), compounds that target the receptor for degradation. Currently, ICI 182,780 (ICI, fulvestrant) is the only SERD approved for the treatment of breast cancer. However, the poor pharmaceutical properties of this injectable drug and its lack of superiority over second line aromatase inhibitors in late stage breast cancer have negatively impacted its clinical use. These findings have provided the impetus to develop second generation, orally bioavailable SERDs with which quantitative turnover of ERα in tumors can be achieved. Interestingly however, the contribution of SERD activity to fulvestrant efficacy is unclear, making it difficult to define the characteristics desired of the next generation of ER antagonists. It is of significance therefore, that we have determined that the antagonist activity of ICI and its ability to induce ERα degradation are not coupled processes. Specifically, our results indicate that it is the ability of ICI to interact with ERα and to (a) competitively displace estradiol and (b) induce a conformational change in ER incompatible with transcriptional activation that are likely to be the most important pharmacological characteristics of this drug. Collectively, these data argue for a renewed emphasis on the development of high affinity, orally bioavailable pure antagonists and suggest that SERD activity though proven effective may not be required for ERα antagonism in breast cancer. PMID:21501600

Study on the diuretic activity of Euphorbia fusiformis Buch.-Ham. in albino rats.

PubMed

Ashok, B K; Bhat, Savitha D; Shukla, V J; Ravishankar, B

2011-07-01

The present study was undertaken to evaluate diuretic activity of Euphorbia fusiformis root powder in Wistar strain albino rats. Randomly selected animals were divided into three groups of six animals each. The root powder was suspended in distilled water and administered orally at a dose of 90 mg/kg therapeutically equivalent dose (TED) and 180 mg/kg (TED × 02) to overnight fasted rats. The diuretic activity was evaluated by determination of urine volume and urinary electrolyte concentrations. Test drug showed significant increase in urine volume and urinary electrolyte excretion in a dose-dependant manner. Thus, from this study, it can be concluded that roots of E. fusiformis possess diuretic activity.

A scoping review of skills and tools oral health professionals need to engage children and parents in dietary changes to prevent childhood obesity and consumption of sugar-sweetened beverages.

PubMed

Mallonee, Lisa F; Boyd, Linda D; Stegeman, Cynthia

2017-06-01

Increased consumption of sugar-sweetened beverages (SSBs) has been linked to obesity. Obesity now affects one in six children in the United States. The purpose of this scoping review is to identify and review published studies that discuss skills and tools oral health professionals can use with children (under age 12) and their parents to encourage dietary changes to aid in preventing childhood obesity and reducing consumption of SSBs. Key search terms were identified and used to examine selected databases via PubMed, EMBASE, CINAHL, and Cochrane Database of Systematic Reviews. A total of 637 records were identified. After duplicates were removed and records were screened for eligibility, 33 remained. Six met established inclusion/exclusion criteria and were included in the review. Only two full-text articles included dental-office-based weight interventions. Patient response to education on healthy habits and weight maintenance in the dental setting was favorable. Literature supports oral health professionals expanding their role in health care delivery by offering nutrition and physical activity recommendations to prevent and/or reduce chronic disease. Active listening and motivational interviewing were techniques identified to promote beneficial lifestyle changes. There is limited research on behavior modification tools and skills that have been effectively implemented in the dental setting to decrease risk of obesity. Oral health professionals are uniquely positioned to address consumption of SSBs and promote positive dietary habits for improved weight management. Future studies are needed to identify effective techniques that techniques that oral health professionals can integrate into preventive patient care. © 2017 American Association of Public Health Dentistry.

Persistence of the Oral Probiotic Streptococcus salivarius M18 Is Dose Dependent and Megaplasmid Transfer Can Augment Their Bacteriocin Production and Adhesion Characteristics

PubMed Central

Burton, Jeremy P.; Wescombe, Philip A.; Macklaim, Jean M.; Chai, Melissa H. C.; MacDonald, Kyle; Hale, John D. F.; Tagg, John; Reid, Gregor; Gloor, Gregory B.; Cadieux, Peter A.

2013-01-01

Bacteriocin-producing probiotic Streptococcus salivarius M18 offers beneficial modulatory capabilities within the oral microbiome, apparently through potent inhibitory activity against potentially deleterious bacteria, such as Streptococcus pyogenes. The oral cavity persistence of S. salivarius M18 was investigated in 75 subjects receiving four different doses for 28 days. Sixty per cent of the subjects already had some inhibitor-producing S. salivarius in their saliva prior to probiotic intervention. Strain M18’s persistence was dependent upon the dose, but not the period of administration. Culture analysis indicated that in some individuals the introduced strain had almost entirely replaced the indigenous S. salivarius, though the total numbers of the species did not increase. Selected subjects showing either high or low probiotic persistence had their salivary populations profiled using Illumina sequencing of the V6 region of the 16S rRNA gene. Analysis indicated that while certain bacterial phenotypes were markedly modulated, the overall composition of the oral microbiome was not modified by the probiotic treatment. Megaplasmids encoding bacteriocins and adhesion factors were transferred in vitro to generate a transconjugant S. salivarius exhibiting enhanced antimicrobial production and binding capabilities to HEp-2 cells. Since no widespread perturbation of the existing indigenous microbiota was associated with oral instillation and given its antimicrobial activity against potentially pathogenic streptococci, it appears that application of probiotic strain M18 offers potential low impact alternative to classical antibiotic prophylaxis. For candidate probiotic strains having relatively poor antimicrobial or adhesive properties, unique derivatives displaying improved probiotic performance may be engineered in vitro by megaplasmid transfer. PMID:23785463

Persistence of the oral probiotic Streptococcus salivarius M18 is dose dependent and megaplasmid transfer can augment their bacteriocin production and adhesion characteristics.

PubMed

Burton, Jeremy P; Wescombe, Philip A; Macklaim, Jean M; Chai, Melissa H C; Macdonald, Kyle; Hale, John D F; Tagg, John; Reid, Gregor; Gloor, Gregory B; Cadieux, Peter A

2013-01-01

Bacteriocin-producing probiotic Streptococcus salivarius M18 offers beneficial modulatory capabilities within the oral microbiome, apparently through potent inhibitory activity against potentially deleterious bacteria, such as Streptococcus pyogenes. The oral cavity persistence of S. salivarius M18 was investigated in 75 subjects receiving four different doses for 28 days. Sixty per cent of the subjects already had some inhibitor-producing S. salivarius in their saliva prior to probiotic intervention. Strain M18's persistence was dependent upon the dose, but not the period of administration. Culture analysis indicated that in some individuals the introduced strain had almost entirely replaced the indigenous S. salivarius, though the total numbers of the species did not increase. Selected subjects showing either high or low probiotic persistence had their salivary populations profiled using Illumina sequencing of the V6 region of the 16S rRNA gene. Analysis indicated that while certain bacterial phenotypes were markedly modulated, the overall composition of the oral microbiome was not modified by the probiotic treatment. Megaplasmids encoding bacteriocins and adhesion factors were transferred in vitro to generate a transconjugant S. salivarius exhibiting enhanced antimicrobial production and binding capabilities to HEp-2 cells. Since no widespread perturbation of the existing indigenous microbiota was associated with oral instillation and given its antimicrobial activity against potentially pathogenic streptococci, it appears that application of probiotic strain M18 offers potential low impact alternative to classical antibiotic prophylaxis. For candidate probiotic strains having relatively poor antimicrobial or adhesive properties, unique derivatives displaying improved probiotic performance may be engineered in vitro by megaplasmid transfer.

Metabolism and urinary disposition of N,N-dimethyltryptamine after oral and smoked administration: a comparative study.

PubMed

Riba, Jordi; McIlhenny, Ethan H; Bouso, José Carlos; Barker, Steven A

2015-05-01

N,N-dimethyltryptamine (DMT) is a widely distributed plant alkaloid that displays partial agonist activity at the 5-HT2A receptor and induces intense psychedelic effects in humans when administered parenterally. However, self-administration studies have reported a total lack of activity following oral intake. This is thought to be due to extensive degradation by monoamine oxidase (MAO). Despite increased use of DMT and DMT-containing preparations, such as the plant tea ayahuasca, the biotransformation of DMT in humans when administered alone is relatively unknown. Here we used high performance liquid chromatography (HPLC)/electrospray ionization (ESI)/selected reaction monitoring (SRM)/tandem mass spectrometry (MS/MS) to characterize the metabolism and disposition of oral and smoked DMT. Twenty-four-hour urine samples were obtained from 6 DMT users before and after intake of 25 mg DMT doses on two separate sessions. In one session, DMT was taken orally and in another it was smoked. After oral ingestion, no psychotropic effects were experienced and no DMT was recovered in urine. MAO-dependent indole-3-acetic acid (IAA) represented 97% of the recovered compounds, whereas DMT-N-oxide (DMT-NO) accounted for only 3%. When the smoked route was used, the drug was fully psychoactive, unmetabolized DMT and DMT-NO rose to 10% and 28%, respectively, and IAA levels dropped to 63%. An inverse correlation was found between the IAA/DMT-NO ratio and subjective effects scores. These findings show that in the smoked route a shift from the highly efficient MAO-dependent to the less efficient CYP-dependent metabolism takes place. This shift leads to psychoactivity and is analogous to that observed in ayahuasca preparations combining DMT with MAO inhibitors. Copyright © 2014 John Wiley & Sons, Ltd.

Abrus agglutinin promotes irreparable DNA damage by triggering ROS generation followed by ATM-p73 mediated apoptosis in oral squamous cell carcinoma.

PubMed

Sinha, Niharika; Panda, Prashanta K; Naik, Prajna P; Das, Durgesh N; Mukhopadhyay, Subhadip; Maiti, Tapas K; Shanmugam, Muthu K; Chinnathambi, Arunachalam; Zayed, M E; Alharbi, Sulaiman A; Sethi, Gautam; Agarwal, Rajesh; Bhutia, Sujit K

2017-11-01

Oral cancer, a type of head and neck cancer, is ranked as one of the top most malignancies in India. Herein, we evaluated the anticancer efficacy of Abrus agglutinin (AGG), a plant lectin, in oral squamous cell carcinoma. AGG selectively inhibited cell growth, and caused cell cycle arrest and mitochondrial apoptosis through a reactive oxygen species (ROS)-mediated ATM-p73 dependent pathway in FaDu cells. AGG-induced ROS accumulation was identified as the major mechanism regulating apoptosis, DNA damage and DNA-damage response, which were significantly reversed by ROS scavenger N-acetylcysteine (NAC). Moreover, AGG was found to interact with mitochondrial manganese-dependent superoxide dismutase that might inhibit its activity and increase ROS in FaDu cells. In oral cancer p53 is mutated, thus we focused on p73; AGG resulted in p73 upregulation and knock down of p73 caused a decrease in AGG-induced apoptosis. Interestingly, AGG-dependent p73 expression was found to be regulated by ROS, which was reversed by NAC treatment. A reduction in the level of p73 in AGG-treated shATM cells was found to be associated with a decreased apoptosis. Moreover, administration of AGG (50 μg/kg body weight) significantly inhibited the growth of FaDu xenografts in athymic nude mice. In immunohistochemical analysis, the xenografts from AGG-treated mice displayed a decrease in PCNA expression and an increase in caspase-3 activation as compared to the controls. In conclusion, we established a connection among ROS, ATM and p73 in AGG-induced apoptosis, which might be useful in enhancing the therapeutic targeting of p53 deficient oral squamous cell carcinoma. © 2017 Wiley Periodicals, Inc.

Oral cancer prognosis based on clinicopathologic and genomic markers using a hybrid of feature selection and machine learning methods

PubMed Central

2013-01-01

Background Machine learning techniques are becoming useful as an alternative approach to conventional medical diagnosis or prognosis as they are good for handling noisy and incomplete data, and significant results can be attained despite a small sample size. Traditionally, clinicians make prognostic decisions based on clinicopathologic markers. However, it is not easy for the most skilful clinician to come out with an accurate prognosis by using these markers alone. Thus, there is a need to use genomic markers to improve the accuracy of prognosis. The main aim of this research is to apply a hybrid of feature selection and machine learning methods in oral cancer prognosis based on the parameters of the correlation of clinicopathologic and genomic markers. Results In the first stage of this research, five feature selection methods have been proposed and experimented on the oral cancer prognosis dataset. In the second stage, the model with the features selected from each feature selection methods are tested on the proposed classifiers. Four types of classifiers are chosen; these are namely, ANFIS, artificial neural network, support vector machine and logistic regression. A k-fold cross-validation is implemented on all types of classifiers due to the small sample size. The hybrid model of ReliefF-GA-ANFIS with 3-input features of drink, invasion and p63 achieved the best accuracy (accuracy = 93.81%; AUC = 0.90) for the oral cancer prognosis. Conclusions The results revealed that the prognosis is superior with the presence of both clinicopathologic and genomic markers. The selected features can be investigated further to validate the potential of becoming as significant prognostic signature in the oral cancer studies. PMID:23725313

Discovery of 5-Chloro-1-(5-chloro-2-(methylsulfonyl)benzyl)-2-imino-1,2-dihydropyridine-3-carboxamide (TAK-259) as a Novel, Selective, and Orally Active α1D Adrenoceptor Antagonist with Antiurinary Frequency Effects: Reducing Human Ether-a-go-go-Related Gene (hERG) Liabilities.

PubMed

Sakauchi, Nobuki; Kohara, Yasuhisa; Sato, Ayumu; Suzaki, Tomohiko; Imai, Yumi; Okabe, Yuichi; Imai, Shigemitsu; Saikawa, Reiko; Nagabukuro, Hiroshi; Kuno, Haruhiko; Fujita, Hisashi; Kamo, Izumi; Yoshida, Masato

2016-04-14

A novel structural class of iminopyridine derivative 1 was identified as a potent and selective human α1D adrenoceptor (α1D adrenergic receptor; α1D-AR) antagonist against α1A- and α1B-AR through screening of an in-house compound library. From initial structure-activity relationship studies, we found lead compound 9m with hERG K(+) channel liability. To develop analogues with reduced hERG K(+) channel inhibition, a combination of site-directed mutagenesis and docking studies was employed. Further optimization led to the discovery of (R)-9s and 9u, which showed antagonistic activity by a bladder strip test in rats with bladder outlet obstruction, as well as ameliorated cystitis-induced urinary frequency in rats. Ultimately, 9u was selected as a clinical candidate. This is the first study to show the utility of iminopyridine derivatives as selective α1D-AR antagonists and evaluate their effects in vivo.

Contemporary developments in the discovery of selective factor Xa inhibitors: A review.

PubMed

Patel, Nirav R; Patel, Dushyant V; Murumkar, Prashant R; Yadav, Mange Ram

2016-10-04

Thrombosis is a leading cause of death in cardiovascular diseases such as myocardial infarction (MI), unstable angina and acute coronary syndrome (ACS) in the industrialized world. Venous thromboembolism is observed in about 1 million people every year in United States causing significant morbidity and mortality. Conventional antithrombotic therapy has been reported to have several disadvantages and limitations like inconvenience in oral administration, bleeding risks (heparin analogs), narrow therapeutic window and undesirable interactions with food and drugs (vitamin K antagonist-warfarin). The unmet medical demand for orally active safe anticoagulants has generated widespread interest among the medicinal chemists engaged in this field. To modulate blood coagulation, various enzymes involved in the coagulation process have received great attention as potential targets by various research groups for the development of oral anticoagulants. Among these enzymes, factor Xa (FXa) has remained the centre of attention in the last decade. Intensive research efforts have been made by various research groups for the development of small, safe and orally bioavailable FXa inhibitors. This review is an attempt to compile the research work of various researchers in the direction of development of FXa inhibitors reported since 2010 onward. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Development and application of bio-sample quantification to evaluate stability and pharmacokinetics of inulin-type fructo-oligosaccharides from Morinda Officinalis.

PubMed

Chi, Liandi; Chen, Lingxiao; Zhang, Jiwen; Zhao, Jing; Li, Shaoping; Zheng, Ying

2018-07-15

Inulin-type fructooligosaccharides (FOS) purified from Morinda Officinalis, with degrees of polymerization (DP) from 3 to 9, have been approved in China as an oral prescribed drug for mild and moderate depression episode, while the stability and oral absorption of this FOS mixtures are largely unknown. As the main active component and quality control marker for above FOS, DP5 was selected as the representative FOS in this study. Desalting method by ion exchange resin was developed to treat bio-sample, followed by separation and quantification by high performance liquid chromatography-charged aerosol detector. Results showed that the DP5 was stepwisely hydrolyzed in simulated gastric fluid and gut microbiota, while maintained stable in intestinal fluid. DP5 has poor permeability across Caco-2 monolayer with P app of 5.22 × 10 -7  cm/s, and very poor oral absorption with bioavailability of (0.50 ± 0.12)% in rat. In conclusion, FOS in Morinda Officinalis demonstrated poor chemical stability in simulated gastric fluid and human gut microbiota, and low oral absorption in rats. Copyright © 2018 Elsevier B.V. All rights reserved.

Amixicile, a novel strategy for targeting oral anaerobic pathogens.

PubMed

Hutcherson, Justin A; Sinclair, Kathryn M; Belvin, Benjamin R; Gui, Qin; Hoffman, Paul S; Lewis, Janina P

2017-09-05

The oral microflora is composed of both health-promoting as well as disease-initiating bacteria. Many of the disease-initiating bacteria are anaerobic and include organisms such as Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, and Tannerella forsythia. Here we investigated a novel therapeutic, amixicile, that targets pyruvate:ferredoxin oxidoreductase (PFOR), a major metabolic enzyme involved in energy generation through oxidative decarboxylation of pyruvate. PFOR is present in these anaerobic pathogenic bacteria and thus we hypothesized that amixicile would effectively inhibit their growth. In general, PFOR is present in all obligate anaerobic bacteria, while oral commensal aerobes, including aerotolerant ones, such as Streptococcus gordonii, use pyruvate dehydrogenase to decarboxylate pyruvate. Accordingly, we observed that growth of the PFOR-containing anaerobic periodontal pathogens, grown in both monospecies as well as multispecies broth cultures was inhibited in a dose-dependent manner while that of S. gordonii was unaffected. Furthermore, we also show that amixicile is effective against these pathogens grown as monospecies and multispecies biofilms. Finally, amixicile is the first selective therapeutic agent active against bacteria internalized by host cells. Together, the results show that amixicile is an effective inhibitor of oral anaerobic bacteria and as such, is a good candidate for treatment of periodontal diseases.

A selective androgen receptor modulator with minimal prostate hypertrophic activity restores lean body mass in aged orchidectomized male rats.

PubMed

Allan, George; Sbriscia, Tifanie; Linton, Olivia; Lai, Muh-Tsann; Haynes-Johnson, Donna; Bhattacharjee, Sheela; Ng, Raymond; Sui, Zhihua; Lundeen, Scott

2008-06-01

Androgens are required for the maintenance of normal sexual activity in adulthood and for enhancing muscle growth and lean body mass in adolescents and adults. Androgen receptor (AR) ligands with tissue selectivity (selective androgen receptor modulators, or SARMs) have potential for treating muscle wasting, hypogonadism of aging, osteoporosis, female sexual dysfunction, and other indications. JNJ-37654032 is a nonsteroidal AR ligand with mixed agonist and antagonist activity in androgen-responsive cell-based assays. It is an orally active SARM with muscle selectivity in orchidectomized rat models. It stimulated growth of the levator ani muscle with ED(50) 0.8 mg/kg, stimulating maximal growth at a dose of 3mg/kg. In contrast, it stimulated ventral prostate growth to 21% of its full size at 3mg/kg. At the same time, JNJ-37654032 reduced prostate weight in intact rats by 47% at 3mg/kg, while having no inhibitory effect on muscle. Using magnetic resonance imaging to monitor body composition, JNJ-37654032 restored about 20% of the lean body mass lost following orchidectomy in aged rats. JNJ-37654032 reduced follicle-stimulating hormone levels in orchidectomized rats and reduced testis size in intact rats. JNJ-37654032 is a potent prostate-sparing SARM with the potential for clinical benefit in muscle-wasting diseases.

A selective androgen receptor modulator with minimal prostate hypertrophic activity enhances lean body mass in male rats and stimulates sexual behavior in female rats.

PubMed

Allan, George F; Tannenbaum, Pamela; Sbriscia, Tifanie; Linton, Olivia; Lai, Muh-Tsann; Haynes-Johnson, Donna; Bhattacharjee, Sheela; Zhang, Xuqing; Sui, Zhihua; Lundeen, Scott G

2007-08-01

Androgen receptor (AR) ligands with tissue selectivity (selective androgen receptor modulators, or SARMs) have potential for treating muscle wasting, hypogonadism of aging, osteoporosis, female sexual dysfunction, and other indications. JNJ-28330835 is a nonsteroidal AR ligand with mixed agonist and antagonist activity in androgen-responsive cell-based assays. It is an orally active SARM with muscle selectivity in orchidectomized rat models. It stimulated growth of the levator ani muscle, stimulating maximal growth at a dose of 10 mg/kg. At the same time, JNJ-28330835 reduced prostate weight in intact rats by a mean of 30% at 10 mg/kg, while having no inhibitory effect on muscle. Using magnetic resonance imaging (MRI) to monitor body composition, it prevented half of the loss of lean body mass associated with orchidectomy, and restored about 30% of lost lean mass to aged orchidectomized rats. It had agonist effects on markers of both osteoclast and osteoblast activity, suggesting that it reduces bone turnover. In a model of sexual behavior, JNJ-28330835 enhanced the preference of ovariectomized female rats for sexually intact male rats over nonsexual orchidectomized males. JNJ-28330835 is a prostate-sparing SARM with the potential for clinically beneficial effects in muscle-wasting diseases and sexual function disorders.

Survey of faculty educator development award recipients.

PubMed

Aziz, Shahid R; Ziccardi, Vincent B

2011-01-01

Since 2002, the American Association of Oral and Maxillofacial Surgeons and the Oral and Maxillofacial Surgery Foundation have annually awarded the Faculty Educator Development Award (FEDA) to select junior full-time oral and maxillofacial surgery faculty. To date, 33 individuals have received this award. The purpose of this study was to evaluate the FEDA's impact on the recipients' career and assess the FEDA's strengths and weaknesses from the perspective of the recipients. A complete list of FEDA recipients was obtained from the American Association of Oral and Maxillofacial Surgeons, to whom a 19-question survey was electronically mailed for completion. Twenty-two of the 33 surveys were completed and returned. Strengths of the FEDA included encouraging faculty recruitment and retention and financial support. Weaknesses included unknown selection criteria for the FEDA, unknown FEDA selection committee, and that the financial component of the award was available for only 3 of the 6 years of the FEDA requirement. Although there are some weaknesses in the FEDA, it is the only award of its kind available to the specialty of oral and maxillofacial surgery. As such, consideration should be given to expanding the number of awards given and increasing the amount of the award. In addition, academic oral and maxillofacial surgery needs to improve its recruitment and retention of junior surgical faculty to ensure the continued viability of the specialty and training programs. Suggestions for improvement are discussed. Copyright © 2011 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Opportunities and challenges to promoting oral health in primary schools.

PubMed

Gill, P; Chestnutt, I G; Channing, D

2009-09-01

Inequalities in oral health in areas of socio-economic disadvantage are well recognised. As children spend a considerable proportion of their lives in education, schools can play a significant role in promoting children's health and oral health. However, to what extent schools are able to do this is unclear. The aim of this study was therefore to investigate opportunities and challenges to promoting oral health in primary schools. A purposive sample of 20 primary schools from socially and economically disadvantaged areas of Cardiff, UK were selected to participate in this qualitative study. Data were collected through semi-structured interviews conducted with head teachers or their nominated deputies. General awareness of health and oral health was good, with all schools promoting the consumption of fruit, water and milk and discouraging products such as carbonated drinks and confectionaries. Health promotion schemes wereimplemented primarily to improve the health of the children, although schools felt they also offered the potential to improve classroom behaviour and attendance. However, oral health was viewed as a separate entity to general health and perceived to be inadequately promoted. Successful health promotion schemes were also influenced by the attitudes of headteachers. Most schools had no or limited links with local dental services and, or oral health educators, although such input, when it occurred, was welcomed and highly valued. Knowledge of how to handle dental emergencies was limited and only two schools operated toothbrushing schemes, although all expressed an interest in such programmes. This study identified a positive predisposition to promoting health in primary schools. The challenge for the dental team, however, is to promote and integrate oral health into mainstream health promotion activities in schools. The paper also makes recommendations for further research.

Induction of protective immune responses against challenge of Actinobacillus pleuropneumoniae by oral administration with Saccharomyces cerevisiae expressing Apx toxins in pigs.

PubMed

Shin, Min-Kyoung; Kang, Mi Lan; Jung, Myung Hwan; Cha, Seung-Bin; Lee, Won-Jung; Kim, Jung-Mi; Kim, Dae-Hyuk; Yoo, Han Sang

2013-01-15

Actinobacillus pleuropneumoniae is a causative agent of porcine pleuropneumonia, a highly contagious endemic disease of pigs worldwide, inducing significant economic losses worldwide. Apx toxins, which are correlated with the virulence of A. pleuropneumoniae, were expressed in Saccharomyces cerevisiae and its possible use as an oral vaccine has been confirmed in our previous studies using a murine model. The present study was undertaken to test the hypothesis that oral immunization using S. cerevisiae expressing either ApxI or ApxII could protect pigs against A. pleuropneumoniae as an effective way of inducing both mucosal and systemic immune responses. The surface-displayed ApxIIA#5 expressing S. cerevisiae was selected as an oral vaccine candidate by finding on induction of higher immune responses in mice after oral vaccination. The surface-displayed ApxIIA#5 expressing S. cerevisiae and the ApxIA expressing S. cerevisiae were developed to serve as an oral vaccine in pigs. The vaccinated pigs showed higher specific IgG- and IgA-related antibody activities than the non-treated control and vector control pigs. Additionally, the induced immune responses were found to protect pigs infected with A. pleuropneumoniae according to the analysis of clinical signs and the gross and microscopic pulmonary lesions. These results suggested that the surface-displayed ApxIIA#5 and ApxIA in S. cerevisiae might be a potential oral vaccine to protect pigs against porcine pleuropneumonia. Thus the present study is expected to contribute to the development of a live oral vaccine against porcine pleuropneumonia as an alternative to current conventional vaccines. Copyright © 2012 Elsevier B.V. All rights reserved.

Extracellular Ca(2+)-dependent enhancement of cytocidal potency of zoledronic acid in human oral cancer cells.

PubMed

Inoue, Sayaka; Arai, Naoya; Tomihara, Kei; Takashina, Michinori; Hattori, Yuichi; Noguchi, Makoto

2015-08-15

Direct antitumor effects of bisphosphonates (BPs) have been demonstrated in various cancer cells in vitro. However, the effective concentrations of BPs are typically much higher than their clinically relevant concentrations. Oral cancers frequently invade jawbone and may lead to the release of Ca(2+) in primary lesions. We investigated the effects of the combined application of zoledronic acid (ZA) and Ca(2+) on proliferation and apoptosis of oral cancer cells. Human oral cancer cells, breast cancer cells, and colon cancer cells were treated with ZA at a wide range of concentrations in different Ca(2+) concentration environments. Under a standard Ca(2+) concentration (0.6mM), micromolar concentrations of ZA were required to inhibit oral cancer cell proliferation. Increasing extracellular Ca(2+) concentrations greatly enhanced the potency of the ZA cytocidal effect. The ability of Ca(2+) to enhance the cytocidal effects of ZA was negated by the Ca(2+)-selective chelator EGTA. In contrast, the cytocidal effect of ZA was less pronounced in breast and colon cancer cells regardless of whether extracellular Ca(2+) was elevated. In oral cancer cells incubated with 1.6mM Ca(2+), ZA up-regulated mitochondrial Bax expression and increased mitochondrial Ca(2+) uptake. This was associated with decreased mitochondrial membrane potential and increased release of cytochrome c. We suggest that ZA can specifically produce potent cytocidal activity in oral cancer cells in an extracellular Ca(2+)-dependent manner, implying that BPs may be useful for treatment of oral squamous cell carcinoma with jawbone invasion leading to the hypercalcemic state. Copyright © 2015 Elsevier B.V. All rights reserved.

Evaluation of an acute oral gavage method for assessment of pesticide toxicity in terrestrial amphibians.

PubMed

Fort, Douglas J; Mathis, Michael B; Kee, Faith; Whatling, Paul; Clerkin, David; Staveley, Jane; Habig, Clifford

2018-02-01

Development of an acute oral toxicity test with a terrestrial-phase amphibian was considered necessary to remove the uncertainty within the field of agrochemical risk assessments. The bullfrog (Lithobates catesbeianus) was selected for use as it is a representative of the family Ranidae and historically this species has been used as an amphibian test model species. Prior to definitive study, oral gavage methods were developed with fenthion and tetraethyl pyrophosphate. Dimethoate and malathion were subsequently tested with both male and female juvenile bullfrogs in comprehensive acute oral median lethal dose (LD50) studies. Juvenile bullfrogs were administered a single dose of the test article via oral gavage of a single gelatin capsule of dimethoate technical (dimethoate) or neat liquid Fyfanon ® Technical (synonym malathion), returned to their respective aquaria, and monitored for survival for 14 d. The primary endpoint was mortality, whereas behavioral responses, food consumption, body weight, and snout-vent length (SVL) were used to evaluate indications of sublethal toxicity (secondary endpoints). Acute oral LD50 values (95% fiducial interval) for dimethoate were 1459 (1176-1810, males) and 1528 (1275-1831, females), and for malathion they were 1829 (1480-2259, males) and 1672 (1280-2183, females) mg active substance/kg body weight, respectively. Based on the results of these studies, the methodology for the acute oral gavage administration of test items to terrestrial-phase amphibians was demonstrated as being a practical method of providing data for risk assessments. Environ Toxicol Chem 2018;37:436-450. © 2017 SETAC. © 2017 SETAC.

Evaluation of the specificity and effectiveness of selected oral hygiene actives in salivary biofilm microcosms.

PubMed

Ledder, Ruth G; Sreenivasan, Prem K; DeVizio, William; McBain, Andrew J

2010-12-01

The microbiological effects of biocidal products used for the enhancement of oral hygiene relate to the active compound(s) as well as other formulation components. Here, we test the specificities of selected actives in the absence of multiple excipients. Salivary ecosystems were maintained in tissue culture plate-based hydroxyapatite disc models (HDMs) and modified drip-flow biofilm reactors (MDFRs). Test compounds stannous fluoride (SF), SDS, triclosan (TCS), zinc lactate (ZL) and ZL with SF in combination (ZLSF) were delivered to the HDMs once and four times daily for 6 days to MDFRs. Plaques were characterized by differential viable counting and PCR-denaturing gradient gel electrophoresis (DGGE). TCS and SDS were the most effective compounds against HDM plaques, significantly reducing total viable counts (P<0.05), whilst SF, ZL and ZLSF were comparatively ineffective. TCS exhibited specificity for streptococci (P<0.01) and Gram-negative anaerobes (P<0.01) following a single dosing and also on repeated dosing in MDFRs. In contrast to single exposures, multiple dosing with ZLSF also significantly reduced all bacterial groups, whilst SF and ZL caused significant but transient reductions. According to PCR-DGGE analyses, significant (P<0.05) reductions in eubacterial diversity occurred following 6 day dosing with both TCS and ZLSF. Concordance of MDFR eubacterial profiles with salivary inocula ranged between 58 and 97%. TCS and ZL(SF) exhibited similar specificities to those reported for formulations. TCS was the most potent antibacterial, after single and multiple dosage regimens.

Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor α Activation.

PubMed

Benoit, Thibaut; Valera, Marie-Cecile; Fontaine, Coralie; Buscato, Melissa; Lenfant, Francoise; Raymond-Letron, Isabelle; Tremollieres, Florence; Soulie, Michel; Foidart, Jean-Michel; Game, Xavier; Arnal, Jean-Francois

2017-11-01

The genitourinary syndrome of menopause has a negative impact on quality of life of postmenopausal women. The treatment of vulvovaginal atrophy includes administration of estrogens. However, oral estrogen treatment is controversial because of its potential risks on venous thrombosis and breast cancer. Estetrol (E4) is a natural estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered as a weak estrogen. However, E4 was recently evaluated in phase 1 to 2 clinical studies and found to act as an oral contraceptive in combination with a progestin, without increasing the level of coagulation factors. We recently showed that E4 stimulates uterine epithelial proliferation through nuclear estrogen receptor (ER) α, but failed to elicit endothelial responses. Herein, we first evaluated the morphological and functional impacts of E4 on the vagina of ovariectomized mice, and we determined the molecular mechanism mediating these effects. Vaginal epithelial proliferation and lubrication after stimulation were found to increase after E4 chronic treatment. Using a combination of pharmacological and genetic approaches, we demonstrated that these E4 effects on the vagina are mediated by nuclear ERα activation. Altogether, we demonstrate that the selective activation of nuclear ERα is both necessary and sufficient to elicit functional and structural effects on the vagina, and therefore E4 appears promising as a therapeutic option to improve vulvovaginal atrophy. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Lingual lipase activity in the orosensory detection of fat by humans

PubMed Central

Kulkarni, Bhushan V.

2014-01-01

Lingual lipase generates nonesterified fatty acids (NEFA) from dietary fats during oral processing by lipolysis. Lingual lipase in rodents has strong lipolytic activity and plays a critical role in oral detection of fats. The functional activity of lingual lipase during oral processing of high-fat foods in humans remains poorly characterized. Five commonly consumed high-fat foods varying in physical states and fatty acid composition (almond, almond butter, olive oil, walnut, and coconut) were masticated by 15 healthy human subjects at the rate of one chew per second with and without lipase inhibitor orlistat. Salivary NEFA concentrations were measured. To determine the role of lingual lipase in oral fat detection, sensory ratings were obtained from the same 15 human subjects for almond butter with and without orlistat. Lingual lipase was active during oral processing of almond and coconut. No activity of lingual lipase was detected during processing of almond butter. There was only weak evidence lingual lipase is a determinant of oral fat detection. Lingual lipase may only contribute to NEFA generation and oral fat detection of fatty foods that require stronger oral processing effort. PMID:24694384

PAMPA--critical factors for better predictions of absorption.

PubMed

Avdeef, Alex; Bendels, Stefanie; Di, Li; Faller, Bernard; Kansy, Manfred; Sugano, Kiyohiko; Yamauchi, Yukinori

2007-11-01

PAMPA, log P(OCT), and Caco-2 are useful tools in drug discovery for the prediction of oral absorption, brain penetration and for the development of structure-permeability relationships. Each approach has its advantages and limitations. Selection criteria for methods are based on many different factors: predictability, throughput, cost and personal preferences (people factor). The PAMPA concerns raised by Galinis-Luciani et al. (Galinis-Luciani et al., 2007, J Pharm Sci, this issue) are answered by experienced PAMPA practitioners, inventors and developers from diverse research organizations. Guidelines on how to use PAMPA are discussed. PAMPA and PAMPA-BBB have much better predictivity for oral absorption and brain penetration than log P(OCT) for real-world drug discovery compounds. PAMPA and Caco-2 have similar predictivity for passive oral absorption. However, it is not advisable to use PAMPA to predict absorption involving transporter-mediated processes, such as active uptake or efflux. Measurement of PAMPA is much more rapid and cost effective than Caco-2 and log P(OCT). PAMPA assay conditions are critical in order to generate high quality and relevant data, including permeation time, assay pH, stirring, use of cosolvents and selection of detection techniques. The success of using PAMPA in drug discovery depends on careful data interpretation, use of optimal assay conditions, implementation and integration strategies, and education of users. Copyright 2007 Wiley-Liss, Inc.

Research and Trends in the Studies of School-Based Oral English Assessment from 2003 to 2011: A Review of Selected Journals

ERIC Educational Resources Information Center

Kamal, Nur Diana Mohd; Siraj, Saedah; Alias, Norlidah; Attaran, Mohammad

2013-01-01

Assessing oral proficiency is a real challenge for English language practitioners. Throughout the process of assessing, many features of oral competence are worth given attention by teachers as the assessors. As such, the Malaysian Ministry of Education has urged for another alternative for oral assessment in 2002 with the intention of revamping…

The Oral Health Needs of Wisconsin Farmers and the Need for Patient Activation: A Pilot Study.

PubMed

Schroeder, Kelly; Gurenlian, JoAnn; Portillo, Karen

2017-01-01

This study aimed to determine the level of oral health need of Wisconsin farmers based on sociodemographic variables, perceived oral health, and actual oral health, and to evaluate the effectiveness of a dental hygiene patient activation intervention. Oral health screenings were administered by calibrated dental hygienists to 60 Wisconsin farmers attending the 2016 Wisconsin Farm Technology Days. Study participants self-administered the Oral Health Inventory Profile-14 survey and participated in an Adult Basic Screening Survey. Validity and reliability of both instruments have been established in previous studies. A follow-up phone call for Wisconsin farmers with a moderate- to high-risk oral health condition determined study participants followed the dental hygiene recommendations signified if study participants followed the dental hygiene recommendations and if patient activation had been achieved. Study participants represented Wisconsin farmers (N = 60; n = 32 men, n = 28 women) with an average age range between 50 and 60 years old. The Oral Health Impact Profile-14 survey results indicated that this group of Wisconsin farmers did not perceive themselves to have an oral health problem. The Adult Basic Screening Survey results also indicated that the majority of study participants did not currently have active oral disease. There were 32% (n = 19) who qualified for follow-up phone call, with 15% (n = 3) seeking oral health care based on the dental hygiene recommendation. Significant associations between sociodemographic variables and actual oral health were not found, and the null hypotheses were not rejected. Findings suggest that this group of Wisconsin farmers is receiving regular oral health care and patient activation despite literature suggesting that farmers and rural individuals might face unique barriers to health and oral health care.

Dormancy activation mechanism of oral cavity cancer stem cells.

PubMed

Chen, Xiang; Li, Xin; Zhao, Baohong; Shang, Dehao; Zhong, Ming; Deng, Chunfu; Jia, Xinshan

2015-07-01

Radiotherapy and chemotherapy are targeted primarily at rapidly proliferating cancer cells and are unable to eliminate cancer stem cells in the G0 phase. Thus, these treatments cannot prevent the recurrence and metastasis of cancer. Understanding the mechanisms by which cancer stem cells are maintained in the dormant G0 phase, and how they become active is key to developing new cancer therapies. The current study found that the anti-cancer drug 5-fluorouracil, acting on the oral squamous cell carcinoma KB cell line, selectively killed proliferating cells while sparing cells in the G0 phase. Bisulfite sequencing PCR showed that demethylation of the Sox2 promoter led to the expression of Sox2. This then resulted in the transformation of cancer stem cells from the G0 phase to the division stage and suggested that the transformation of cancer stem cells from the G0 phase to the division stage is closely related to an epigenetic modification of the cell.

Geographic tongue and psoriasis: clinical, histopathological, immunohistochemical and genetic correlation - a literature review*

PubMed Central

Picciani, Bruna Lavinas Sayed; Domingos, Tábata Alves; Teixeira-Souza, Thays; dos Santos, Vanessa de Carla Batista; Gonzaga, Heron Fernando de Sousa; Cardoso-Oliveira, Juliana; Gripp, Alexandre Carlos; Dias, Eliane Pedra; Carneiro, Sueli

2016-01-01

Geographic tongue is a chronic, inflammatory, and immune-mediated oral lesion of unknown etiology. It is characterized by serpiginous white areas around the atrophic mucosa, which alternation between activity, remission and reactivation at various locations gave the names benign migratory glossitis and wandering rash of the tongue. Psoriasis is a chronic inflammatory disease with frequent cutaneous involvement and an immunogenetic basis of great importance in clinical practice. The association between geographic tongue and psoriasis has been demonstrated in various studies, based on observation of its fundamental lesions, microscopic similarity between the two conditions and the presence of a common genetic marker, human leukocyte antigen (HLA) HLA-C*06. The difficulty however in accepting the diagnosis of geographic tongue as oral psoriasis is the fact that not all patients with geographic tongue present psoriasis. Some authors believe that the prevalence of geographic tongue would be much greater if psoriatic patients underwent thorough oral examination. This study aimed to develop a literature review performed between 1980 and 2014, in which consultation of theses, dissertations and selected scientific articles were conducted through search in Scielo and Bireme databases, from Medline and Lilacs sources, relating the common characteristics between geographic tongue and psoriasis. We observed that the frequency of oral lesions is relatively common, but to establish a correct diagnosis of oral psoriasis, immunohistochemical and genetic histopathological analyzes are necessary, thus highlighting the importance of oral examination in psoriatic patients and cutaneous examination in patients with geographic tongue. PMID:27579734

Antiemetic effects of a potent and selective neurokinin-1 receptor antagonist, FK886, on cisplatin- and apomorphine-induced emesis in dogs.

PubMed

Furukawa, Takako Yoshino; Nakayama, Hiroe; Kikuchi, Aya; Imazumi, Katsunori; Yamakuni, Hisashi; Sogabe, Hajime; Yamasaki, Sachiko; Takeshita, Koji; Matsuo, Masahiko; Manda, Toshitaka; Uchida, Wataru

2013-01-01

The antiemetic properties of a novel neurokinin-1 (NK1) receptor antagonist, FK886 ([3,5-bis(trifluoromethyl)phenyl][(2R)-2-(3-hydroxy-4-methylbenzyl)-4-{2-[(2S)-2-(methoxymethyl)morpholin-4-yl]ethyl}piperazin-1-yl]methanone dihydrochloride), were studied in dog models of cisplatin- and apomorphine-induced emesis. Intravenously administered FK886 (0.32-1 mg/kg) significantly inhibited cisplatin-induced acute emesis during the 5-h observation period. Nearly complete inhibition was observed at 1 mg/kg. At an equivalent dose range, orally administered FK886 also significantly inhibited emesis, indicating good oral absorption. Similarly, FK886 inhibited apomorphine-induced emetic responses effectively following both intravenous and oral administration. The effects were long lasting, with 1.6 mg/kg of FK886 completely blocking apomorphine-induced retching and vomiting after a 12-h pretreatment period. Furthermore, FK886 showed rapid onset of antiemetic activity after oral administration. At doses of 0.32 mg/kg or more, a pretreatment time of 0.5 h was sufficient for complete inhibition of apomorphine-induced emetic responses. This fast onset after oral administration was supported by pharmacokinetic data, which demonstrated plasma levels of FK886 after oral administration reached levels similar to those 30 min after intravenous administration. These results suggest that FK886 has excellent antiemetic properties in dogs, and that its rapid-onset and long-lasting properties might make it a promising antiemetic agent.

Arginine mimetic structures in biologically active antagonists and inhibitors.

PubMed

Masic, Lucija Peterlin

2006-01-01

Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active peptides. L-Arginine is a guanidino group-containing basic amino acid, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes. Many enzymes display a preference for the arginine residue that is found in many natural substrates and in synthetic inhibitors of many trypsin-like serine proteases, e.g. thrombin, factor Xa, factor VIIa, trypsin, and in integrin receptor antagonists, used to treat many blood-coagulation disorders. Nitric oxide (NO), which is produced by oxidation of L-arginine in an NADPH- and O(2)-dependent process catalyzed by isoforms of nitric oxide synthase (NOS), exhibits diverse roles in both normal and pathological physiologies and has been postulated to be a contributor to the etiology of various diseases. Development of NOS inhibitors as well as analogs and mimetics of the natural substrate L-arginine, is desirable for potential therapeutic use and for a better understanding of their conformation when bound in the arginine binding site. The guanidino residue of arginine in many substrates, inhibitors, and antagonists forms strong ionic interactions with the carboxylate of an aspartic acid moiety, which provides specificity for the basic amino acid residue in the active side. However, a highly basic guanidino moiety incorporated in enzyme inhibitors or receptor antagonists is often associated with low selectivity and poor bioavailability after peroral application. Thus, significant effort is focused on the design and preparation of arginine mimetics that can confer selective inhibition for specific trypsin-like serine proteases and NOS inhibitors as well as integrin receptor antagonists and possess reduced basicity for enhanced oral bioavailability. This review will describe the survey of arginine mimetics designed to mimic the function of the arginine moiety in numerous peptidomimetic compounds (thrombin inhibitors, factor Xa inhibitors, factor VIIa inhibitors, integrin receptor antagonists, nitric oxide synthase inhibitors), with the aim of obtaining better activity, selectivity and oral bioavailability.

Maraviroc (UK-427,857), a Potent, Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity

PubMed Central

Dorr, Patrick; Westby, Mike; Dobbs, Susan; Griffin, Paul; Irvine, Becky; Macartney, Malcolm; Mori, Julie; Rickett, Graham; Smith-Burchnell, Caroline; Napier, Carolyn; Webster, Rob; Armour, Duncan; Price, David; Stammen, Blanda; Wood, Anthony; Perros, Manos

2005-01-01

Maraviroc (UK-427,857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin (geometric mean 90% inhibitory concentration of 2.0 nM). Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. There was little difference in the sensitivity of the 200 viruses to maraviroc, as illustrated by the biological cutoff in this assay (= geometric mean plus two standard deviations [SD] of 1.7-fold). The mechanism of action of maraviroc was established using cell-based assays, where it blocked binding of viral envelope, gp120, to CCR5 to prevent the membrane fusion events necessary for viral entry. Maraviroc did not affect CCR5 cell surface levels or associated intracellular signaling, confirming it as a functional antagonist of CCR5. Maraviroc has no detectable in vitro cytotoxicity and is highly selective for CCR5, as confirmed against a wide range of receptors and enzymes, including the hERG ion channel (50% inhibitory concentration, >10 μM), indicating potential for an excellent clinical safety profile. Studies in preclinical in vitro and in vivo models predicted maraviroc to have human pharmacokinetics consistent with once- or twice-daily dosing following oral administration. Clinical trials are ongoing to further investigate the potential of using maraviroc for the treatment of HIV-1 infection and AIDS. PMID:16251317

Decaleside: a new class of natural insecticide targeting tarsal gustatory sites

NASA Astrophysics Data System (ADS)

Rajashekar, Yallappa; Rao, Lingamallu J. M.; Shivanandappa, Thimmappa

2012-10-01

Natural sources for novel insecticide molecules hold promise in view of their eco-friendly nature, selectivity, and mammalian safety. Recent progress in understanding the biology of insect olfaction and taste offers new strategies for developing selective pest control agents. We have isolated two natural insecticidal molecules from edible roots of Decalepis hamiltonii named Decalesides I and II, which are novel trisaccharides, highly toxic to household insect pests and stored-product insects. We have experimentally shown that insecticidal activity requires contact with tarsi on the legs but is not toxic orally. The insecticidal activity of molecules is lost by hydrolysis, and various sugars modify toxic response, showing that the insecticidal activity is via gustatory sites on the tarsi. Selective toxicity to insects by virtue of their gustatory site of action and the mammalian safety of the new insecticides is inherent in their chemical structure with 1-4 or 1-1 α linkage that is easily hydrolyzed by digestive enzymes of mammals. Decalesides represent a new chemical class of natural insecticides with a unique mode of action targeting tarsal chemosensory/gustatory system of insects.

ST7612AA1, a thioacetate-ω(γ-lactam carboxamide) derivative selected from a novel generation of oral HDAC inhibitors.

PubMed

Giannini, Giuseppe; Vesci, Loredana; Battistuzzi, Gianfranco; Vignola, Davide; Milazzo, Ferdinando M; Guglielmi, Mario Berardino; Barbarino, Marcella; Santaniello, Mosè; Fantò, Nicola; Mor, Marco; Rivara, Silvia; Pala, Daniele; Taddei, Maurizio; Pisano, Claudio; Cabri, Walter

2014-10-23

A systematic study of medicinal chemistry aimed at identifying a new generation of HDAC inhibitors, through the introduction of a thiol zinc-binding group (ZBG) and of an amide-lactam in the ω-position of the polyethylene chain of the vorinostat scaffold, allowed the selection of a new class of potent pan-HDAC inhibitors (pan-HDACis). Simple, highly versatile, and efficient synthetic approaches were used to synthesize a library of these new derivatives, which were then submitted to a screening for HDAC inhibition as well as to a preliminary in vitro assessment of their antiproliferative activity. Molecular docking into HDAC crystal structures suggested a binding mode for these thiol derivatives consistent with the stereoselectivity observed upon insertion of amide-lactam substituents in the ω-position. ST7612AA1 (117), selected as a drug candidate for further development, showed an in vitro activity in the nanomolar range associated with a remarkable in vivo antitumor activity, highly competitive with the most potent HDAC inhibitors, currently under clinical trials. A preliminary study of PK and metabolism is also illustrated.

Formulation and Optimization of Candesartan Cilexetil Nano Lipid Carrier: In Vitro and In Vivo Evaluation.

PubMed

Paudel, Anjan; Ameeduzzafar; Imam, Syed Sarim; Fazil, Mohd; Khan, Shahroz; Hafeez, Abdul; Ahmad, Farhan Jalees; Ali, Asgar

2017-01-01

The objective of this study was to formulate and optimize Candesartan Cilexetil (CC) loaded nanostructured lipid carriers (NLCs) for enhanced oral bioavailability. Glycerol monostearate (GMS), Oleic acid, Tween 80 and Span 40 were selected as a solid lipid, liquid lipid, surfactant and co- surfactant, respectively. The CC-NLCs were prepared by hot emulsion probe sonication technique and optimized using experimental design approach. The formulated CC-NLCs were evaluated for various physicochemical parameters and further optimized formulation (CC-NLC-Opt) was assessed for in vivo pharmacokinetic and pharmacodynamic activity. The optimized formulation (CC-NLC-Opt) showed particle size (183.5±5.89nm), PDI (0.228±0.13), zeta potential (-28.2±0.99mV), and entrapment efficiency (88.9±3.69%). The comparative in vitro release study revealed that CC-NLC-Opt showed significantly better (p<0.05) release and enhanced permeation as compared to CC-suspension. The in vivo pharmacokinetic study gave many folds increase in oral bioavailability than CC suspension, which was further confirmed by antihypertensive activity in a murine model. Thus, the results of ex vivo permeation, pharmacokinetic study and pharmacodynamics study suggest the potential of CC-NLCs for improved oral delivery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Subchronic toxicity, mutagenicity and allergenicity studies of a cultured dextrose food product.

PubMed

Buard, A; Carlton, B D; Floch, F; Simon, G S

2003-05-01

MicroGARD(R) 200 is a fermented dextrose product used to extend food shelf-life by inhibiting spoilage due to Gram-negative bacteria, selected yeast and molds. The present studies were conducted to evaluate the safety of this food ingredient for determination of GRAS status. MicroGARD 200 was subjected to a bacterial reverse mutation assay, a subchronic oral toxicity study and an oral antigenicity study. It showed no evidence of mutagenic potential or toxicity in four strains of Salmonella typhimurium or in Escherichia coli strain WP2 uvrA with and without metabolic activation. MicroGARD 200 was orally administered to rats for 13 consecutive weeks at dietary concentrations of 0, 0.5, 2.0 or 5.0%. Water consumption and urinary excretion of sodium were slightly increased in both sexes at the high dose due to the sodium content of the test substance (about 6%). Increases in fasting glucose and decreased plasma creatinine were not accompanied by treatment-related histopathological changes and were within the normal range for historical controls. The potential antigenic properties of MicroGARD 200 were investigated via gavage in guinea pigs using an active systemic anaphylaxis (ASA) challenge [Annals of Allergy 67 (1991) 400; Allergy 49 (1994) 361]. There was no evidence of any anaphylactic sensitizing properties for MicroGARD 200.

The Use of C. S. Lewis's "Poems" for Oral Interpretation.

ERIC Educational Resources Information Center

Keefe, Carolyn

Suggestions are offered in this paper for adapting C. S. Lewis's poems for oral interpretation. A discussion of Lewis's lifelong correspondence with his friend Arthur Greeves provides insights into Lewis's perceptions of his own writing. Eighty poems selected from Lewis's "Poems" as appropriate for oral interpretation are classified…

Assessment of a Brief Oral Presentation Assignment in Biopsychology

ERIC Educational Resources Information Center

Sleigh, Merry J.

2013-01-01

This study examined the suitability of a brief oral presentation exercise as an assessment method in biopsychology. Undergraduate students researched and presented a five-minute, self-selected fact related to course material, allowing them to practice oral communication skills, such as clearly explaining and carefully listening. Biopsychology…

Role of nitric oxide and antioxidant enzymes in the pathogenesis of oral cancer.

PubMed

Patel, Jayendrakumar B; Shah, Franky D; Shukla, Shilin N; Shah, Pankaj M; Patel, Prabhudas S

2009-01-01

Oral cancer is the leading malignancy in India. Nitric oxide and antioxidant enzymes play an important role in etiology of oral cancer. Therefore, the present study evaluates nitric oxide and antioxidant enzyme levels in healthy individual without tobacco habits (NHT, N=30) and healthy individuals with tobacco habits (WHT, n=90), patients with oral precancers (OPC, n=15) and oral cancer patients (n=126). Blood samples were collected from the subjects. NO2 + NO3 (nitrite+nitrate), superoxide dismutase (SOD) and catalase levels were estimated using highly specific spectrophotometeric methods. Statistical analysis was done by SPSS statistical software version 10. Mean plasma NO2 + NO3 levels were elevated in patients with OPC and oral cancer patients as compared to the controls. Mean activities of erythrocyte SOD and catalase were higher in WHT than NHT. Erythrocyte SOD and catalase levels were higher in WHT and patients with OPC as compared to NHT. The erythrocyte SOD and catalase activities were lower in oral cancer patients than patients with OPC. The erythrocyte SOD activity was higher in advanced oral cancer than the early disease. Erythrocyte catalase activity was lower in poorly differentiated tumors than well and moderately differentiated tumors. Pearson's correlation analysis revealed that alterations in plasma NO2 + NO3 levels were negatively associated with changes in erythrocyte SOD activities. The data revealed that the alterations in antioxidant activities were associated with production of nitric oxide in oral cancer, which may have significant role in oral carcinogenesis.

Discovery of novel Ponatinib analogues for reducing KDR activity as potent FGFRs inhibitors.

PubMed

Liu, Yang; Peng, Xia; Guan, Xiaocong; Lu, Dong; Xi, Yong; Jin, Shiyu; Chen, Hui; Zeng, Limin; Ai, Jing; Geng, Meiyu; Hu, Youhong

2017-01-27

FGF receptors (FGFRs) are tyrosine kinases that are overexpressed in diverse tumors by genetic alterations such as gene amplifications, somatic mutations and translocations. Owing to this characteristic, FGFRs are attractive targets for cancer treatment. It has been demonstrated that most multi-targeted, ATP competitive tyrosine kinase inhibitors are active against FGFRs as well as other kinases. The design of new and more selective inhibitors of FGFRs, which might be reduced off-target and side effects, is a difficult yet significant challenge. The results of the current investigation, show that novel Ponatinib analogues are highly active as FGFR inhibitors and that they possess reduced kinase insert domain receptor (KDR) activities. Observations made in a structure and activity relationship (SAR) investigation led to the development of a promising, orally available lead compound 4, which displays a 50-100 fold in vitro selectivity for inhibition of FGFR1-3 over KDR. In addition, biological evaluation of compound 4 showed that it displays significant antitumor activities in FGFR1-amplificated H1581 and FGFR2-amplificated SNU-16 xenograft models. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors.

PubMed

Boyd, Michael J; Bandarage, Upul K; Bennett, Hamilton; Byrn, Randal R; Davies, Ioana; Gu, Wenxin; Jacobs, Marc; Ledeboer, Mark W; Ledford, Brian; Leeman, Joshua R; Perola, Emanuele; Wang, Tiansheng; Bennani, Youssef; Clark, Michael P; Charifson, Paul S

2015-05-01

VX-787 is a first in class, orally bioavailable compound that offers unparalleled potential for the treatment of pandemic and seasonal influenza. As a part of our routine SAR exploration, carboxylic acid isosteres of VX-787 were prepared and tested against influenza A. It was found that the negative charge is important for maintaining potency and selectivity relative to kinase targets. Neutral carboxylic acid replacements generally resulted in compounds that were significantly less potent and less selective relative to the charged species. Copyright © 2015 Elsevier Ltd. All rights reserved.

21 CFR 310.534 - Drug products containing active ingredients offered over-the-counter (OTC) for human use as oral...

Code of Federal Regulations, 2014 CFR

2014-04-01

... offered over-the-counter (OTC) for human use as oral wound healing agents. 310.534 Section 310.534 Food... active ingredients offered over-the-counter (OTC) for human use as oral wound healing agents. (a... aqueous solution have been present in oral mucosal injury drug products for use as oral wound healing...

21 CFR 310.534 - Drug products containing active ingredients offered over-the-counter (OTC) for human use as oral...

Code of Federal Regulations, 2012 CFR

2012-04-01

... offered over-the-counter (OTC) for human use as oral wound healing agents. 310.534 Section 310.534 Food... active ingredients offered over-the-counter (OTC) for human use as oral wound healing agents. (a... aqueous solution have been present in oral mucosal injury drug products for use as oral wound healing...

21 CFR 310.534 - Drug products containing active ingredients offered over-the-counter (OTC) for human use as oral...

Code of Federal Regulations, 2013 CFR

2013-04-01

... offered over-the-counter (OTC) for human use as oral wound healing agents. 310.534 Section 310.534 Food... active ingredients offered over-the-counter (OTC) for human use as oral wound healing agents. (a... aqueous solution have been present in oral mucosal injury drug products for use as oral wound healing...

21 CFR 310.534 - Drug products containing active ingredients offered over-the-counter (OTC) for human use as oral...

Code of Federal Regulations, 2011 CFR

2011-04-01

... offered over-the-counter (OTC) for human use as oral wound healing agents. 310.534 Section 310.534 Food... active ingredients offered over-the-counter (OTC) for human use as oral wound healing agents. (a... aqueous solution have been present in oral mucosal injury drug products for use as oral wound healing...

21 CFR 310.534 - Drug products containing active ingredients offered over-the-counter (OTC) for human use as oral...

Code of Federal Regulations, 2010 CFR

2010-04-01

... offered over-the-counter (OTC) for human use as oral wound healing agents. 310.534 Section 310.534 Food... active ingredients offered over-the-counter (OTC) for human use as oral wound healing agents. (a... aqueous solution have been present in oral mucosal injury drug products for use as oral wound healing...

Substituted 7-amino-5-thio-thiazolo[4,5-d]pyrimidines as potent and selective antagonists of the fractalkine receptor (CX3CR1).

PubMed

Karlström, Sofia; Nordvall, Gunnar; Sohn, Daniel; Hettman, Andreas; Turek, Dominika; Åhlin, Kristofer; Kers, Annika; Claesson, Martina; Slivo, Can; Lo-Alfredsson, Yvonne; Petersson, Carl; Bessidskaia, Galina; Svensson, Per H; Rein, Tobias; Jerning, Eva; Malmberg, Åsa; Ahlgen, Charlotte; Ray, Colin; Vares, Lauri; Ivanov, Vladimir; Johansson, Rolf

2013-04-25

We have developed two parallel series, A and B, of CX3CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo[4,5-d]pyrimidine core structure, we were able to achieve compounds with high selectivity for CX3CR1 over the closely related CXCR2 receptor. The structure-activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with α-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds 18a and 24h. We show the preparation of the first potent and selective orally available CX3CR1 antagonists.

Discovery of Indazoles as Potent, Orally Active Dual Neurokinin 1 Receptor Antagonists and Serotonin Transporter Inhibitors for the Treatment of Depression.

PubMed

Degnan, Andrew P; Tora, George O; Huang, Hong; Conlon, David A; Davis, Carl D; Hanumegowda, Umesh M; Hou, Xiaoping; Hsiao, Yi; Hu, Joanna; Krause, Rudolph; Li, Yu-Wen; Newton, Amy E; Pieschl, Rick L; Raybon, Joseph; Rosner, Thorsten; Sun, Jung-Hui; Taber, Matthew T; Taylor, Sarah J; Wong, Michael K; Zhang, Huiping; Lodge, Nicholas J; Bronson, Joanne J; Macor, John E; Gillman, Kevin W

2016-12-21

Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.

The analysis of oral air using selected ion flow tube mass spectrometry in persons with and without a history of oral malodour.

PubMed

Ross, B M; Dadgostar, N; Bloom, M; McKeown, L

2009-05-01

Oral malodour is a common disorder predominantly caused by bacterial metabolism of food stuffs in the mouth. It is routinely diagnosed and monitored by either the subjective rating or the measurement of oral volatile sulphur compound (VSC) levels. Non-sulphur compounds are also believed to contribute significantly to the condition although there is currently no direct means to assess their levels. In this study, we utilized selective flow tube mass spectrometry (SIFT-MS) to measure, in real time, a range of sulphur and non-sulphur containing compounds in oral air to determine whether the technique can be used to objectively monitor oral malodour. Oral malodour was assessed using organoleptic scores in subjects with and without a history of oral malodour (n = 18) by a trained rater, while the chemical composition of oral air was analysed by both VSC sensor and SIFT-MS. Total VSC levels were significantly correlated with levels of hydrogen sulphide and methylmercaptan measured by SIFT-MS, but not with organoleptic scores. In subjects with elevated organoleptic score, only levels of methylmercaptan were significantly elevated. In three subjects with elevated tongue organoleptic scores but normal total VSC levels, SIFT-MS suggested that one subject possessed high levels of oral acetone while another had high oral levels of acetic acid. Our data suggest that SIFT-MS can be used to assess a wide range of compounds in oral air in addition to VSC to provide a clearer picture of the chemical nature of malodour. This may assist in the diagnosis and monitoring of the condition.

Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garcia Fortanet, Jorge; Chen, Christine Hiu-Tung; Chen, Ying-Nan P.

SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealedmore » the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein–ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.« less

Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)

PubMed Central

2013-01-01

The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition. PMID:24256217

Structure-based design of orally bioavailable 1H-pyrrolo[3,2-c]pyridine inhibitors of mitotic kinase monopolar spindle 1 (MPS1).

PubMed

Naud, Sébastien; Westwood, Isaac M; Faisal, Amir; Sheldrake, Peter; Bavetsias, Vassilios; Atrash, Butrus; Cheung, Kwai-Ming J; Liu, Manjuan; Hayes, Angela; Schmitt, Jessica; Wood, Amy; Choi, Vanessa; Boxall, Kathy; Mak, Grace; Gurden, Mark; Valenti, Melanie; de Haven Brandon, Alexis; Henley, Alan; Baker, Ross; McAndrew, Craig; Matijssen, Berry; Burke, Rosemary; Hoelder, Swen; Eccles, Suzanne A; Raynaud, Florence I; Linardopoulos, Spiros; van Montfort, Rob L M; Blagg, Julian

2013-12-27

The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.

Children's understanding of and motivations for toothbrushing: a qualitative study.

PubMed

Gill, P; Stewart, K; Chetcuti, D; Chestnutt, I G

2011-02-01

To explore children's understanding of why they do or do not brush their teeth and their motivations for toothbrushing. Individual semi-structured interviews were conducted with 66 children aged 6-7 years and 10-11 years in four purposively selected primary schools in Cardiff, UK. Data were analysed using a constructive process of Thematic Content Analysis and techniques of open and selective coding. While a routine activity, toothbrushing was prompted rather than monitored by parents and easily fell by the wayside because of tiredness, excitement or distraction. Rationalizations for toothbrushing were poorly formed in the children's accounts and related to 'doom scenarios' such as teeth falling out, or to issues of personal grooming and cleanliness rather than caries prevention. Electric (powered) toothbrushes were popular and had engaged the children's interest. Social and domestic circumstances, such as when children stayed with different parents at different times, impacted on toothbrushing routines. This study has revealed information that is of value in directing oral health education messages, oral health promotion programmes and has identified issues that potentially affect compliance with toothbrushing that merit further investigation. © 2010 John Wiley & Sons A/S.

Newly discovered orally active pure antiestrogens.

PubMed

Kanbe, Yoshitake; Kim, Myung-Hwa; Nishimoto, Masahiro; Ohtake, Yoshihito; Yoneya, Takaaki; Ohizumi, Iwao; Tsunenari, Toshiaki; Taniguchi, Kenji; Kaiho, Shin-ichi; Nabuchi, Yoshiaki; Araya, Hiroshi; Kawata, Setsu; Morikawa, Kazumi; Jo, Jae-Chon; Kwon, Hee-An; Lim, Hyun-Suk; Kim, Hak-Yeop

2006-09-15

In order to develop orally active pure antiestrogens, we incorporated the carboxy-containing side chains into the 7alpha-position of the steroid scaffold and found that 17-keto derivative CH4893237 (12b) functioned as a pure antiestrogen with its oral activity much superior to clinically used pure antiestrogen, ICI182,780. Results from the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing in mice attributed to both improved absorption from the intestinal wall and metabolic stability in liver.

Boswellia carterii liquisolid systems with promoted anti-inflammatory activity.

PubMed

Mostafa, Dina Mahmoud; Ammar, Nagwa Mohammed; Abd El-Alim, Sameh Hosam; Kassem, Ahmed Alaa; Hussein, Rehab Ali; Awad, Gamal; El-Awdan, Sally Abdul-Wanees

2015-01-01

Boswellia carterii (BC) Birdwood oleogum resin is an ancient remedy of inflammation processes known since Ancient Egyptian time. Of boswellic acids, 3-acetyl-11-keto-β-boswellic acid (AKBA) is the most potent anti-inflammatory active principle. Liquisolid systems of the biologically active fraction of BC oleogum resin were prepared for improving dissolution properties using low dose oral delivery to achieve enhanced anti-inflammatory activity, in comparison with the standard oral anti-inflammatory; Indomethacin. AKBA was assayed, employing an accurate and sensitive HPLC method. Detection was carried out at 210 nm using UV/Vis detector. A solubility study for the bioactive fraction was conducted. Microcrystalline cellulose and Aeroperl®300 Pharma were used as carrier and coating materials. Angle of slide, liquid load factor and Carr's flow index were estimated. Six systems were prepared using polyethylene glycol 400, solvent and two drug loading concentrations; 20 and 40 %. For each concentration, three carrier: coat ratios were dispensed; 20:1, 10:1, and 5:1. Dissolution study was performed and two systems were selected for characterization and in vivo evaluation by investigating upper GIT ulcerogenic effect and anti-inflammatory efficacy in rats. Results indicate absence of ulcers and significantly higher and prolonged anti-inflammatory efficacy for formulations F1 and F2, with carrier: coat ratio, 5:1 and drug loads of 20 and 40 %, respectively, compared with standard oral indomethacin. We conclude higher efficacy of BC bioactive fraction liquisolids compared with Indomethacin with greater safety on GIT, longer duration of action and hence better patient compliance.

Activity and safety of the antiestrogen EM-800, the orally active precursor of acolbifene, in tamoxifen-resistant breast cancer.

PubMed

Labrie, Fernand; Champagne, Pierre; Labrie, Claude; Roy, Jean; Laverdière, Jacques; Provencher, Louise; Potvin, Martin; Drolet, Yvan; Pollak, Michael; Panasci, Lawrence; L'Espérance, Bernard; Dufresne, Jean; Latreille, Jean; Robert, Jean; Samson, Benoît; Jolivet, Jacques; Yelle, Louise; Cusan, Lionel; Diamond, Pierre; Candas, Bernard

2004-03-01

To determine the efficacy and safety of EM-800 (SCH-57050), the precursor of acolbifene, a new, highly potent, orally active, pure antiestrogen in the mammary gland and endometrium, for the treatment of tamoxifen-resistant breast cancer. Forty-three post menopausal/ovariectomized women with breast cancer who had received tamoxifen, either for metastatic disease or as adjuvant to surgery for > or = 1 year, and had relapsed were treated in a prospective, multicenter, phase II study with EM-800 (20 mg/d [n = 21] or 40 mg/d [n = 22] orally). Results Thirty-seven patients had estrogen receptor (ER)-positive tumors (>10 fmol/mg; mean, 146 fmol/mg cytosolic protein), three patients had ER-negative/progesterone receptor-positive tumors, and three patients had undetermined ER status. The objective response rate to EM-800 was 12%, with one complete response and four partial responses. Ten patients (23%) had stable disease for > or = 3 months, and 7 patients (16%) had stable disease for > or = 6 months. With a median follow-up of 29 months, median duration of response was 8 months (range, 7 to 71+ months). Treatment with EM-800 was well tolerated. No significant adverse events related to the study drug were observed clinically or biochemically. EM-800 produced responses in a significant proportion of patients with tamoxifen-resistant breast cancer, thus showing that this highly potent, selective estrogen receptor modulator, which lacks estrogenic activity in the mammary gland and endometrium, has incomplete cross-resistance with tamoxifen, thus suggesting additional benefits in the treatment of breast cancer.

Candida virulence and ethanol-derived acetaldehyde production in oral cancer and non-cancer subjects.

PubMed

Alnuaimi, A D; Ramdzan, A N; Wiesenfeld, D; O'Brien-Simpson, N M; Kolev, S D; Reynolds, E C; McCullough, M J

2016-11-01

To compare biofilm-forming ability, hydrolytic enzymes and ethanol-derived acetaldehyde production of oral Candida isolated from the patients with oral cancer and matched non-oral cancer. Fungal biofilms were grown in RPMI-1640 medium, and biofilm mass and biofilm activity were assessed using crystal violet staining and XTT salt reduction assays, respectively. Phospholipase, proteinase, and esterase production were measured using agar plate method, while fungal acetaldehyde production was assessed via gas chromatography. Candida isolated from patients with oral cancer demonstrated significantly higher biofilm mass (P = 0.031), biofilm metabolic activity (P < 0.001), phospholipase (P = 0.002), and proteinase (P = 0.0159) activity than isolates from patients with non-oral cancer. High ethanol-derived acetaldehyde-producing Candida were more prevalent in patients with oral cancer than non-oral cancer (P = 0.01). In univariate regression analysis, high biofilm mass (P = 0.03) and biofilm metabolic activity (P < 0.001), high phospholipase (P = 0.003), and acetaldehyde production ability (0.01) were significant risk factors for oral cancer; while in the multivariate regression analysis, high biofilm activity (0.01) and phospholipase (P = 0.01) were significantly positive influencing factors on oral cancer. These data suggest a significant positive association between the ability of Candida isolates to form biofilms, to produce hydrolytic enzymes, and to metabolize alcohol to acetaldehyde with their ability to promote oral cancer development. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Clinical considerations on the posology of direct oral anticoagulants.

PubMed

Sáez-Peñataro, J; Avendaño-Solá, C; González-Juanatey, J R

2016-10-01

The efficacy of dicoumarin anticoagulants has been shown in patients with nonvalvular atrial fibrillation. However, they have drawbacks such as the need to adjust the dosage and the interaction with drugs and food. Direct oral anticoagulants are an effective and safe alternative and have a less complicated clinical management. There is considerable debate on the selection criteria for the posology regimens of direct oral anticoagulants. The differences among them and their administration regimens have raised questions about the clinical, pharmacokinetic and pharmacodynamic selection criteria that support the posology. This review critically analyses the available evidence and its impact on the final selection of the dosage regimen. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Effects of Actinobolin on Growth and Some Metabolic Activities of Cariogenic Streptococci In Vitro and In Vivo

PubMed Central

Keele, Bernard B.; Powell, Hubert L.; Navia, Juan M.; McGhee, Jerry

1971-01-01

Actinobolin, a known inhibitor of protein synthesis, has been shown not to interfere selectively with acid production or dextransucrase activity in a cariogenic streptococcus when the antibiotic is added to a concentration of 500 μg/ml. It has also been shown that actinobolin does not alter the total in vivo flora of the oral cavity of the rat when tested in a rat caries model system. A culture of cariogenic streptococci, adapted to in vitro growth in the presence of 1 mg of actinobolin per ml, has also been isolated. PMID:4944810

Diamidines as antitrypanosomal, antileishmanial and antimalarial agents.

PubMed

Werbovetz, Karl

2006-02-01

Diamidine-containing compounds have a long history of use in the treatment of African trypanosomiasis and leishmaniasis. The discovery that diamidine prodrugs possess in vivo antimicrobial activity when administered orally has led to a renewed interest in this class of compounds for the treatment of parasitic infections. In this review, the selectivity of diamidines against trypanosomes, Leishmania and Plasmodium is rationalized through mechanism-of-action studies. An overview of the antiprotozoal activities of newer diamidines and diamidine prodrugs is also presented, along with a summary of the progress made toward the clinical development of new diamidines for use against these parasitic diseases.

Rationalizing the selection of oral lipid based drug delivery systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs.

PubMed

Dahan, Arik; Hoffman, Amnon

2008-07-02

As a consequence of modern drug discovery techniques, there has been a consistent increase in the number of new pharmacologically active lipophilic compounds that are poorly water soluble. A great challenge facing the pharmaceutical scientist is making these molecules into orally administered medications with sufficient bioavailability. One of the most popular approaches to improve the oral bioavailability of these molecules is the utilization of a lipid based drug delivery system. Unfortunately, current development strategies in the area of lipid based delivery systems are mostly empirical. Hence, there is a need for a simplified in vitro method to guide the selection of a suitable lipidic vehicle composition and to rationalize the delivery system design. To address this need, a dynamic in vitro lipolysis model, which provides a very good simulation of the in vivo lipid digestion process, has been developed over the past few years. This model has been extensively used for in vitro assessment of different lipid based delivery systems, leading to enhanced understanding of the suitability of different lipids and surfactants as a delivery system for a given poorly water soluble drug candidate. A key goal in the development of the dynamic in vitro lipolysis model has been correlating the in vitro data of various drug-lipidic delivery system combinations to the resultant in vivo drug profile. In this paper, we discuss and review the need for this model, its underlying theory, practice and limitations, and the available data accumulated in the literature. Overall, the dynamic in vitro lipolysis model seems to provide highly useful initial guidelines in the development process of oral lipid based drug delivery systems for poorly water soluble drugs, and it predicts phenomena that occur in the pre-enterocyte stages of the intestinal absorption cascade.

Growth Media Affect Assessment of Antimicrobial Activity of Plant-Derived Polyphenols.

PubMed

Xu, Xin; Ou, Zhen M; Wu, Christine D

2018-01-01

This study aimed to investigate the effects of different microbial growth media on the laboratory assessment of antimicrobial activity of natural polyphenolic compounds. The inhibition of the tea polyphenol EGCG on growth of selected oral microorganisms was evaluated in complex media and a protein-free chemically defined medium (CDM). Other antimicrobial agents (polyphenolic grape seed extract, plant alkaloid berberine, methyl salicylate, and chlorhexidine gluconate) were also tested in the study. The presence of proteins and their effects on the antimicrobial activity of EGCG were investigated by the addition of BSA to the CDM. The MICs of EGCG against test oral microorganisms were 4 to 64 times higher in complex media than in CDM. The polyphenolic grape seed extract exhibited similar discrepancies. However, the MICs of the nonpolyphenolic compounds (berberine, methyl salicylate, and chlorhexidine) were not significantly different between the two growth media. The MIC of EGCG against S. mutans UA159 in CDM with added BSA was 16 times higher than that in CDM alone. Therefore, nonproteinaceous CDM should be used to avoid interference of proteins with the active ingredients when testing the antimicrobial activity of plant-derived polyphenolic compounds against microorganisms. This will also minimize the discrepancies noted in results obtained by different investigators.

In Vitro Cultivation of 'Unculturable' Oral Bacteria, Facilitated by Community Culture and Media Supplementation with Siderophores.

PubMed

Vartoukian, Sonia R; Adamowska, Aleksandra; Lawlor, Megan; Moazzez, Rebecca; Dewhirst, Floyd E; Wade, William G

2016-01-01

Over a third of oral bacteria are as-yet-uncultivated in-vitro. Siderophores have been previously shown to enable in-vitro growth of previously uncultivated bacteria. The objective of this study was to cultivate novel oral bacteria in siderophore-supplemented culture media. Various compounds with siderophore activity, including pyoverdines-Fe-complex, desferricoprogen and salicylic acid, were found to stimulate the growth of difficult-to-culture strains Prevotella sp. HOT-376 and Fretibacterium fastidiosum. Furthermore, pyrosequencing analysis demonstrated increased proportions of the as-yet-uncultivated phylotypes Dialister sp. HOT-119 and Megasphaera sp. HOT-123 on mixed culture plates supplemented with siderophores. Therefore a culture model was developed, which incorporated 15 μg siderophore (pyoverdines-Fe-complex or desferricoprogen) or 150 μl neat subgingival-plaque suspension into a central well on agar plates that were inoculated with heavily-diluted subgingival-plaque samples from subjects with periodontitis. Colonies showing satellitism were passaged onto fresh plates in co-culture with selected helper strains. Five novel strains, representatives of three previously-uncultivated taxa (Anaerolineae bacterium HOT-439, the first oral taxon from the Chloroflexi phylum to have been cultivated; Bacteroidetes bacterium HOT-365; and Peptostreptococcaceae bacterium HOT-091) were successfully isolated. All novel isolates required helper strains for growth, implying dependence on a biofilm lifestyle. Their characterisation will further our understanding of the human oral microbiome.

The Lyn kinase activator MLR-1023 is a novel insulin receptor potentiator that elicits a rapid-onset and durable improvement in glucose homeostasis in animal models of type 2 diabetes.

PubMed

Ochman, Alexander R; Lipinski, Christopher A; Handler, Jeffrey A; Reaume, Andrew G; Saporito, Michael S

2012-07-01

MLR-1023 [Tolimidone; CP-26154; 2(1H)-pyrimidinone, 5-(3-methylphenoxy)] is an allosteric Lyn kinase activator that reduces blood glucose levels in mice subjected to an oral glucose tolerance test (J Pharmacol Exp Ther 342:15-22, 2012). The current studies were designed to define the role of insulin in MLR-1023-mediated blood glucose lowering, to evaluate it in animal models of type 2 diabetes, and to compare it to the activities of selected existing diabetes therapeutics. Results from these studies show that in an acute oral glucose tolerance test MLR-1023 evoked a dose-dependent blood glucose-lowering response that was equivalent in magnitude to that of metformin without eliciting a hypoglycemic response. In streptozotocin-treated, insulin-depleted mice, MLR-1023 administration did not affect blood glucose levels. However, MLR-1023 potentiated the glucose-lowering activity of exogenously administered insulin, showing that MLR-1023-mediated blood glucose lowering was insulin-dependent. In a hyperinsulinemic/euglycemic clamp study, orally administered MLR-1023 increased the glucose infusion rate required to sustain blood glucose levels, demonstrating that MLR-1023 increased insulin receptor sensitivity. In chronically treated db/db mice, MLR-1023 elicited a dose-dependent and durable glucose-lowering effect, reduction in HbA1c levels and preservation of pancreatic β-cells. The magnitude of effect was equivalent to that seen with rosiglitazone but with a faster onset of action and without causing weight gain. These studies show that MLR-1023 is an insulin receptor-potentiating agent that produces a rapid-onset and durable blood glucose-lowering activity in diabetic animals.

Isolation, characterization, and evaluation of wild isolates of Lactobacillus reuteri from pig feces.

PubMed

Lee, Deog Yong; Seo, Yeon-Soo; Rayamajhi, Nabin; Kang, Mi Lan; Lee, Su In; Yoo, Han Sang

2009-12-01

Lactic acid bacteria (LAB) are a well-used probiotics for health improvements in both humans and animals. Despite of several benefits, non-host-specific LAB showed poor probiotics effects due to difficulty in colonization and competition with normal flora. Therefore, the feasibility of porcine LAB isolates was evaluated as a probiotics. Ten of 49 Lactobacillus spp. isolates harbored 2 approximately 10 kb plasmid DNA. Seven strains were selected based on the safety test, such as hemolytic activity, ammonia, indole, and phenylalanine production. After safety test, five strains were selected again by several tests, such as epithelial adherence, antimicrobial activity, tolerance against acid, bile, heat, and cold-drying, and production of acid and hydrogen peroxide. Then, enzyme profiles (ZYM test) and antibiotics resistance were analyzed for further characterization. Five Lactobacillus reuteri isolates from pig feces were selected by safety and functional tests. The plasmid DNA which was able to develop vector system was detected in the isolates. Together with these approaches, pig-specific Lactobacillus spp. originated from pigs were selected. These strains may be useful tools to develop oral delivery system.

Enzymatic Activity of Candida spp. from Oral Cavity and Urine in Children with Nephrotic Syndrome.

PubMed

Olczak-Kowalczyk, Dorota; Roszkowska-Blaim, Maria; Dąbkowska, Maria; Swoboda-Kopeć, Ewa; Gozdowski, Dariusz; Mizerska-Wasiak, Małgorzata; Demkow, Urszula; Pańczyk-Tomaszewska, Małgorzata

2017-01-01

Oral colonization with Candida spp. is not synonymous with a systemic active infection. The aim of the study was to evaluate enzymatic activity of Candida strains isolated from the oral cavity in patients with nephrotic syndrome (NS) and to compare it with the activity determined in urine. We studied 32 children with NS and 26 control healthy children. Children with NS were treated with glucocorticosteroids, cyclosporin A, mycophenolate mofetil or azathioprine. In all children, API-ZYM enzymatic tests were performed to evaluate hydrolytic enzymes of Candida isolated from the oral cavity and in urine. Candida spp. were isolated from the oral cavity in 11 patients with NS (34.4%), all receiving immunosuppressive treatment. All strains produced valine arylamidase, 9 alpha-glucosidase (E16), and 9 N-acetyl-beta-glucosaminidase (E18). A positive correlation between the presence of Candida in the oral cavity and E16 and E18 enzymatic activity in both oral cavity and urine was found. A dose of cyclosporin A had an effect on the enzymatic activity (p < 0.05). We conclude that immunosuppressive treatment of NS in children may predispose to systemic Candida invasion. The results of this study suggest that oral candida infection should be monitored in children with nephrotic syndrome, particularly those treated with immunosuppressive agents.

Oral cancer awareness and its determinants among a selected Malaysian population.

PubMed

Ghani, Wan Maria Nabillah; Doss, Jennifer Geraldine; Jamaluddin, Marhazlinda; Kamaruzaman, Dinan; Zain, Rosnah Binti

2013-01-01

To assess oral cancer awareness, its associated factors and related sources of information among a selected group of Malaysians. A cross-sectional survey was conducted on all Malaysian ethnic groups aged ≥15 years old at eight strategically chosen shopping malls within a two week time period. Data were analysed using chi-square tests and multiple logistic regression. Significance level was set at α<0.05. Most (84.2%) respondents had heard of oral cancer. Smoking was the most (92.4%) recognized high risk habit. Similar levels of awareness were seen for unhealed ulcers (57.3%) and red/white patches (58.0%) as signs of oral cancer. Age, gender, ethnicity, marital status, education, occupation and income were significantly associated with oral cancer awareness (p<0.05). There was a general lack of awareness regarding the risk habits, early signs and symptoms, and the benefits of detecting this disease at an early stage. Mass media and health campaigns were the main sources of information about oral cancer. In our Malaysian population, gender and age were significantly associated with the awareness of early signs and symptoms and prevention of oral cancer, respectively.

A selective medium for the isolation of Microbacterium species in oral cavities.

PubMed

Tsuzukibashi, Osamu; Uchibori, Satoshi; Kobayashi, Taira; Saito, Masanori; Umezawa, Koji; Ohta, Mitsuhiro; Shinozaki-Kuwahara, Noriko

2015-09-01

The genus Microbacterium has been isolated from the environment, dairy goods, and human clinical specimens. Although, in our previous studies, some Microbacterium species were infrequently detected in oral samples collected from humans, there is currently no report that these organisms, which are capable of causing serious systemic infections, were isolated from the human oral cavity. The aim of the present study was to develop a selective medium to isolate the representative Microbacterium species most frequently detected in human clinical specimens, and reveal the distribution of individual Microbacterium species in the oral cavity. The growth recoveries of representative Microbacterium species on the selective medium, designated as MSM, were sufficient. Moreover, the growth of other representative oral bacteria was markedly inhibited on the selective medium. The proportion of Microbacterium species in the saliva samples of 60 subjects, 20 of whom were removable denture wearers, was then examined. The proportion of these organisms was also examined in environmental samples obtained by swabbing 20 washstands. PCR primers were designed for representative Microbacterium species. The genus Microbacterium was detected in 45% of the saliva and denture plaque samples collected from the twenty removable denture wearers, but was absent in the saliva of the forty non-denture wearers. On the other hand, these organisms were detected in all environmental samples. The genus Microbacterium accounted for 0.00003%, 0.0001%, and 12.6% of the total cultivable bacteria number on the BHI medium in the saliva and denture plaque samples of removable denture wearers and in the environmental samples, respectively. The most predominant Microbacterium species in all positive samples was Microbacterium oxydans. These results indicated that the genus Microbacterium was not a part of the normal flora in the human oral cavity, except for subjects wearing dentures that were contaminated by the environment, and the selective medium, designated as MSM, was useful for isolating Microbacterium species, which are frequently encountered in human clinical specimens, from the various samples. Copyright © 2015 Elsevier B.V. All rights reserved.

Discovery of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442): a temperature-neutral transient receptor potential vanilloid-1 (TRPV1) antagonist with analgesic efficacy.

PubMed

Voight, Eric A; Gomtsyan, Arthur R; Daanen, Jerome F; Perner, Richard J; Schmidt, Robert G; Bayburt, Erol K; DiDomenico, Stanley; McDonald, Heath A; Puttfarcken, Pamela S; Chen, Jun; Neelands, Torben R; Bianchi, Bruce R; Han, Ping; Reilly, Regina M; Franklin, Pamela H; Segreti, Jason A; Nelson, Richard A; Su, Zhi; King, Andrew J; Polakowski, James S; Baker, Scott J; Gauvin, Donna M; Lewis, LaGeisha R; Mikusa, Joseph P; Joshi, Shailen K; Faltynek, Connie R; Kym, Philip R; Kort, Michael E

2014-09-11

The synthesis and characterization of a series of selective, orally bioavailable 1-(chroman-4-yl)urea TRPV1 antagonists is described. Whereas first-generation antagonists that inhibit all modes of TRPV1 activation can elicit hyperthermia, the compounds disclosed herein do not elevate core body temperature in preclinical models and only partially block acid activation of TRPV1. Advancing the SAR of this series led to the eventual identification of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442, 52), an analogue that possesses excellent pharmacological selectivity, has a favorable pharmacokinetic profile, and demonstrates good efficacy against osteoarthritis pain in rodents.

Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.

PubMed

Madar, David J; Kopecka, Hana; Pireh, Daisy; Yong, Hong; Pei, Zhonghua; Li, Xiaofeng; Wiedeman, Paul E; Djuric, Stevan W; Von Geldern, Thomas W; Fickes, Michael G; Bhagavatula, Lakshmi; McDermott, Todd; Wittenberger, Steven; Richards, Steven J; Longenecker, Kenton L; Stewart, Kent D; Lubben, Thomas H; Ballaron, Stephen J; Stashko, Michael A; Long, Michelle A; Wells, Heidi; Zinker, Bradley A; Mika, Amanda K; Beno, David W A; Kempf-Grote, Anita J; Polakowski, James; Segreti, Jason; Reinhart, Glenn A; Fryer, Ryan M; Sham, Hing L; Trevillyan, James M

2006-10-19

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.

Selumetinib, an Oral Anti-Neoplastic Drug, May Attenuate Cardiac Hypertrophy via Targeting the ERK Pathway

PubMed Central

Yang, Hao; Luo, Fangbo; Chen, Lihong; Cai, Huawei; Li, Yajiao; You, Guiying; Long, Dan; Li, Shengfu; Zhang, Qiuping; Rao, Li

2016-01-01

Aims Although extracellular-regulated kinases (ERK) are a well-known central mediator in cardiac hypertrophy, no clinically available ERK antagonist has been tested for preventing cardiac hypertrophy. Selumetinib is a novel oral MEK inhibitor that is currently under Phase II and Phase III clinical investigation for advanced solid tumors. In this study, we investigated whether Selumetinib could inhibit the aberrant ERK activation of the heart in response to stress as well as prevent cardiac hypertrophy. Methods and Results In an in vitro model of PE-induced cardiac hypertrophy, Selumetinib significantly inhibited the ERK activation and prevented enlargement of cardiomyocytes or reactivation of certain fetal genes. In the pathologic cardiac hypertrophy model of ascending aortic constriction, Selumetinib provided significant ERK inhibition in the stressed heart but not in the other organs. This selective ERK inhibition prevented left ventricular (LV) wall thickening, LV mass increase, fetal gene reactivation and cardiac fibrosis. In another distinct physiologic cardiac hypertrophy model of a swimming rat, Selumetinib provided a similar anti-hypertrophy effect, except that no significant fetal gene reactivation or cardiac fibrosis was observed. Conclusions Selumetinib, a novel oral anti-cancer drug with good safety records in a number of Phase II clinical trials, can inhibit ERK activity in the heart and prevent cardiac hypertrophy. These promising results indicate that Selumetinib could potentially be used to treat cardiac hypertrophy. However, this hypothesis needs to be validated in human clinical trials. PMID:27438013

In vitro and in vivo antiplasmodial activity of three Rwandan medicinal plants and identification of their active compounds.

PubMed

Muganga, Raymond; Angenot, Luc; Tits, Monique; Frédérich, Michel

2014-04-01

In our previous study, we reported the interesting in vitro antiplasmodial activity of some Rwandan plant extracts. This gave rise to the need for these extracts to also be evaluated in vivo and to identify the compounds responsible for their antiplasmodial activity. The aim of our study was, on the one hand, to evaluate the antiplasmodial activity in vivo and the safety of the selected Rwandan medicinal plants used in the treatment of malaria, with the objective of promoting the development of improved traditional medicines and, on the other hand, to identify the active ingredients in the plants. Plant extracts were selected according to their selectivity index. The in vivo antiplasmodial activity of aqueous, methanolic, and dichloromethane extracts was then evaluated using the classical 4-day suppressive test on Plasmodium berghei infected mice. The activity of the plant extracts was estimated by measuring the percentage of parasitemia reduction, and the survival of the experimental animals was recorded. A bioguided fractionation was performed for the most promising plants, in terms of antiplasmodial activity, in order to isolate active compounds identified by means of spectroscopic and spectrometric methods. The highest level of antiplasmodial activity was observed with the methanolic extract of Fuerstia africana (> 70 %) on days 4 and 7 post-treatment after intraperitoneal injection and on day 7 using oral administration. After oral administration, the level of parasitemia reduction observed on day 4 post-infection was 44 % and 37 % with the aqueous extract of Terminalia mollis and Zanthoxylum chalybeum, respectively. However, the Z. chalybeum extract presented a high level of toxicity after intraperitoneal injection, with no animals surviving on day 1 post-treatment. F. africana, on the other hand, was safer with 40 % mouse survival on day 20 post-treatment. Ferruginol is already known as the active ingredient in F. Africana, and ellagic acid (IC50 = 175 ng/mL) and nitidine (IC50 = 77.5 ng/mL) were identified as the main active constituents of T. mollis and Z. chalybeum, respectively. F. africana presented very promising antiplasmodial activity in vivo. Although most of the plants tested showed some level of antiplasmodial activity, some of these plants may be toxic. This study revealed for the first time the role of ellagic acid and nitidine as the main antimalarial compounds in T. mollis and Z. chalybeum, respectively. Georg Thieme Verlag KG Stuttgart · New York.

Studying Urban History through Oral History and Q Methodology: A Comparative Analysis.

ERIC Educational Resources Information Center

Jimenez, Rebecca S.

Oral history and Q methodology (a social science technique designed to document objectively and numerically the reactions of individuals to selected issues) were used to investigate urban renewal in Waco, Texas. Nineteen persons directly involved in the city's relocation and rehabilitation projects granted interviews. From these oral histories, 70…

Longitudinal Stability and Predictors of Poor Oral Comprehenders and Poor Decoders

PubMed Central

Elwér, Åsa; Keenan, Janice M.; Olson, Richard K.; Byrne, Brian; Samuelsson, Stefan

2012-01-01

Two groups of 4th grade children were selected from a population sample (N= 926) to either be Poor Oral Comprehenders (poor oral comprehension but normal word decoding), or Poor Decoders (poor decoding but normal oral comprehension). By examining both groups in the same study with varied cognitive and literacy predictors, and examining them both retrospectively and prospectively, we could assess how distinctive and stable the predictors of each deficit are. Predictors were assessed retrospectively at preschool, at the end of kindergarten, 1st, and 2nd grades. Group effects were significant at all test occasions, including those for preschool vocabulary (worse in poor oral comprehenders) and rapid naming (RAN) (worse in poor decoders). Preschool RAN and Vocabulary prospectively predicted grade 4 group membership (77–79% correct classification) within the selected samples. Reselection in preschool of at-risk poor decoder and poor oral comprehender subgroups based on these variables led to significant but relatively weak prediction of subtype membership at grade 4. Implications of the predictive stability of our results for identification and intervention of these important subgroups are discussed. PMID:23528975

Population-based screening program for reducing oral cancer mortality in 2,334,299 Taiwanese cigarette smokers and/or betel quid chewers.

PubMed

Chuang, Shu-Lin; Su, William Wang-Yu; Chen, Sam Li-Sheng; Yen, Amy Ming-Fang; Wang, Cheng-Ping; Fann, Jean Ching-Yuan; Chiu, Sherry Yueh-Hsia; Lee, Yi-Chia; Chiu, Han-Mo; Chang, Dun-Cheng; Jou, Yann-Yuh; Wu, Chien-Yuan; Chen, Hsiu-Hsi; Chen, Mu-Kuan; Chiou, Shu-Ti

2017-05-01

To reduce oral cancer mortality, an organized, population-based screening program for the early detection of oral premalignancy and oral cancer was designed for high-risk individuals with habits of betel quid chewing, cigarette smoking, or both. The objective of this report was to evaluate the long-term effectiveness of this program in reducing the incidence of advanced disease and deaths from oral cancer. A nationwide, population-based screening program for oral cancer has been conducted in Taiwan since 2004. Residents aged ≥ 18 years with oral habits of cigarette smoking and/or betel quid chewing were invited. The standardized mortality ratio method was used to compare the observed numbers of advanced oral cancers and deaths from oral cancer among screening attendees with the expected numbers derived from mortality among nonattendees. An intention-to-treat analysis of the relative rate of reductions in advanced-stage oral cancers and oral cancer mortality also was conducted. The overall screening rate was 55.1%. The relative risk of death from oral cancer was 0.53 (95% confidence interval [CI], 0.51-0.56) as a result of screening compared with the expected risk of oral cancer deaths in the absence of screening. The corresponding relative risk was 0.74 (95% CI, 0.72-0.77) after adjusting for self-selection bias. The relative risk of advanced oral cancer for the screened group versus the nonscreened group was 0.62 (95% CI, 0.59-0.64), which increased to 0.79 (95% CI, 0.76-0.82) after adjustment for self-selection bias. An organized, population-based oral cancer screening program targeting more than 2 million Taiwanese cigarette smokers and/or betel quid chewers demonstrated the effectiveness of reducing stage III or IV oral cancers and oral cancer mortality. These evidence-based findings corroborate and support the screening strategy of oral visual inspection for the prevention of oral cancer among high-risk individuals in areas with a high incidence of oral cancer. Cancer 2017;123:1597-1609. © 2017 American Cancer Society. © 2017 American Cancer Society.

High levels of telomere dysfunction bestow a selective disadvantage during the progression of human oral squamous cell carcinoma.

PubMed

Gordon, Katrina E; Ireland, Hazel; Roberts, Meryl; Steeghs, Karen; McCaul, James A; MacDonald, D Gordon; Parkinson, E Kenneth

2003-01-15

Human epithelial cells experience multiple barriers to cellular immortality in culture (mortality mechanisms 0, 1, and 2). Mortality mechanism 2 (M2) is termed crisis and involves telomere dysfunction due to lack of telomerase. However, proliferating normal keratinocytes in vivo can express telomerase, so it is unclear whether human squamous cell carcinomas (SCCs), which usually have high telomerase levels, develop from preexisting telomerase-positive precursors or by the activation of telomerase in telomerase-deficient somatic cells. We show that 6 of 29 oral SCCs show characteristics of M2 crisis in vivo, as indicated by a high anaphase bridge index (ABI), which is a good correlate of telomere dysfunction, and that 25 of 29 tumors possess some anaphase bridges. ABIs in excess of 0.2 in the primary tumor showed a decrease in the corresponding lymph node metastases. This suggests that high levels of telomere dysfunction (>0.2) and, by inference, M2 crisis bestow a selective disadvantage on SCCs during progression stages of the disease. Supporting this, SCCs with high levels of telomere dysfunction grow poorly in culture, and the ectopic expression of telomerase corrects this, together with other features of M2 crisis. Our data suggest that a substantial proportion of oral SCCs in vivo ultimately arise from telomerase-deficient keratinocytes rather than putative telomerase-proficient cells in the undifferentiated parts of the epithelium. Furthermore, the presence of significant levels of telomere dysfunction in a high proportion of SCCs at diagnosis but not in the normal epithelium implies that the therapeutic inhibition of telomerase should selectively compromise the growth of such tumors.

Development of an Oral Barley Beta-Glucan Adjuvant That Augments the Tumoricidal Activity of Antibodies or Vaccines Used for the Immunotherapy of Breast Cancer

DTIC Science & Technology

2003-07-01

These Data provided strong evidence for the efficacy of an oral beta - glucan adjuvant for use in combination with anti-tumor antibodies such as...oral beta - glucan . The data showing that antibodies must activate complement and deposit iC3b on tumors means that antibodies that do not to activate complement would not benefit from oral beta - glucan .

Knowledge of Oral Health Issues Among Low–Income Baltimore Adults: A Pilot Study

PubMed Central

Macek, Mark D.; Manski, Marion C.; Schneiderman, MaryAnn T.; Meakin, Sarah J.; Haynes, Don; Wells, William; Bauer–Leffler, Simon; Cotten, P. Ann; Parker, Ruth M.

2013-01-01

Purpose This pilot study documents conceptual knowledge of oral health among low–income adults in Baltimore. Methods Selected questions from the Baltimore Health Literacy and Oral Health Knowledge Project, a cross–sectional, population–based investigation of oral health literacy, were used for this analysis. Participants were asked questions during face–to–face interviews about basic oral health and the prevention and management of dental caries and periodontal diseases. Descriptive analyses included tests of association with selected socio–demographic variables (age, sex, education level, annual household income). Results The majority of respondents were African American women, 45 to 64 years of age, with 12 years of education and an income less than or equal to $25,000. Ninety–one percent of respondents knew that sugar caused dental caries, while 82% understood that the best way to prevent tooth decay was to brush and floss every day. Knowledge of oral hygiene practices and the prevention and management of gingivitis and periodontitis was mixed. Seventy–six percent understood that the best way to remove tartar was by a dental cleaning. However, only 15% knew how often to floss their teeth and only 21% knew that plaque was composed of germs. Conclusion Conceptual oral health knowledge is one component of oral health literacy. In turn, oral health literacy impacts communication. Practitioners should account for limited conceptual knowledge when they discuss oral health issues with their low–income and minority patients. If this is not accounted for, they will probably find that their oral hygiene education messages are being ignored and health promotion is being adversely affected. PMID:21396263

Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study.

PubMed

Fan, Xiaozhou; Alekseyenko, Alexander V; Wu, Jing; Peters, Brandilyn A; Jacobs, Eric J; Gapstur, Susan M; Purdue, Mark P; Abnet, Christian C; Stolzenberg-Solomon, Rachael; Miller, George; Ravel, Jacques; Hayes, Richard B; Ahn, Jiyoung

2018-01-01

A history of periodontal disease and the presence of circulating antibodies to selected oral pathogens have been associated with increased risk of pancreatic cancer; however, direct relationships of oral microbes with pancreatic cancer have not been evaluated in prospective studies. We examine the relationship of oral microbiota with subsequent risk of pancreatic cancer in a large nested case-control study. We selected 361 incident adenocarcinoma of pancreas and 371 matched controls from two prospective cohort studies, the American Cancer Society Cancer Prevention Study II and the National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. From pre-diagnostic oral wash samples, we characterised the composition of the oral microbiota using bacterial 16S ribosomal RNA (16S rRNA) gene sequencing. The associations between oral microbiota and risk of pancreatic cancer, controlling for the random effect of cohorts and other covariates, were examined using traditional and L1-penalised least absolute shrinkage and selection operator logistic regression. Carriage of oral pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans , were associated with higher risk of pancreatic cancer (adjusted OR for presence vs absence=1.60 and 95% CI 1.15 to 2.22; OR=2.20 and 95% CI 1.16 to 4.18, respectively). Phylum Fusobacteria and its genus Leptotrichia were associated with decreased pancreatic cancer risk (OR per per cent increase of relative abundance=0.94 and 95% CI 0.89 to 0.99; OR=0.87 and 95% CI 0.79 to 0.95, respectively). Risks related to these phylotypes remained after exclusion of cases that developed within 2 years of sample collection, reducing the likelihood of reverse causation in this prospective study. This study provides supportive evidence that oral microbiota may play a role in the aetiology of pancreatic cancer. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

An assessment of adhesion, aggregation and surface charges of Lactobacillus strains derived from the human oral cavity.

PubMed

Piwat, S; Sophatha, B; Teanpaisan, R

2015-07-01

There is limited information concerning the adhesion and aggregation of human oral lactobacilli. In this study, the adhesion of 10 Lactobacillus species was investigated using H357 oral keratinocyte cells as an in vitro model for oral mucosa. Coaggregation with the representative oral pathogen, Streptococcus mutans ATCC 25175, and the physicochemical cell properties was also evaluated. The results demonstrated significant variations in adhesion (42-96%) and aggregation (autoaggregation, 14-95%; coaggregation, 19-65%). All strains showed a high affinity for chloroform, and most strains had a moderate-to-high hydrophobicity. All strains, except Lactobacillus casei and Lactobacillus gasseri, showed a moderate affinity for ethyl acetate. There was a strong association of autoaggregation with coaggregation (rs = 0·883, P < 0·001). The highest mean for autoaggregation (74%) and coaggregation (47%) belonged to the Lact. gasseri strains. Correlations between the adhesion and surface characteristics and aggregation were observed among the Lactobacillus fermentum and Lactobacillus paracasei strains; however, there was a variation in the strains properties within and between species. This study indicated that the Lact. gasseri, Lact. fermentum, and Lact. paracasei strains might be potential probiotics for the human oral cavity given their desirable properties. It should also be emphasized that a selective process for probiotic strains is required. Adhesion to host tissues and bacterial aggregation (auto- and coaggregation) are the highly important criteria for selecting strains with probiotic potential. These abilities are commonly involved with surface-charged characteristics. This is the first study to investigate the oral Lactobacillus species using an oral keratinocyte cell line. Significant results were found for the correlations between the adhesion and surface charge characteristics and for aggregation among certain strains of Lactobacillus gasseri, Lactobacillus fermentum and Lactobacillus paracasei. This observation could be useful when collecting background information for the selection of probiotic strains for use in oral health. © 2015 The Society for Applied Microbiology.

Anaerobic bacteremia in a neutropenic patient with oral mucositis.

PubMed

Vidal, A M; Sarria, J C; Kimbrough, R C; Keung, Y K

2000-03-01

An increasing number of anaerobic bloodstream infections in neutropenic cancer patients have been reported in the last decade. The type of anaerobes isolated from most of these patients suggests an oral source of infection. We describe a case of anaerobic bacteremia in a neutropenic patient with oral mucositis that highlights the importance of considering these organisms when selecting empiric prophylactic or therapeutic antimicrobial regimens, especially in the setting of periodontal disease or oral mucositis.

miR-494 represses HOXA10 expression and inhibits cell proliferation in oral cancer.

PubMed

Libório-Kimura, Tatiana N; Jung, Hyun Min; Chan, Edward K L

2015-02-01

miR-494 was identified as a candidate of the most significantly underexpressed microRNAs (miRNAs) in our oral cancer screen. The aim of this study was to validate whether miR-494 has a functional role in oral cancer. Quantitative miRNA analyses were performed on oral tumor RNA and oral cancer cell lines. HOXA10 was selected for further analysis based on bioinformatics analysis of miR-494 targets and a previous report of overexpression of HOXA10 in oral cancer. Transient transfection of miRNA-mimic and inhibitor were performed in SCC-25 (tongue), CAL 27 (tongue), and FaDu (pharynx) cancer cells and regulation of HOXA10 by miR-494 was investigated. Dual luciferase assay was used to verify the interaction between miR-494 and HOXA10 in reporter cells. The effect of miR-494 on cell proliferation was examined. Our data showed that miR-494 was underexpressed whereas HOXA10 was overexpressed in oral cancer compared to normal tissues. An inverse correlation between miR-494 and HOXA10 was observed in the human tissues (p<0.05). Transient transfection of miR-494 in all cancer cell lines significantly reduced the expression of HOXA10 mRNA. The luciferase reporter that contains the 3'UTR of HOXA10 showed a significantly reduced luciferase activity by miR-494 indicating a direct interaction between HOXA10 and miR-494. Significant reduction in cell proliferation was demonstrated in tongue cancer cells transfected with miR-494. miR-494 repressed the expression of HOXA10 and also reduced the proliferation of oral cancer cells. These data give more evidence of the role of miR-494 as a tumor suppressor miRNA in oral cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

Skin permeation mechanism and bioavailability enhancement of celecoxib from transdermally applied nanoemulsion

PubMed Central

Shakeel, Faiyaz; Baboota, Sanjula; Ahuja, Alka; Ali, Javed; Shafiq, Sheikh

2008-01-01

Background Celecoxib, a selective cyclo-oxygenase-2 inhibitor has been recommended orally for the treatment of arthritis and osteoarthritis. Long term oral administration of celecoxib produces serious gastrointestinal side effects. It is a highly lipophilic, poorly soluble drug with oral bioavailability of around 40% (Capsule). Therefore the aim of the present investigation was to assess the skin permeation mechanism and bioavailability of celecoxib by transdermally applied nanoemulsion formulation. Optimized oil-in-water nanoemulsion of celecoxib was prepared by the aqueous phase titration method. Skin permeation mechanism of celecoxib from nanoemulsion was evaluated by FTIR spectral analysis, DSC thermogram, activation energy measurement and histopathological examination. The optimized nanoemulsion was subjected to pharmacokinetic (bioavailability) studies on Wistar male rats. Results FTIR spectra and DSC thermogram of skin treated with nanoemulsion indicated that permeation occurred due to the disruption of lipid bilayers by nanoemulsion. The significant decrease in activation energy (2.373 kcal/mol) for celecoxib permeation across rat skin indicated that the stratum corneum lipid bilayers were significantly disrupted (p < 0.05). Photomicrograph of skin sample showed the disruption of lipid bilayers as distinct voids and empty spaces were visible in the epidermal region. The absorption of celecoxib through transdermally applied nanoemulsion and nanoemulsion gel resulted in 3.30 and 2.97 fold increase in bioavailability as compared to oral capsule formulation. Conclusion Results of skin permeation mechanism and pharmacokinetic studies indicated that the nanoemulsions can be successfully used as potential vehicles for enhancement of skin permeation and bioavailability of poorly soluble drugs. PMID:18613981

Knowledge, perceived skills and activities of nursing staff to support oral home care among older domiciliary care clients.

PubMed

Salmi, Riikka; Tolvanen, Mimmi; Suhonen, Riitta; Lahti, Satu; Närhi, Timo

2018-04-25

Increasing number of older adults lives in their own homes, but needs help in many daily routines. Domiciliary care nursing staff (DCNS) is often needed to support oral home care. However, information of nursing staff's knowledge, skills and activity in this task is sparse. The study aimed to assess DCNS knowledge, perceived skills and activities to support oral home care of older domiciliary care clients. The study was conducted among DCNS in one of the largest cities in Finland. All DCNS members (n = 465) received a questionnaire with 14 multiple choice and open questions regarding the perceived skills, knowledge and activities of oral health guidance of older domiciliary care clients. In total, 115 (25%) DCNS members returned the questionnaires. Frequencies, percentages, means and standard deviations were used to describe the samples and study variables. DCNS was categorised according to age and working years for group comparisons, which were assessed with chi-squared test. Knowledge concerning oral health was mostly on a high level. Around 50% of DCNS considered their knowledge regarding dental prosthesis hygiene as sufficient. Of the DCNS, 67% informed that they had received education on oral health care. However, over 50% of the DCNS had a need for further education in issues related to oral home care. DCNS were active in supporting most oral and prosthesis hygiene means, yet less in guidance concerning toothbrushing. Activity to support cleaning the interdental spaces was the weakest, in which only 12% of the respondents considered having average or excellent skills. Younger DCNS had better knowledge on oral home care due to recent education, but older staff members were more skilful in performing oral hygiene measures. There is a need for structured instructions and training on oral home care for DCNS. Oral home care should be taken into account more often and regularly. © 2018 Nordic College of Caring Science.

Developing an Activity and Absorption-based Quality Control Platform for Chinese Traditional Medicine: Application to Zeng-Sheng-Ping

PubMed Central

Yin, Taijun; Yang, Guanyi; Ma, Yong; Xu, Beibei; Hu, Ming; You, Ming; Gao, Song

2015-01-01

Ethnopharmacological relevance Zeng-Sheng-Ping (ZSP) is a marketed Chinese traditional medicine used for cancer prevention. Aim of the study Currently, for the quality control of Chinese traditional medicines, marker compounds are not selected based on bioactivities and pharmaceutical behaviors in most of the cases. Therefore, even if the “quality” of the medicine is controlled, the pharmacological effect could still be inconsistent. The aim of this study is to establish an activity and absorption-based platform to select marker compound(s) for the quality control of Chinese traditional medicines. Materials and methods We used ZSP as a reference Chinese traditional medicine to establish the platform. Activity guided fractionation approach was used to purify the major components from ZSP. NMR and MS spectra were used to elucidate the structure of the isolated compounds. MTT assay against oral carcinoma cell line (SCC2095) was performed to evaluate the activities. UPLC-MS/MS was used to quantify the pure compounds in ZSP and the active fraction. The permeabilities of the identified compounds were evaluated in the Caco-2 cell culture model. The intracellular accumulation of the isolated compounds was evaluated in the SCC2095 cells. Results The major compounds were identified from ZSP. The contents, anti-proliferation activities, permeabilities, and intracellular accumulations of these compounds were also evaluated. The structure of these purified compounds were identified by comparing the NMR and MS data with those of references as rutaevine (1), limonin (2) , evodol (3), obacunone (4), fraxinellone (5), dictamnine (6), maackiain (7), trifolirhizin (8), and matrine (9). The IC50 of compounds 5, 6, and 7 against SCC2095 cells were significantly lower than that of ZSP. The uptake permeability of compounds 5, 6, and 7 were 2.58 ± 0. 3 × 10−5, 4.33 ± 0.5 × 10−5, and 4.27 ± 0.8 × 10−5 respectively in the Caco-2 cell culture model. The intracellular concentrations of these compounds showed that compounds 5, 6, and 7 were significantly accumulated inside the cells. Conclusion Based on the activity against oral carcinoma cell line as well as the absorption permeability, compound 5, 6, and 7 are selected as quality control markers for ZSP. A activity and absorption-based platform was established and successfully used for the quality control of ZSP. PMID:26099633

[Quality of the structured abstracts presented at a congress].

PubMed

dos Santos, Edilson F; Pereira, Maurício G

2007-01-01

To assess and compare quality of abstracts presented at a medical congress (XIV Congresso da Sociedade Brasileira de Infectologia, November, 2005). The hypothesis is that material of better quality is chosen for oral presentation. All the 63 abstracts selected for oral presentation were compared with a random sample (n=63) of the 664 abstracts registered as poster presentations. Quality was measured by a structured questionnaire comprised of 33 criteria, distributed in eight categories: purpose, research design, setting, subjects, intervention, measurement, results and conclusions. The questionnaire was applied by one of the authors who were not blind to the objective of the study. The final score could range from 0 (bad) to 1 (excellent). Abstracts quality was considered moderately good. The overall mean quality scores were 0.60 and 0.62 respectively, for poster and oral presentation (p = 0.086). The criteria rated poorly were: subjects, variable measurements, location and conclusion. The tested hypothesis of better quality in abstracts selected for oral presentation has not been confirmed. It is recommended that organizers of the congresses the use of objective quality criteria to select the form of presentation while improving on quality.

MEN15596, a novel nonpeptide tachykinin NK2 receptor antagonist.

PubMed

Cialdai, Cecilia; Tramontana, Manuela; Patacchini, Riccardo; Lecci, Alessandro; Catalani, Claudio; Catalioto, Rose-Marie; Meini, Stefania; Valenti, Claudio; Altamura, Maria; Giuliani, Sandro; Maggi, Carlo Alberto

2006-11-07

The pharmacological profile of MEN15596 or (6-methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide), a novel potent and selective tachykinin NK2 receptor antagonist endowed with oral activity, is described. At the human recombinant tachykinin NK2 receptor, MEN15596 showed subnanomolar affinity (pKi 10.1) and potently antagonized (pKB 9.1) the neurokinin A-induced intracellular calcium release. MEN15596 selectivity for the tachykinin NK2 receptor was assessed by binding studies at the recombinant tachykinin NK1 (pKi 6.1) and NK3 (pKi 6.4) receptors, and at a number of 34 molecular targets including receptors, transporters and ion channels. In isolated smooth muscle preparations MEN15596 showed a marked species selectivity at the tachykinin NK2 receptor with the highest antagonist potency in guinea-pig colon, human and pig bladder (pKB 9.3, 9.2 and 8.8, respectively) whereas it was three orders of magnitude less potent in the rat and mouse urinary bladder (pKB 6.3 and 5.8, respectively). In agreement with binding experiments, MEN15596 showed low potency in blocking selective NK1 or NK3 receptor agonist-induced contractions of guinea-pig ileum preparations (pA2

Selected Articles on Feeding Children Who Have a Neuromuscular Disorder. TIES: Therapy in Educational Settings.

ERIC Educational Resources Information Center

Hall, Sandra; And Others

The manual contains articles about evaluating and addressing the feeding needs of children who have oral-motor dysfunctions. "Helpful Hints for Feeding Children with Oral-Motor Dysfunction" (Janet Wilson) offers 20 suggestions relating to such areas as positioning the child, monitoring food preferences, and attending to oral hygiene.…

Miscue Analysis of Oral Reading among Less Proficient Readers in Primary Schools in Brunei Darussalam

ERIC Educational Resources Information Center

Hamid, Juliana Bte Haji Abdul; Abosi, Okechukwu

2011-01-01

Reading disability is the most common disability. At least one in five children has significant challenges learning to read. This study focused on the oral reading performance of 30 Year-Three students. The students were identified as less proficient readers from two randomly selected primary schools in Brunei Darussalam. The oral reading…

A novel double-tracer technique to characterize absorption, distribution, metabolism and excretion (ADME) of [14C]tofogliflozin after oral administration and concomitant intravenous microdose administration of [13C]tofogliflozin in humans.

PubMed

Schwab, Dietmar; Portron, Agnes; Backholer, Zoe; Lausecker, Berthold; Kawashima, Kosuke

2013-06-01

Human mass balance studies and the assessment of absolute oral bioavailability (F) are usually assessed in separate studies. Intravenous microdose administration of an isotope tracer concomitant to an unlabeled oral dose is an emerging technique to assess F. We report a novel double-tracer approach implemented for tofogliflozin combining oral administration of a radiolabel tracer with concomitant intravenous administration of a stable isotope tracer. Tofogliflozin is a potent and selective sodium/glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus currently in clinical development. The objectives of the present study were to assess the systemic exposure of major circulating metabolites, excretion balance, F and contribution of renal clearance (CLR) to total clearance (CL) of tofogliflozin in healthy subjects within one study applying a novel double-tracer technique. Six healthy male subjects received 20 mg [(12)C/(14)C]tofogliflozin (3.73 MBq) orally and a concomitant microdose of 0.1 mg [(13)C]tofogliflozin intravenously. Pharmacokinetics of tofogliflozin were determined for the oral and intravenous route; the pharmacokinetics of the metabolites M1 and M5 were determined for the oral route. Quantification of [(12)C]tofogliflozin in plasma and urine and [(13)C]tofogliflozin in plasma was performed by selective LC-MS/MS methods. For the pre-selected metabolites of tofogliflozin, M1 and M5, a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to plasma and urine samples. Total radioactivity was assessed in plasma, urine and feces. Pharmacokinetic analysis was conducted by non-compartmental methods. The pharmacokinetics of tofogliflozin in healthy subjects were characterized by an F of 97.5 ± 12.3 %, CL of 10.0 ± 1.3 l/h and volume of distribution at steady-state (V(ss)) of 50.6 ± 6.7 l. The main route of elimination of total drug-related material was by excretion into urine (77.0 ± 4.1 % of the dose). The observed CL(R) of 25.7 ± 5.0 ml/min was higher than the product of the estimated glomerular filtration rate (eGFR) and fraction unbound in plasma (f(u)) (eGFR × f(u) 15 ml/min), indicating the presence of net active tubular secretion in the renal elimination of tofogliflozin. However, CLR contributed only 15.5 % to the CL of tofogliflozin, suggesting that reductions in CLR by renal impairment won't significantly affect systemic exposure to tofogliflozin. Tofogliflozin and its metabolite M1 were the only major circulating entities accounting for 46 ± 8.6 and 50 ± 8.2 %, respectively, of total circulating drug-related material, while the metabolite M5 was a minor circulating metabolite accounting for 3.0 ± 0.3 % of total circulating drug-related material. Both the M1 and M5 metabolites were excreted into urine and the major metabolite M1 did not exhibit active tubular secretion. These results demonstrate the utility of the double-tracer approach to provide essential pharmacokinetic data and excretion data for drug-related material in one study at the same dosing occasion. The data obtained allowed the characterization of absorption, distribution, metabolism and excretion of tofogliflozin. Tofogliflozin exhibited highly favorable pharmacokinetic properties as demonstrated by its high F, low CL and a low V(ss. The presence of only one major circulating metabolite of tofogliflozin was unambiguously demonstrated. As a drug targeting the kidney, luminal exposure of the kidney is achieved by renal filtration and active tubular secretion.

Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates, in Ulcerative Colitis: systematic review and meta-analysis.

PubMed

Ford, Alexander C; Khan, Khurram J; Achkar, Jean-Paul; Moayyedi, Paul

2012-02-01

Efficacy of 5-aminosalicylic acids (5-ASAs) in ulcerative colitis (UC) has been studied previously in meta-analyses. However, no recent meta-analysis has studied the relative efficacies of differing routes of administration. MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through May 2011). Eligible trials recruited adults with mildly to moderately active UC, or quiescent UC, and compared oral 5-ASAs with either topical 5-ASAs or a combination of oral and topical 5-ASAs. Dichotomous data were pooled to obtain relative risk (RR) of failure to achieve remission in active UC, and RR of relapse of disease activity in quiescent UC, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference. The search identified 3,061 citations, and 12 randomized controlled trials (RCTs) were eligible. Four compared topical with oral 5-ASAs in active UC remission, with an RR of no remission with topical 5-ASAs of 0.82 (95% CI=0.52-1.28). Four trials compared combined with oral 5-ASAs in active UC (RR of no remission=0.65; 95% CI=0.47-0.91; NNT=5). Three RCTs compared intermittent topical with oral 5-ASAs in preventing relapse of quiescent UC (RR=0.64; 95% CI=0.43-0.95; NNT=4), and two compared combined with oral 5-ASAs (RR of relapse=0.48; 95% CI=0.17-1.38). Combined 5-ASA therapy appeared superior to oral 5-ASAs for induction of remission of mildly to moderately active UC. Intermittent topical 5-ASAs appeared superior to oral 5-ASAs for preventing relapse of quiescent UC.

Design of microemulsion system suitable for the oral delivery of poorly aqueous soluble beta-carotene.

PubMed

Peng, Cheng; Svirskis, Darren; Lee, Sung Je; Oey, Indrawati; Kwak, Hae-Soo; Chen, Guanyu; Bunt, Craig; Wen, Jingyuan

2017-02-14

Beta-carotene is a potent antioxidant for maintaining human health. However, its oral absorption is low due to poor aqueous solubility of less than 1 μg/ml. A microemulsion delivery system was designed to solubilize beta-carotene toward enhancing its oral bioavailability. From seven pseudoternary diagrams constructed, three systems were selected with large microemulsion areas suitable for oral administration and dilution in the predominately aqueous gastrointestinal fluids. Conductivity and rheology characterization were conducted along four dilution lines within the selected systems. Three pseudoternary-phase diagrams were selected with large microemulsion regions, >60% of the total phase diagram area, which provide microemulsions with higher drug-loading capacity. A phenomenon was observed by which both propylene glycol and Capmul MCM EP stabilize the microstructure of the microemulsions has been proposed based on the characterization studies. An optimal bicontinuous microemulsion formulation was selected comprising 12% orange oil, 24% Capmul MCM, 18% Tween 20, 6% Labrasol, 20% propylene glycol and 20% water, with a high beta-carotene loading capacity of 140.8 μg/ml and droplet size of 117.4 nm. In conclusion, the developed novel microemulsion formulation allows solubilizing beta-carotene and is a promising basis for further development as a functional beverage.

[Proteinase activity in Candida albicans strains isolated from the oral cavity of immunocompromised patients, with oral candidiasis and in healthy subjects].

PubMed

Hernández-Solís, Sandra E; Rueda-Gordillo, Florencio; Rojas-Herrera, Rafael A

2014-01-01

Candida albicans has a variety of virulence factors, including secreted aspartyl proteases, which are determinant factors in the pathogenesis of this yeast in immunocompromised patients. Proteinase activity was identified in C. albicans strains isolated from the oral cavity of immunocompromised patients with cancer, diabetes and HIV+, with oral candidiasis and in healthy subjects. Two hundred and fifty C. albicans strains were analyzed, distributed in 5 different groups: patients with cancer, diabetes, HIV+, with oral candidiasis and healthy subjects. Proteolytic activity was identified in 46% of the strains from cancer patients, 54% from HIV+ patients, 60% from diabetics, 70% from oral candidiasis patients, and 42% from healthy subjects. Activity was higher in strains from immunocompromised and oral candidiasis patients than in healthy subjects. Differences were observed between the candidiasis-healthy, candidiasis-HIV+, and diabetic-healthy groups. No differences were observed between the oral candidiasis, diabetes and cancer patients, between the diabetes and HIV+ patients, or between the cancer patients, HIV+ patients and healthy subjects. The present results suggest that although secreted aspartyl proteases are important in the pathogenesis of C. albicans, their activity depends on host conditions. Copyright © 2012 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

Comparative biodistribution and safety profiling of olmesartan medoxomil oil-in-water oral nanoemulsion.

PubMed

Gorain, Bapi; Choudhury, Hira; Tekade, Rakesh Kumar; Karan, Saumen; Jaisankar, P; Pal, Tapan Kumar

2016-12-01

Poor aqueous solubility and unfavourable de-esterification of olmesartan medoxomil (a selective angiotensin II receptor blocker), results in low oral bioavailability of less than 26%. Improvement of oral bioavailability with prolonged pharmacodynamics activity of olmesartan in Wistar rats had been approached by nanoemulsification strategy in our previous article [Colloid Surface B, 115, 2014: 286]. In continuation to that work, we herewith report the biodistribution behaviour and 28-day repeated dose sub-chronic toxicity of olmesartan medoxomil nanoemulsion in Wistar rats following oral administration. The levels of olmesartan in collected biological samples were estimated using our validated LC-MS/MS technique. Our biodistribution study showed significantly higher brain concentrations of olmesartan (0.290 ± 0.089 μg/mL, 0.333 ± 0.071 μg/mL and 0.217 ± 0.062 μg/mL at 0.5, 2.0 and 8.0 h post dosing, respectively) when administered orally as nanoemulsion formulation as compared to the aqueous suspension. In addition, the olmesartan nanoemulsion was found to be safe and non-toxic, as it neither produced any lethality nor remarkable haematological, biochemical and structural adverse effects as observed during the 28-days sub-chronic toxicity studies in experimental Wistar rats. It is herewith envisaged that the developed nanoemulsion formulation approach for the delivery of olmesartan medoxomil via oral route can further be explored in memory dysfunction and brain ischemia, for better brain penetration and improved clinical application in stroke patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Oral delivery of insulin via polyethylene imine-based nanoparticles for colonic release allows glycemic control in diabetic rats.

PubMed

Salvioni, Lucia; Fiandra, Luisa; Del Curto, Maria Dorly; Mazzucchelli, Serena; Allevi, Raffaele; Truffi, Marta; Sorrentino, Luca; Santini, Benedetta; Cerea, Matteo; Palugan, Luca; Corsi, Fabio; Colombo, Miriam

2016-08-01

In this study, insulin-containing nanoparticles were loaded into pellet cores and orally administered to diabetic rats. Polyethylene imine-based nanoparticles, either placebo or loaded with insulin, were incorporated by extrusion and spheronization technology into cores that were subsequently coated with three overlapping layers and a gastroresistant film. The starting and coated systems were evaluated in vitro for their physico-technololgical characteristics, as well as disintegration and release performance. Nanoparticles-loaded cores showed homogeneous particle size distribution and shape. When a superdisintegrant and a soluble diluent were included in the composition enhanced disintegration and release performance were observed. The selected formulations, coated either with enteric or three-layer films, showed gastroresistant and release delayed behavior in vitro, respectively. The most promising formulations were finally tested for their hypoglycemic effect in diabetic rats. Only the nanoformulations loaded into the three-layer pellets were able to induce a significant hypoglycemic activity in diabetic rats. Our results suggest that this efficient activity could be attributed to a retarded release of insulin into the distal intestine, characterized by relatively low proteolytic activity and optimal absorption. Copyright © 2016 Elsevier Ltd. All rights reserved.

Immunomodulatory properties of 1,2-dihydro-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxamide derivative VL15.

PubMed

Malfitano, Anna Maria; Laezza, Chiara; Bertini, Simone; Marasco, Daniela; Tuccinardi, Tiziano; Bifulco, Maurizio; Manera, Clementina

2017-04-01

1,2-Dihydro-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxamide derivative VL15 has been recently developed as a selective cannabinoid CB2 receptor compound. Given the high selectivity of this compound at the cannabinoid CB2 receptor and the well-known protective function of this receptor in neurological disorders with autoimmune component like multiple sclerosis, we assessed the immunomodulatory properties of VL15. We assessed on activated peripheral blood mononuclear cells), proliferation and viability, cell cycle progression and measured activation markers and the expression of phosphorylated proteins. We found that VL15 reduces PBMC proliferation slightly affecting cell vitality, blocks the cell cycle progression and down-regulates the levels of T cell activation markers as well as the expression of phosphorylated proteins, NF-kB, IKKαβ, IKBα, ERK and Akt. VL15 was also used in drug-permeability assays on Caco-2 cell line to evaluate its oral bioavailability and on MDCKII-hMDR1 cell lines to estimate its propensity to cross the blood-brain barrier by passive diffusion, in order to potentially maintain its efficiency on the infiltrating auto-reactive lymphocytes in the central nervous system. In these models, VL15 showed high intestinal absorption and good blood-brain barrier penetration. Our findings suggest that VL15, by controlling the immune response, might find potential application as orally administered drug in pathologies like multiple sclerosis. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Blocking the mineralocorticoid receptor improves effectiveness of steroid treatment for low back pain in rats

PubMed Central

Ye, Ling; Xie, Wenrui; Strong, Judith A.; Zhang, Jun-Ming

2014-01-01

Background Localized inflammation of lumbar dorsal root ganglia (DRG) may contribute to low back pain. Local injections of corticosteroids used for low back pain are sometimes ineffective. Many corticosteroids activate not only the target glucocorticoid receptor (GR) but also the mineralocorticoid receptor (MR), which may have pro-inflammatory effects countering the effects of GR activation. Methods A low back pain model was implemented in rats (n = 6 -10 per group) by locally inflaming the L5 DRG. Sensory neuron excitability and mechanical hypersensitivity of the hind paws were measured. Tested steroids were applied locally to the inflamed DRG or orally. Results The selective MR blocker eplerenone reduced pain behaviors when given orally starting at the time of surgery, or starting 7 days later. The highly GR-selective agonist fluticasone, applied locally to the inflamed DRG, was much more effective in reducing mechanical hypersensitivity. The MR/GR agonist 6-α methylprednisolone, commonly injected for low back pain, reduced mechanical hypersensitivity when applied locally to the DRG, but was less effective than fluticasone. Its effectiveness was improved by combining it with local eplerenone. All tested steroids reduced hyperexcitability of myelinated sensory neurons (n = 71 – 220 cells per group) after inflammation, particularly abnormal spontaneous activity. Conclusions This preclinical study indicates the MR may play an important role in low back pain involving inflammation. Some MR effects may occur at the level of the sensory neuron. It may be useful to consider the action of clinically used steroids at the MR as well as at the GR. PMID:24781496

A novel orally available small molecule that inhibits hepatitis B virus expression.

PubMed

Mueller, Henrik; Wildum, Steffen; Luangsay, Souphalone; Walther, Johanna; Lopez, Anaïs; Tropberger, Philipp; Ottaviani, Giorgio; Lu, Wenzhe; Parrott, Neil John; Zhang, Jitao David; Schmucki, Roland; Racek, Tomas; Hoflack, Jean-Christophe; Kueng, Erich; Point, Floriane; Zhou, Xue; Steiner, Guido; Lütgehetmann, Marc; Rapp, Gianna; Volz, Tassilo; Dandri, Maura; Yang, Song; Young, John A T; Javanbakht, Hassan

2018-03-01

The hallmarks of chronic HBV infection are a high viral load (HBV DNA) and even higher levels (>100-fold in excess of virions) of non-infectious membranous particles containing the tolerogenic viral S antigen (HBsAg). Currently, standard treatment effectively reduces viremia but only rarely results in a functional cure (defined as sustained HBsAg loss). There is an urgent need to identify novel therapies that reduce HBsAg levels and restore virus-specific immune responsiveness in patients. We report the discovery of a novel, potent and orally bioavailable small molecule inhibitor of HBV gene expression (RG7834). RG7834 antiviral characteristics and selectivity against HBV were evaluated in HBV natural infection assays and in a urokinase-type plasminogen activator/severe combined immunodeficiency humanized mouse model of HBV infection, either alone or in combination with entecavir. Unlike nucleos(t)ide therapies, which reduce viremia but do not lead to an effective reduction in HBV antigen expression, RG7834 significantly reduced the levels of viral proteins (including HBsAg), as well as lowering viremia. Consistent with its proposed mechanism of action, time course RNA-seq analysis revealed a fast and selective reduction in HBV mRNAs in response to RG7834 treatment. Furthermore, oral treatment of HBV-infected humanized mice with RG7834 led to a mean HBsAg reduction of 1.09 log 10 compared to entecavir, which had no significant effect on HBsAg levels. Combination of RG7834, entecavir and pegylated interferon α-2a led to significant reductions of both HBV DNA and HBsAg levels in humanized mice. We have identified a novel oral HBV viral gene expression inhibitor that blocks viral antigen and virion production, that is highly selective for HBV, and has a unique antiviral profile that is clearly differentiated from nucleos(t)ide analogues. We discovered a novel small molecule viral expression inhibitor that is highly selective for HBV and unlike current therapy inhibits the expression of viral proteins by specifically reducing HBV mRNAs. RG7834 can therefore potentially provide anti-HBV benefits and increase HBV cure rates, by direct reduction of viral agents needed to complete the viral life cycle, as well as a reduction of viral agents involved in evasion of the host immune responses. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Oral health among Liberian refugees in Ghana.

PubMed

Mickenautsch, S; Rudolph, M J; Ogunbodede, E O; Chikte, U M

1999-04-01

To promote community involvement in the provision of oral health services. The project consisted of a four-week training course in oral health for selected refugees, an oral health survey based on WHO guidelines and conducted by the refugees themselves and the provision of oral health care services to the community by the trained refugees. Liberian refugee camp, Gomoa Buduburam in Ghana. Liberian refugees of all ages. Twelve refugees were given short term training in oral health. In the oral health survey, 196 refugees were clinically examined for dental caries, periodontal disease and malocclusion. DMFT (for dental caries), CPITN (for periodontal disease), and malocclusion scores for selected subjects. Also clinical services rendered. Oral health survey revealed a mean age (+/- SD) of 25.7 (+/- 9.5) years. Only thirty nine (19.9%) of the subjects were caries-free, and total DMFT was 2.5 +/- 2.2. Based on the CPITN, 107 (54.6%) required oral hygiene instructions (OHI), and 41 (20.9%) required prophylactic scaling with OHI. Forty four (22.5%) of the subjects had normal occlusion and 152 (77.5%) mild to severe malocclusion. Periodontal (75.5%), prosthetic (52.5%) interventions and extractions (34.2%) constituted the bulk of the treatment needs required. Clinical treatment was rendered by the trained refugees to 846 patients over a twelve month period. Relief programmes for refugees should emphasise a primary health care approach, focusing on prevention, based on appropriate technology, and promoting involvement by the refugee community in the provision of services.

Evidence for recombination between a sialidase (nanH) of Actinomyces naeslundii and Actinomyces oris, previously named ‘Actinomyces naeslundii genospecies 1 and 2’

PubMed Central

Do, Thuy; Henssge, Uta; Gilbert, Steven C; Clark, Douglas; Beighton, David

2008-01-01

Actinomyces spp., predominant members of human oral biofilms, may use extracellular sialidase to promote adhesion, deglycosylate immunoglobulins and liberation of nutrients. Partial nanH gene sequences (1077 bp) from Actinomyces oris (n =74), Actinomyces naeslundii (n =30), Actinomyces viscosus (n =1) and Actinomyces johnsonii (n =2) which included the active-site region and the bacterial neuraminidase repeats (BNRs) were compared. The sequences were aligned and each species formed a distinct cluster with five isolates having intermediate positions. These five isolates (two A. oris and three A. naeslundii) exhibited interspecies recombination. The nonsynonymous/synonymous ratio was <1 for both A. oris and A. naeslundii indicating that nanH in both species is under stabilizing selective pressure; nonsynonymous mutations are not selected. However, for A. oris significant negative values in tests for neutral selection suggested the rate of mutation in A. oris was greater than in A. naeslundii but with selection against nonsynonymous mutations. This was supported by the observation that the frequency of polymorphic sites in A. oris, which were monomorphic in A. naeslundii was significantly greater than the frequency of polymorphic sites in A. naeslundii which were monomorphic in A. oris (χ2=7.011; P =0.00081). The higher proportions of A. oris in the oral biofilm might be explained by the higher mutation rate facilitating an increased ability to respond successfully to environmental stress. PMID:18823396

Drug delivery strategies for poorly water-soluble drugs.

PubMed

Fahr, Alfred; Liu, Xiangli

2007-07-01

The drug candidates coming from combinatorial chemistry research and/or the drugs selected from biologically based high-throughput screening are quite often very lipophilic, as these drug candidates exert their pharmacological action at or in biological membranes or membrane-associated proteins. This challenges drug delivery institutions in industry or academia to develop carrier systems for the optimal oral and parenteral administration of these drugs. To mention only a few of the challenges for this class of drugs: their oral bioavailability is poor and highly variable, and carrier development for parenteral administration is faced with problems, including the massive use of surface-active excipients for solubilisation. Formulation specialists are confronted with an even higher level of difficulties when these drugs have to be delivered site specifically. This article addresses the emerging formulation designs for delivering of poorly water-soluble drugs.

Did Aboriginal Australians record a simultaneous eclipse and aurora in their oral traditions?

NASA Astrophysics Data System (ADS)

Fuller, Robert S.; Hamacher, Duane W.

2017-12-01

We investigate an Australian Aboriginal cultural story that seems to describe an extraordinary series of astronomical events occurring at the same time. We hypothesise that this was a witnessed natural event and explore natural phenomena that could account for the description. We select a thunderstorm, total solar eclipse, and strong Aurora Australis as the most likely candidates, then conclude a plausible date of 764 CE. We evaluate the different factors that would determine whether all these events could have been visible, include meteorological data, alternative total solar eclipse dates, solar activity cycles, aurorae appearances, and sky brightness during total solar eclipses. We conduct this study as a test-case for rigorously and systematically examining descriptions of rare natural phenomena in oral traditions, highlighting the difficulties and challenges with interpreting this type of hypothesis.

[In vitro antimicrobial, antiadherent and antifungal activity of Brazilian medicinal plants on oral biofilm microorganisms and strains of the genus Candida].

PubMed

Alves, Pollianna Muniz; Queiroz, Lélia Maria Guedes; Pereira, Jozinete Vieira; Pereira, Maria do Socorro Vieira

2009-01-01

The antimicrobial, antifungal and antiadherent activity of aroeira-do-sertão, mallow and guava tree on oral biofilm microorganisms and oral candidiasis was evaluated in vitro. The extracts were shown to be effective in inhibiting the growth of bacteria of the oral biofilm and fungi of oral candidiasis, thus suggesting that these extracts can be used as alternative means of dental therapy.

A RT-PCR method for selective amplification and phenotypic characterization of all three serotypes of Sabin-related polioviruses from viral mixtures.

PubMed

Costa, Eliane Veiga da; Campos, Renata de Mendonça; Tavares, Fernando Neto; Grégio, Cátia Regina Valério; Burlandy, Fernanda Marcicano; Silva, Edson Elias da

2012-08-01

Outbreaks caused by vaccine-derived polioviruses are challenging the final eradication of paralytic poliomyelitis. Therefore, the surveillance of the acute flaccid paralysis cases based on poliovirus isolation and characterization remains an essential activity. Due to the use of trivalent oral poliovirus vaccine (OPV), mixtures containing more than one serotype of Sabin-related polioviruses are frequently isolated from clinical samples. Because each poliovirus isolate needs to be individually analyzed, we designed polymerase chain reaction primers that can selectively distinguish and amplify a genomic segment of the three Sabin-related poliovirus serotypes present in mixtures, thus, optimizing the diagnosis and providing prompt information to support epidemiologic actions.

A genetic programming approach to oral cancer prognosis.

PubMed

Tan, Mei Sze; Tan, Jing Wei; Chang, Siow-Wee; Yap, Hwa Jen; Abdul Kareem, Sameem; Zain, Rosnah Binti

2016-01-01

The potential of genetic programming (GP) on various fields has been attained in recent years. In bio-medical field, many researches in GP are focused on the recognition of cancerous cells and also on gene expression profiling data. In this research, the aim is to study the performance of GP on the survival prediction of a small sample size of oral cancer prognosis dataset, which is the first study in the field of oral cancer prognosis. GP is applied on an oral cancer dataset that contains 31 cases collected from the Malaysia Oral Cancer Database and Tissue Bank System (MOCDTBS). The feature subsets that is automatically selected through GP were noted and the influences of this subset on the results of GP were recorded. In addition, a comparison between the GP performance and that of the Support Vector Machine (SVM) and logistic regression (LR) are also done in order to verify the predictive capabilities of the GP. The result shows that GP performed the best (average accuracy of 83.87% and average AUROC of 0.8341) when the features selected are smoking, drinking, chewing, histological differentiation of SCC, and oncogene p63. In addition, based on the comparison results, we found that the GP outperformed the SVM and LR in oral cancer prognosis. Some of the features in the dataset are found to be statistically co-related. This is because the accuracy of the GP prediction drops when one of the feature in the best feature subset is excluded. Thus, GP provides an automatic feature selection function, which chooses features that are highly correlated to the prognosis of oral cancer. This makes GP an ideal prediction model for cancer clinical and genomic data that can be used to aid physicians in their decision making stage of diagnosis or prognosis.

Effect of an oxygenating agent on oral bacteria in vitro and on dental plaque composition in healthy young adults.

PubMed

Fernandez y Mostajo, Mercedes; van der Reijden, Wil A; Buijs, Mark J; Beertsen, Wouter; Van der Weijden, Fridus; Crielaard, Wim; Zaura, Egija

2014-01-01

Oral bacteria live in symbiosis with the host. Therefore, when mouthwashes are indicated, selective inhibition of taxa contributing to disease is preferred instead of broad-spectrum antimicrobials. The potential selectivity of an oxygenating mouthwash, Ardox-X® (AX), has not been assessed. The aim of this study was to determine the antimicrobial potential of AX and the effects of a twice-daily oral rinse on dental plaque composition. In vitro, 16 oral bacterial strains were tested using agar diffusion susceptibility, minimum inhibitory and minimum bactericidal concentration tests. A pilot clinical study was performed with 25 healthy volunteers. Clinical assessments and microbiological sampling of supragingival plaque were performed at 1 month before the experiment (Pre-exp), at the start of the experiment (Baseline) and after the one-week experimental period (Post-exp). During the experiment individuals used AX mouthwash twice daily in absence of other oral hygiene measures. The microbiological composition of plaque was assessed by 16S rRNA gene amplicon sequencing. AX showed high inter-species variation in microbial growth inhibition. The tested Prevotella strains and Fusobacterium nucleatum showed the highest sensitivity, while streptococci and Lactobacillus acidophilus were most resistant to AX. Plaque scores at Pre-exp and Baseline visits did not differ significantly (p = 0.193), nor did the microbial composition of plaque. During a period of 7-days non-brushing but twice daily rinsing plaque scores increased from 2.21 (0.31) at Baseline to 2.43 (0.39) Post-exp. A significant microbial shift in composition was observed: genus Streptococcus and Veillonella increased while Corynebacterium, Haemophilus, Leptotrichia, Cardiobacterium and Capnocytophaga decreased (p ≤ 0.001). AX has the potential for selective inhibition of oral bacteria. The shift in oral microbiome after 1 week of rinsing deserves further research.

Characterization of a novel non-peptide vasopressin V1 receptor antagonist (OPC-21268) in the rat.

PubMed

Burrell, L M; Phillips, P A; Stephenson, J; Risvanis, J; Hutchins, A M; Johnston, C I

1993-08-01

A non-peptide, orally effective, vasopressin (AVP) V1 receptor antagonist 1-(1-[4-(3-acetylaminopropoxy) benzoyl]-4-piperidyl)-3,4-dihydro-2(1H)-quinolinone (OPC-21268) has recently been described. This paper reports the in-vitro and in-vivo characterization of OPC-21268 binding to vasopressin receptors in rat liver and kidney. OPC-21268 caused a concentration-dependent displacement of the selective V1 receptor antagonist radioligand, 125I-labelled [d(CH2)5,sarcosine7]AVP to V1 receptors in both rat liver and kidney medulla membranes. The concentration of OPC-21268 that displaced 50% of specific AVP binding (IC50) was 40 +/- 3 nmol/l for liver V1 and 15 +/- 2 nmol/l for kidney V1 receptors (mean +/- S.E.M.; n = 3). OPC-21268 had little effect on the selective V2 antagonist radioligand [3H]desGly-NH2(9)]d(CH2)5,D-Ile2,Ile4] AVP binding to V2 receptors in renal medulla membranes (IC50 > 0.1 mmol/l). After oral administration to rats, OPC-21268 was an effective V1 antagonist in a time- and dose-dependent manner. Binding kinetic studies showed that OPC-21268 acted as a competitive antagonist at the liver V1 receptor in vitro and in vivo, in addition to its in-vitro competitive effects at the renal V1 receptor. OPC-21268 shows promise as an orally active V1 antagonist.

In vitro evaluation of tigemonam, a novel oral monobactam.

PubMed Central

Tanaka, S K; Summerill, R A; Minassian, B F; Bush, K; Visnic, D A; Bonner, D P; Sykes, R B

1987-01-01

Tigemonam, a novel, orally administered monobactam, exhibited potent and specific activity in vitro against members of the family Enterobacteriaceae, Haemophilus influenzae, and Neisseria gonorrhoeae. Its activity was variable to poor against gram-positive bacteria, Acinetobacter spp., Pseudomonas aeruginosa, and anaerobes. Within its spectrum of activity, tigemonam was far superior to oral antibiotics currently available, including amoxicillin-clavulanic acid, cefaclor, and trimethoprim-sulfamethoxazole. In addition, tigemonam was superior to cefuroxime, which is under development as an oral pro-drug, and more active than cefixime against several genera of the Enterobacteriaceae. The activity of tigemonam against the enteric bacteria, Haemophilus species, and Neisseria species was, in general, comparable to that of the quinolone norfloxacin. The excellent activity of tigemonam against beta-lactamase-producing bacteria reflected its marked stability to hydrolysis by isolated enzymes. The expanded spectrum of activity against gram-negative bacteria observed with tigemonam thus extends oral beta-lactam coverage to include members of the Enterobacteriaceae that are intrinsically or enzymatically resistant to broad-spectrum penicillins and cephalosporins. PMID:3105448

Curriculum influence on interdisciplinary oral health education and practice.

PubMed

Clark, Melinda; Quinonez, Rocio; Bowser, Jonathan; Silk, Hugh

2017-06-01

Oral diseases are very prevalent across the lifespan and impact overall health, yet are largely preventable. The Smiles for Life (SFL) curriculum was created to educate healthcare providers about oral disease and support integration of oral health and primary care. This study examines SFL's influence on clinical practice and education. Surveys were sent to registered users of SFL. Users who self-identified as direct care providers (DCPs), or educators, were included in the analysis. Survey response rate was 18 percent, with 87 percent identifying as DCPs and 13 percent as educators. Across professions, 85 percent of DCPs reported SFL influencing their practice to some degree, with variance among profession type and experience. DCPs most commonly reported that SFL led them to improve how they conduct oral health activities, with 60 percent performing the activity more skillfully following completion of SFL. Fluoride varnish application was the most common practice behavior initiated, and caries risk assessments was the oral health activity affected to the greatest degree. A majority of educators (94 percent) reported that SFL led them to incorporate or enhance oral health in their teaching. SFL helped educators emphasize the importance of oral health, improved their ability to teach content, raised motivation, and reduced barriers to teaching oral health. Data supports that SFL is positively influencing oral health practice across professions, especially in areas of caries risk assessment and fluoride varnish application. SFL improves the frequency and quality with which DCPs and educators participate in oral health activities, and facilitates oral health inclusion in primary care. © 2017 American Association of Public Health Dentistry.

Unstimulated salivary flow, pH, proteins and oral health in patients with Juvenile Idiopathic Arthritis.

PubMed

Kobus, Agnieszka; Kierklo, Anna; Zalewska, Anna; Kuźmiuk, Anna; Szajda, Sławomir Dariusz; Ławicki, Sławomir; Bagińska, Joanna

2017-06-02

There have been inconsistent conclusions regarding salivary abnormalities and their effect on oral health of Juvenile Idiopathic Arthritis (JIA) patients. The purpose of the study was to evaluate the flow rate and selected biochemical parameters of unstimulated whole saliva in correlation to oral health in JIA children. Thirty-four JIA patients and 34 age- and sex-matched controls not affected by JIA (C) were divided into two groups: with mixed and permanent dentition. DMFT/dmft, gingival and simplified oral hygiene indices were evaluated. Salivary flow rate, pH, lysozyme, lactoferrin, salivary protein concentrations and peroxidase activity were assessed. The salivary flow rate was significantly lower in the total JIA group (0.41 ml/min) as compared with the C (0.51 ml/min) and in the permanent dentition of JIA children (0.43 ml/min) as compared with the C (0.61 ml/min). A significantly lower pH was observed in total (6.74), mixed (6.7) and permanent (6.76) dentition of JIA groups in comparison to the C (7.25, 7.21, 7.28 respectively). The specific activity of peroxidase was significantly higher in JIA patients (total 112.72 IU/l, mixed dentition 112.98 IU/l, permanent dentition 112.5 IU/l) than in the C group (total 70.03 IU/l, mixed dentition 71.83 IU/l, permanent dentition 68.61 IU/l). The lysozyme concentration in JIA patients (total and permanent dentition groups) was significantly higher than in the C group. There were no significant differences in lactoferrin and salivary protein concentrations. There were no statistically significant differences in oral status between JIA patients and C, respectively: DMFT = 5.71, dmft = 3.73, OHI-S = 0.95, GI = 0.25 and DMFT 5.71, dmft = 3.73, OHI-S = 0.85, GI = 0.24. The specific activity of peroxidase in the unstimulated whole saliva was inversely correlated with the GI index, whereas the salivary lysozyme concentration was inversely correlated with the dmft index in JIA patients. In the course of JIA occur a reduction of the resting salivary flow rate and a decrease of saliva pH. In spite of this, no differences in the clinical oral status between the JIA children population and the control group were found. The mobilisation of salivary peroxidase and lysozyme contributes to the maintenance of healthy oral tissues.

Anti-leukaemic activity of the TYK2 selective inhibitor NDI-031301 in T-cell acute lymphoblastic leukaemia.

PubMed

Akahane, Koshi; Li, Zhaodong; Etchin, Julia; Berezovskaya, Alla; Gjini, Evisa; Masse, Craig E; Miao, Wenyan; Rocnik, Jennifer; Kapeller, Rosana; Greenwood, Jeremy R; Tiv, Hong; Sanda, Takaomi; Weinstock, David M; Look, A Thomas

2017-04-01

Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T-cell acute lymphoblastic leukaemia (T-ALL) cells. Here we demonstrate the anti-leukaemic activity of a novel TYK2 inhibitor, NDI-031301. NDI-031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T-ALL cell lines. NDI-031301 treatment of human T-ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI-031301 treatment uniquely leads to activation of three mitogen-activated protein kinases (MAPKs), resulting in phosphorylation of ERK, SAPK/JNK and p38 MAPK coincident with PARP cleavage. Activation of p38 MAPK occurred within 1 h of NDI-031301 treatment and was responsible for NDI-031301-induced T-ALL cell death, as pharmacological inhibition of p38 MAPK partially rescued apoptosis induced by TYK2 inhibitor. Finally, daily oral administration of NDI-031301 at 100 mg/kg bid to immunodeficient mice engrafted with KOPT-K1 T-ALL cells was well tolerated, and led to decreased tumour burden and a significant survival benefit. These results support selective inhibition of TYK2 as a promising potential therapeutic strategy for T-ALL. © 2017 John Wiley & Sons Ltd.

Association between oral health knowledge and practices of Saudi pregnant women in Dammam, Saudi Arabia.

PubMed

Gaffar, B O; El Tantawi, M; Al-Ansari, A; AlAgl, A S

2016-09-25

This study assessed the association between oral health knowledge and practices of pregnant Saudi women selected from visitors to a government hospital in Dammam, Saudi Arabia in 2014. Women answered questions on oral health knowledge during pregnancy and knowledge of infant oral health. Most women (> 70%) knew that dental caries in children can be prevented, that pregnancy affects oral health and that dental treatment during pregnancy can negatively affect infants. Most women (> 80%) performed oral hygiene procedures but only 18% regularly visited the dentist. In a regression analysis, oral health knowledge was not significantly associated with reported oral hygiene practices. Women who visited the dentist regularly were more likely to know how to prevent caries in children, and that dental treatment during pregnancy and infant health were associated.

The Effect of Oral Medication on Wound Healing.

PubMed

Levine, Jeffrey M

2017-03-01

The purpose of this learning activity is to provide information about the effects of oral medications on wound healing. This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. After participating in this educational activity, the participant should be better able to:1. Identify oral medications that aid in wound healing.2. Recognize oral medications that interfere with wound healing. Given the accelerated medical discoveries of recent decades, there is a surprising lack of oral medications that directly improve wound healing. Of the oral medications available, most target ancillary aspects of wound care such as pain management, infection mitigation, and nutrition. This article describes oral pharmacologic agents intended to build new tissue and aid in wound healing, as well as an introduction to oral medications that interfere with wound healing. This review will not discuss the pharmacology of pain management or treatment of infection, nor will it address nutritional supplements.

Fibroblast Activation Protein-Alpha, a Serine Protease that Facilitates Metastasis by Modification of Diverse Microenvironments

DTIC Science & Technology

2011-10-01

lung tissue. We were not able to detect sufficient numbers of cells in this manner. We tried a different procedure for fixing the lungs after they...added after 24 hours. The films were fixed and evaluated microscopically. In four trials, 10 random microscopic fields were selected and... dosing by oral gavage once daily with 1.3 mg/kg L-valine-L-boroproline called talabostat (extracellular & intracellular DASH), 13.3 mg/kg L- glutamyl

TLR7 and 9 agonists are highly effective mucosal adjuvants for norovirus virus-like particle vaccines

PubMed Central

Hjelm, Brooke E; Kilbourne, Jacquelyn; Herbst-Kralovetz, Melissa M

2014-01-01

Virus-like particles (VLPs) are an active area of vaccine research, development and commercialization. Mucosal administration of VLPs provides an attractive avenue for delivery of vaccines with the potential to produce robust immune responses. Nasal and oral delivery routes are particularly intriguing due to differential activation of mucosa-associated lymphoid tissues. We compared both intranasal and oral administration of VLPs with a panel of toll-like receptor (TLR) agonists (TLR3, 5, 7, 7/8, and 9) to determine the mucosal adjuvant activity of these immunomodulators. We selected Norwalk virus (NV) VLPs because it is an effective model antigen and an active area of research and commercialization. To prioritize these adjuvants, VLP-specific antibody production in serum (IgG, IgG1, IgG2a), vaginal lavages (IgG, IgA), and fecal pellets (IgA) were measured across a longitudinal timeseries in vaccinated mice. Additional distal mucosal sites (nasal, brochoalveolar, salivary, and gastrointestinal) were evaluated for VLP-specific responses (IgA). Intranasal co-delivery of VLPs with TLR7 or TLR9 agonists produced the most robust and broad-spectrum immune responses, systemically and at distal mucosal sites inducing VLP-specific antibodies at all sites evaluated. In addition, these VLP-specific antibodies blocked binding of NV VLPs to histo-blood group antigen (H type 1), supporting their functionality. Oral administration and/or other TLR agonists tested in the panel did not consistently enhance VLP-specific immune responses. This study demonstrates that intranasal co-delivery of VLPs with TLR7 or TLR9 agonists provides dose-sparing advantages for induction of specific and functional antibody responses against VLPs (i.e., non-replicating antigens) in the respiratory, gastrointestinal, and reproductive tract. PMID:24280723

Preclinical investigation of the topical administration of phenserine: transdermal flux, cholinesterase inhibition, and cognitive efficacy.

PubMed

Utsuki, Tadanobu; Uchimura, Nao; Irikura, Mitsuru; Moriuchi, Hiroshi; Holloway, Harold W; Yu, Qian-Sheng; Spangler, Edward L; Mamczarz, Jacek; Ingram, Donald K; Irie, Tetsumi; Greig, Nigel H

2007-04-01

Phenserine (PS) was designed as a selective acetylcholinesterase (AChE) inhibitor, with a tartrate form (PST) for oral administration in mild to moderate Alzheimer's disease (AD). Recent phase 3 trials of PST in Europe indicate that any clinically relevant activity of PST may be limited by its duration of action. Like many oral drugs, bioavailability and plasma concentrations of PST are regulated by hepatic and gastrointestinal first-pass effects. To minimize the kinetic limitations of first-pass metabolism, transdermal formulations of PS and PST (ointment/patch) were developed and characterized in vitro and in vivo. Initial in vitro kinetic characterization of PS or PST formulations used a diffusion cell chamber and skin samples isolated from hairless mice. Liquid paraffin and fatty alcohol/propylene glycol (FAPG) were found to be suitable vehicles for ointment formulation. Addition of a penetration enhancer, 1-[2-(decylthio)ethyl]-azacyclopentane-2-one (HPE-101), improved stratum corneum permeability. Application of the optimal formulation of PS/HPE-101/FAPG to the shaved back of rats resulted in significantly lowered plasma and brain AChE activities and improved cognitive performance in animals with scopolamine-induced cognitive impairment. These results suggest that the transdermal application of AChE inhibitors may represent an effective therapeutic strategy for AD. Particular benefits over oral therapies might include avoiding first-pass metabolic effects and improved dosing compliance.

Fourier-transform-infrared-spectroscopy based spectral-biomarker selection towards optimum diagnostic differentiation of oral leukoplakia and cancer.

PubMed

Banerjee, Satarupa; Pal, Mousumi; Chakrabarty, Jitamanyu; Petibois, Cyril; Paul, Ranjan Rashmi; Giri, Amita; Chatterjee, Jyotirmoy

2015-10-01

In search of specific label-free biomarkers for differentiation of two oral lesions, namely oral leukoplakia (OLK) and oral squamous-cell carcinoma (OSCC), Fourier-transform infrared (FTIR) spectroscopy was performed on paraffin-embedded tissue sections from 47 human subjects (eight normal (NOM), 16 OLK, and 23 OSCC). Difference between mean spectra (DBMS), Mann-Whitney's U test, and forward feature selection (FFS) techniques were used for optimising spectral-marker selection. Classification of diseases was performed with linear and quadratic support vector machine (SVM) at 10-fold cross-validation, using different combinations of spectral features. It was observed that six features obtained through FFS enabled differentiation of NOM and OSCC tissue (1782, 1713, 1665, 1545, 1409, and 1161 cm(-1)) and were most significant, able to classify OLK and OSCC with 81.3 % sensitivity, 95.7 % specificity, and 89.7 % overall accuracy. The 43 spectral markers extracted through Mann-Whitney's U Test were the least significant when quadratic SVM was used. Considering the high sensitivity and specificity of the FFS technique, extracting only six spectral biomarkers was thus most useful for diagnosis of OLK and OSCC, and to overcome inter and intra-observer variability experienced in diagnostic best-practice histopathological procedure. By considering the biochemical assignment of these six spectral signatures, this work also revealed altered glycogen and keratin content in histological sections which could able to discriminate OLK and OSCC. The method was validated through spectral selection by the DBMS technique. Thus this method has potential for diagnostic cost minimisation for oral lesions by label-free biomarker identification.

Oral health of early head start children: a qualitative study of staff, parents, and pregnant women.

PubMed

Mofidi, Mahyar; Zeldin, Leslie P; Rozier, R Gary

2009-02-01

We explored the oral health knowledge, attitudes, and activities of Early Head Start (EHS) staff members, parents, and pregnant women, along with their suggestions related to future oral health educational interventions targeting EHS children. Nine focus groups were conducted with EHS staff, parents, and pregnant women. Audiotapes of sessions were transcribed and entered into ATLAS.ti 5.0 for coding and analysis. Attitudes about the importance of children's oral health among parents and pregnant women were mixed. Staff members voiced responsibility for children's oral health but frustration in their inability to communicate effectively with parents. Parents in turn perceived staff criticism regarding how they cared for their children's oral health. Gaps were noted in the oral health activities of EHS programs. Participants expressed confusion regarding the application of Head Start oral health performance standards to EHS. The need for culturally sensitive, hands-on oral health education was highlighted. Tailored, theory-based interventions are needed to improve communication between EHS staff and families. Clear policies on the application of Head Start oral health performance standards to EHS are warranted. Educational activities should address the needs and suggestions of EHS participants.

High In Vitro Activity of the Novel Spiropyrimidinetrione AZD0914, a DNA Gyrase Inhibitor, against Multidrug-Resistant Neisseria gonorrhoeae Isolates Suggests a New Effective Option for Oral Treatment of Gonorrhea

PubMed Central

Jacobsson, Susanne; Golparian, Daniel; Alm, Richard A.; Huband, Michael; Mueller, John; Jensen, Jorgen Skov; Ohnishi, Makoto

2014-01-01

We evaluated the activity of the novel spiropyrimidinetrione AZD0914 (DNA gyrase inhibitor) against clinical gonococcal isolates and international reference strains (n = 250), including strains with diverse multidrug resistance and extensive drug resistance. The AZD0914 MICs were substantially lower than those of most other currently or previously recommended antimicrobials. AZD0914 should be further evaluated, including in vitro selection, in vivo emergence and mechanisms of resistance, pharmacokinetics/pharmacodynamics in humans, optimal dosing, and performance, in appropriate randomized and controlled clinical trials. PMID:24982070

In vitro antimicrobial activity of ten medicinal plants against clinical isolates of oral cancer cases

PubMed Central

2011-01-01

Background Suppression of immune system in treated cancer patients may lead to secondary infections that obviate the need of antibiotics. In the present study, an attempt was made to understand the occurrence of secondary infections in immuno-suppressed patients along with herbal control of these infections with the following objectives to: (a) isolate the microbial species from the treated oral cancer patients along with the estimation of absolute neutrophile counts of patients (b) assess the in vitro antimicrobial activity medicinal plants against the above clinical isolates. Methods Blood and oral swab cultures were taken from 40 oral cancer patients undergoing treatment in the radiotherapy unit of Regional Cancer Institute, Pt. B.D.S. Health University, Rohtak, Haryana. Clinical isolates were identified by following general microbiological, staining and biochemical methods. The absolute neutrophile counts were done by following the standard methods. The medicinal plants selected for antimicrobial activity analysis were Asphodelus tenuifolius Cav., Asparagus racemosus Willd., Balanites aegyptiaca L., Cestrum diurnum L., Cordia dichotoma G. Forst, Eclipta alba L., Murraya koenigii (L.) Spreng. , Pedalium murex L., Ricinus communis L. and Trigonella foenum graecum L. The antimicrobial efficacy of medicinal plants was evaluated by modified Kirby-Bauer disc diffusion method. MIC and MFC were investigated by serial two fold microbroth dilution method. Results Prevalent bacterial pathogens isolated were Staphylococcus aureus (23.2%), Escherichia coli (15.62%), Staphylococcus epidermidis (12.5%), Pseudomonas aeruginosa (9.37%), Klebsiella pneumonia (7.81%), Proteus mirabilis (3.6%), Proteus vulgaris (4.2%) and the fungal pathogens were Candida albicans (14.6%), Aspergillus fumigatus (9.37%). Out of 40 cases, 35 (87.5%) were observed as neutropenic. Eight medicinal plants (A. tenuifolius, A. racemosus, B. aegyptiaca, E. alba, M. koenigii, P. murex R. communis and T. foenum graecum) showed significant antimicrobial activity (P < .05) against most of the isolates. The MIC and MFC values were ranged from 31 to 500 μg/ml. P. aeruginosa was observed highest susceptible bacteria (46.6%) on the basis of susceptible index. Conclusion It can be concluded that treated oral cancer patients were neutropenic and prone to secondary infection of microbes. The medicinal plant can prove as effective antimicrobial agent to check the secondary infections in treated cancer patients. PMID:21599889

In vitro antimicrobial activity of ten medicinal plants against clinical isolates of oral cancer cases.

PubMed

Panghal, Manju; Kaushal, Vivek; Yadav, Jaya P

2011-05-20

Suppression of immune system in treated cancer patients may lead to secondary infections that obviate the need of antibiotics. In the present study, an attempt was made to understand the occurrence of secondary infections in immuno-suppressed patients along with herbal control of these infections with the following objectives to: (a) isolate the microbial species from the treated oral cancer patients along with the estimation of absolute neutrophile counts of patients (b) assess the in vitro antimicrobial activity medicinal plants against the above clinical isolates. Blood and oral swab cultures were taken from 40 oral cancer patients undergoing treatment in the radiotherapy unit of Regional Cancer Institute, Pt. B.D.S. Health University,Rohtak, Haryana. Clinical isolates were identified by following general microbiological, staining and biochemical methods. The absolute neutrophile counts were done by following the standard methods. The medicinal plants selected for antimicrobial activity analysis were Asphodelus tenuifolius Cav., Asparagus racemosus Willd., Balanites aegyptiaca L., Cestrum diurnum L., Cordia dichotoma G. Forst, Eclipta alba L., Murraya koenigii (L.) Spreng. , Pedalium murex L., Ricinus communis L. and Trigonella foenum graecum L. The antimicrobial efficacy of medicinal plants was evaluated by modified Kirby-Bauer disc diffusion method. MIC and MFC were investigated by serial two fold microbroth dilution method. Prevalent bacterial pathogens isolated were Staphylococcus aureus (23.2%), Escherichia coli (15.62%), Staphylococcus epidermidis (12.5%), Pseudomonas aeruginosa (9.37%), Klebsiella pneumonia (7.81%), Proteus mirabilis (3.6%), Proteus vulgaris (4.2%) and the fungal pathogens were Candida albicans (14.6%), Aspergillus fumigatus (9.37%). Out of 40 cases, 35 (87.5%) were observed as neutropenic. Eight medicinal plants (A. tenuifolius, A. racemosus, B. aegyptiaca, E. alba, M. koenigii, P. murex R. communis and T. foenum graecum) showed significant antimicrobial activity (P < .05) against most of the isolates. The MIC and MFC values were ranged from 31 to 500 μg/ml. P. aeruginosa was observed highest susceptible bacteria (46.6%) on the basis of susceptible index. It can be concluded that treated oral cancer patients were neutropenic and prone to secondary infection of microbes. The medicinal plant can prove as effective antimicrobial agent to check the secondary infections in treated cancer patients.

The relationship between oral health education and quality of life in adolescents.

PubMed

Carvalho, Jefferson Calixto; Rebelo, Maria Augusta Bessa; Vettore, Mario Vianna

2013-07-01

There is no study on the association between oral health education and oral health quality of life (OHQoL). To assess the relationship between oral health education activities integrated into primary care services and OHQoL in adolescents. A retrospective observational survey was conducted on 300 randomly selected 12-14 years-of-age adolescents living in two publicly funded health service administrative areas in Manaus, Brazil. Between 2006 and 2008, dental treatment and oral health education were offered in one area (DT/OHE group), whereas in the other area, only dental treatment was provided (DT group). Collected data included socio-demographic characteristics, health services use, health-related behaviours, dental pain, dental caries and Child-OIDP. Independent variables were compared between groups by Mann-Whitney and chi-square tests. The association between one or more OIDP (Child-OIDP ≥ 1) and DT group tested using multivariate logistic regression. Caries, use of dental services and health-related behaviours did not differ between groups (P > 0.05). Child-OIDP ≥ 1 was higher in DT group (90.0%) compared with DT/OHE group (79.3%) (P = 0.01). Child-OIDP ≥ 1 was independently associated with DT group [OR = 4.4 (1.1; 17.0)]. Adolescents living in an area where OHE and DT were provided had better OHRQoL than those living in an area where only DT was provided. © 2012 John Wiley & Sons Ltd, BSPD and IAPD.

[The introduction of generic pharmaceutical products into Galicia].

PubMed

Verdejo González, A; López-Lázaro, L; Rodríguez Moreno, C; Piñeiro Lago, B; Pereira Martínez, M L

1999-11-30

To know the evolution of the introduction of generic drugs (GDs) in Galicia. Secondarily, to evaluate its potential impact on pharmaceutical expenditure. Descriptive study of GDs utilization. Cost-minimization analysis. Galician autonomous region, year 1998. Using data from the prescription billing registry of Social Security we have selected the active ingredients corresponding to GDs with prescriptions in Galicia in 1997. We have analyzed the data for their oral single substance preparations by quarters. Consumption in DHDs of allopurinol, atenolol, captopril, naproxen and ranitidine remained stable during 1998. The market share for their GDs in quantitative terms relative to both total consumption of the active ingredients and to their pharmaceutical equivalents, showed an overall growing trend. The maximum observed value was seen for ranitidine at last quarter. Total expenditure (in final customer prices) during 1998 on the selected active substances was higher than 1864 million pesetas. Potential savings afforded by substitution for the lowest price GD prescribed in Galicia would reach 427 million pesetas. GDs market penetration in Galicia during 1998 was limited but increasing. Its utilization may afford estimated savings of 21-28% of the cost for the selected drugs. However, the expenditure on the above drugs was just 2.7% of total pharmaceutical expenditure.

TS-071 is a novel, potent and selective renal sodium-glucose cotransporter 2 (SGLT2) inhibitor with anti-hyperglycaemic activity.

PubMed

Yamamoto, K; Uchida, S; Kitano, K; Fukuhara, N; Okumura-Kitajima, L; Gunji, E; Kozakai, A; Tomoike, H; Kojima, N; Asami, J; Toyoda, H; Arai, M; Takahashi, T; Takahashi, K

2011-09-01

The renal sodium-glucose cotransporter 2 (SGLT2) plays an important role in the reuptake of filtered glucose in the proximal tubule and therefore may be an attractive target for the treatment of diabetes mellitus. This study characterizes the pharmacological profile of TS-071 ((1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol hydrate), a novel SGLT2 inhibitor in vitro and in vivo. Inhibition of glucose uptake by TS-071 was studied in CHO-K1 cells stably expressing either human SGLT1 or SGLT2. Single oral dosing studies were performed in rats, mice and dogs to assess the abilities of TS-071 to increase urinary glucose excretion and to lower plasma glucose levels. TS-071 inhibited SGLT2 activity in a concentration-dependent manner and was a potent and highly selective inhibitor of SGLT2. Orally administered TS-071 increased urinary glucose excretion in Zucker fatty rats and beagle dogs at doses of 0.3 and 0.03 mg·kg(-1) respectively. TS-071 improved glucose tolerance in Zucker fatty rats without stimulating insulin secretion and reduced hyperglycaemia in streptozotocin (STZ)-induced diabetic rats and db/db mice at a dose of 0.3 mg·kg(-1). These data indicate that TS-071 is a potent and selective SGLT2 inhibitor that improves glucose levels in rodent models of type 1 and 2 diabetes and may be useful for the treatment for diabetes mellitus. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Application of a neutral community model to assess structuring of the human lung microbiome.

PubMed

Venkataraman, Arvind; Bassis, Christine M; Beck, James M; Young, Vincent B; Curtis, Jeffrey L; Huffnagle, Gary B; Schmidt, Thomas M

2015-01-20

DNA from phylogenetically diverse microbes is routinely recovered from healthy human lungs and used to define the lung microbiome. The proportion of this DNA originating from microbes adapted to the lungs, as opposed to microbes dispersing to the lungs from other body sites and the atmosphere, is not known. We use a neutral model of community ecology to distinguish members of the lung microbiome whose presence is consistent with dispersal from other body sites and those that deviate from the model, suggesting a competitive advantage to these microbes in the lungs. We find that the composition of the healthy lung microbiome is consistent with predictions of the neutral model, reflecting the overriding role of dispersal of microbes from the oral cavity in shaping the microbial community in healthy lungs. In contrast, the microbiome of diseased lungs was readily distinguished as being under active selection. We also assessed the viability of microbes from lung samples by cultivation with a variety of media and incubation conditions. Bacteria recovered by cultivation from healthy lungs represented species that comprised 61% of the 16S rRNA-encoding gene sequences derived from bronchoalveolar lavage samples. Neutral distribution of microbes is a distinguishing feature of the microbiome in healthy lungs, wherein constant dispersal of bacteria from the oral cavity overrides differential growth of bacteria. No bacterial species consistently deviated from the model predictions in healthy lungs, although representatives of many of the dispersed species were readily cultivated. In contrast, bacterial populations in diseased lungs were identified as being under active selection. Quantification of the relative importance of selection and neutral processes such as dispersal in shaping the healthy lung microbiome is a first step toward understanding its impacts on host health. Copyright © 2015 Venkataraman et al.

Effects of Compounded Stanford Modified Oral Rinse (MucoLox) on the Survival and Migration of Oral Keratinocytes and Fibroblasts: Implications for Wound Healing.

PubMed

Song, Guiyun; Banov, Daniel; Bassani, August S

2018-01-01

Several oral rinses are commercially available to alleviate the symptoms of oral mucositis. Prolonged retention of active pharmaceutical ingredients in the oral cavity is a major problem. In this study, we modified the Stanford oral rinse by including a proprietary mucoadhesive polymer called MucoLox, which we hypothesized would improve active pharmaceutical ingredient mucoadhesion. Characterization of this newly compounded oral rinse showed absence of cytotoxicity in human oral keratinocyte and fibroblast cell lines. The compounded formulation significantly stimulated the migration of these two cell lines in Oris Cell Migration Assay plates, better than the reference commercial product Magic mouthwash. Based on this in vitro study, the new Stanford modified oral rinse with MucoLox is safe and may promote healing of oral mucositis. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Urothelial conversion of 5-aminolevulinic acid to protoporphyrin IX following oral or intravesical administration

NASA Astrophysics Data System (ADS)

Moore, Ronald B.; Miller, Gerald G.; Brown, Kevin; Bhatnagar, Rakesh; Tulip, John; McPhee, Malcolm S.

1995-03-01

Preferential conversion of 5-aminolevulinic acid (5-ALA) to protoporphyrin-IX (Pp-IX) occurs in malignant tissue, with accumulation to diagnostic and therapeutic levels. Recent studies have suggested selective conversion in epithelial tissue following oral or intravenous administration. Topical application avoids systemic photosensitization. However, the glycosaminoglycan (GAG) layer lining the urinary bladder is believed to be a protective barrier generally limiting mucosal absorption. Our objective was to evaluate uptake and conversion of 5-ALA following intravesical or oral administration. Using a rat model, Pp-IX content within epithelial and muscularis layers was quantitated by fluorescence confocal microscopy. Following intravesical administration, Pp-IX accumulated predominantly in the urothelium; whereas following oral administration, Pp-IX accumulated in both the urothelium and muscularis. Intravesical 5-ALA administration is feasible and may afford selective photosensitization of the urothelium for treatment of carcinoma in situ.

Examination of antimicrobial activity of selected non-antibiotic medicinal preparations.

PubMed

Kruszewska, Hanna; Zareba, Tomasz; Tyski, Stefan

2012-01-01

The aim of this study was to detect and characterize the antimicrobial activity of non-antibiotic drugs, selected from the pharmaceutical products analyzed during the state control performed in National Medicines Institute, Warszawa, Poland. In 2010, over 90 pharmaceutical preparations have been randomly chosen from different groups of drugs. The surveillance study was performed on standard ATCC microbial strains used for drug control: S. aureus, E. coli, P. aeruginosa and C. albicans. It was shown that the drugs listed below inhibited growth of at least one of the examined strains: Arketis 20 mg tab. (paroxetine), Buvasodil 150 mg tab. (buflomedile), Halidor 100 mg tab. (bencyclane), Hydroxyzinum espefa 25 mg tab. (hydroxyzine), Norifaz 35 mg tab. (risedronate), Strattera 60 mg cap. (atomoxetine), Tamiflu 75 mg tab. (oseltamivir), Valpro-ratiopharm Chrono 300 mg tab. with longer dissolution (valproate), Vetminth oral paste 24 g+3 g/100 mL (niclozamide, oxybendazol). Strattera cap. showed broad activity spectrum. It inhibited growth of all examined strains (MIC of active substance -- atomoxetine ranged between 2.6-13 mg/mL).

Who continues to stock oral artemisinin monotherapy? Results of a provider survey in Myanmar.

PubMed

Thein, Si Thu; Sudhinaraset, May; Khin, Hnin Su Su; McFarland, Willi; Aung, Tin

2016-06-22

Artemisinin-based combination therapy (ACT) is a key strategy for global malaria elimination efforts. However, the development of artemisinin-resistant malaria parasites threatens progress and continued usage of oral artemisinin monotherapies (AMT) predisposes the selection of drug resistant strains. This is particularly a problem along the Myanmar/Thailand border. The artemisinin monotherapy replacement programme (AMTR) was established in 2012 to remove oral AMT from stocks in Myanmar, specifically by replacing oral AMT with quality-assured ACT and conducting behavioural change communication activities to the outlets dispensing anti-malarial medications. This study attempts to quantify the characteristics of outlet providers who continue to stock oral AMT despite these concerted efforts. A cross-sectional survey of all types of private sector outlets that were stocking anti-malarial drugs in 13 townships of Eastern Myanmar was implemented from July to August 2014. A total of 573 outlets were included. Bivariate and multivariable logistic regressions were conducted to assess outlet and provider-level characteristics associated with stocking oral AMT. In total, 2939 outlets in Eastern Myanmar were screened for presence of any anti-malarial drugs in August 2014. The study found that 573 (19.5 %) had some kind of oral anti-malarial drug in stock at the time of survey and among them, 96 (16.8 %) stocked oral AMT. In bivariate analyses, compared to health care facilities, itinerant drug vendors, retailers and health workers were less likely to stock oral AMT (33.3 vs 12.9, 10.0, 8.1 %, OR = 0.30, 0.22, 0.18, respectively). Providers who cut blister pack or sell partial courses (40.6 vs 11.7 %, OR 5.18, CI 3.18-8.44) and those who based their stock decision on consumer demand (32.8 vs 12.1 %, OR 3.54, CI 2.21-5.63) were more likely to stock oAMT. Multivariate logistic regressions produced similar significant associations. Private healthcare facilities and drug shops and providers who prioritize consumers' demand instead of recommended practices were more likely to stock oral AMT. Malaria elimination strategies should include targeted interventions to effectively reach those outlets.

Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

PubMed

Heightman, Tom D; Berdini, Valerio; Braithwaite, Hannah; Buck, Ildiko M; Cassidy, Megan; Castro, Juan; Courtin, Aurélie; Day, James E H; East, Charlotte; Fazal, Lynsey; Graham, Brent; Griffiths-Jones, Charlotte M; Lyons, John F; Martins, Vanessa; Muench, Sandra; Munck, Joanne M; Norton, David; O'Reilly, Marc; Palmer, Nick; Pathuri, Puja; Reader, Michael; Rees, David C; Rich, Sharna J; Richardson, Caroline; Saini, Harpreet; Thompson, Neil T; Wallis, Nicola G; Walton, Hugh; Wilsher, Nicola E; Woolford, Alison J-A; Cooke, Michael; Cousin, David; Onions, Stuart; Shannon, Jonathan; Watts, John; Murray, Christopher W

2018-05-31

Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1/2 modulating ERK1/2 inhibitors.

Host-associated bacterial taxa from Chlorobi, Chloroflexi, GN02, Synergistetes, SR1, TM7, and WPS-2 Phyla/candidate divisions

PubMed Central

Camanocha, Anuj; Dewhirst, Floyd E.

2014-01-01

Background and objective In addition to the well-known phyla Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, Spirochaetes, Fusobacteria, Tenericutes, and Chylamydiae, the oral microbiomes of mammals contain species from the lesser-known phyla or candidate divisions, including Synergistetes, TM7, Chlorobi, Chloroflexi, GN02, SR1, and WPS-2. The objectives of this study were to create phyla-selective 16S rDNA PCR primer pairs, create selective 16S rDNA clone libraries, identify novel oral taxa, and update canine and human oral microbiome databases. Design 16S rRNA gene sequences for members of the lesser-known phyla were downloaded from GenBank and Greengenes databases and aligned with sequences in our RNA databases. Primers with potential phylum level selectivity were designed heuristically with the goal of producing nearly full-length 16S rDNA amplicons. The specificity of primer pairs was examined by making clone libraries from PCR amplicons and determining phyla identity by BLASTN analysis. Results Phylum-selective primer pairs were identified that allowed construction of clone libraries with 96–100% specificity for each of the lesser-known phyla. From these clone libraries, seven human and two canine novel oral taxa were identified and added to their respective taxonomic databases. For each phylum, genome sequences closest to human oral taxa were identified and added to the Human Oral Microbiome Database to facilitate metagenomic, transcriptomic, and proteomic studies that involve tiling sequences to the most closely related taxon. While examining ribosomal operons in lesser-known phyla from single-cell genomes and metagenomes, we identified a novel rRNA operon order (23S-5S-16S) in three SR1 genomes and the splitting of the 23S rRNA gene by an I-CeuI-like homing endonuclease in a WPS-2 genome. Conclusions This study developed useful primer pairs for making phylum-selective 16S rRNA clone libraries. Phylum-specific libraries were shown to be useful for identifying previously unrecognized taxa in lesser-known phyla and would be useful for future environmental and host-associated studies. PMID:25317252

The Effectiveness of the Dramatic Activities in the Development of the Oral Performance Skills of Prep Students in English

ERIC Educational Resources Information Center

Zayed, Jihan El-Sayed Ahmed

2003-01-01

The goal of this study was to determine the effect of using some dramatic activities on developing the oral performance skills of second year prep school students in English. The dramatic activities included storytelling, story-acting, pantomime, puppetry, role-playing, reader's theater and choral reading. The oral performance skills were…

Phosphatidylinositol-specific phospholipase C activity in Lactobacillus rhamnosus with capacity to translocate.

PubMed

Rodriguez, A V; Baigorí, M D; Alvarez, S; Castro, G R; Oliver, G

2001-10-16

Phosphatidylinositol-specific phospholipase C (PI-PLC) activity was investigated in 25 different lactic acid bacteria (LAB) strains belonging to the genera Lactobacillus, Weisella, and Enterococcus. PI-PLC activity was detected in 44% of the strains studied in culture medium without carbon source. From the PI-PLC positive strains, Lactobacillus rhamnosus ATCC 7469 was selected for translocation studies. Healthy mice were orally administered with a daily dose of 2.0 x 10(9) of viable L. rhamnosus suspension. Viable bacteria were detected in liver and spleen of mice fed with LAB for 7 days. Bacterial colonies isolated from liver were biochemically characterized, and further subjected to randomly amplified polymorphic DNA. Amplification patterns of five strains displayed identical profiles to L. rhamnosus. PI-PLC activity was determined in the strains recovered from liver.

Chemotherapy of Second Stage Human African Trypanosomiasis: Comparison between the Parenteral Diamidine DB829 and Its Oral Prodrug DB868 in Vervet Monkeys

PubMed Central

Thuita, John K.; Wolf, Kristina K.; Murilla, Grace A.; Bridges, Arlene S.; Boykin, David W.; Mutuku, James N.; Liu, Qiang; Jones, Susan K.; Gem, Charles O.; Ching, Shelley; Tidwell, Richard R.; Wang, Michael Z.; Paine, Mary F.; Brun, Reto

2015-01-01

Human African trypanosomiasis (HAT, sleeping sickness) ranks among the most neglected tropical diseases based on limited availability of drugs that are safe and efficacious, particularly against the second stage (central nervous system [CNS]) of infection. In response to this largely unmet need for new treatments, the Consortium for Parasitic Drug Development developed novel parenteral diamidines and corresponding oral prodrugs that have shown cure of a murine model of second stage HAT. As a rationale for selection of one of these compounds for further development, the pharmacokinetics and efficacy of intramuscular (IM) active diamidine 2,5-bis(5-amidino-2-pyridyl)furan (DB829; CPD-0802) and oral prodrug2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868) were compared in the vervet monkey model of second stage HAT. Treatment was initiated 28 days post-infection of monkeys with T. b. rhodesiense KETRI 2537. Results showed that IM DB829 at 5 mg/kg/day for 5 consecutive days, 5 mg/kg/day every other day for 5 doses, or 2.5 mg/kg/day for 5 consecutive days cured all monkeys (5/5). Oral DB868 was less successful, with no cures (0/2) at 3 mg/kg/day for 10 days and cure rates of 1/4 at 10 mg/kg/day for 10 days and 20 mg/kg/day for 10 days; in total, only 2/10 monkeys were cured with DB868 dose regimens. The geometric mean plasma Cmax of IM DB829 at 5 mg/kg following the last of 5 doses was 25-fold greater than that after 10 daily oral doses of DB868 at 20 mg/kg. These data suggest that the active diamidine DB829, administered IM, should be considered for further development as a potential new treatment for second stage HAT. PMID:25654243

Study of antihyperglycaemic activity of medicinal plant extracts in alloxan induced diabetic rats

PubMed Central

Attanayake, Anoja P.; Jayatilaka, Kamani A. P. W.; Pathirana, Chitra; Mudduwa, Lakmini K. B.

2013-01-01

Background: Diabetes mellitus, for a long time, has been treated with plant derived medicines in Sri Lanka. Aim: The aim of this study is to determine the efficacy and dose response of oral antihyperglycaemic activity of eight Sri Lankan medicinal plant extracts, which are used to treat diabetes in traditional medicine in diabetic rats. Materials and Methods: Medicinal plants selected for the study on the basis of documented effectiveness and wide use among traditional Ayurveda physicians in the Southern region of Sri Lanka for the treatment of diabetes mellitus. The effect of different doses of aqueous stem bark extracts of Spondias pinnata (Anacardiaceae), Kokoona zeylanica (Celastraceae), Syzygium caryophyllatum (Myrtaceae), Gmelina arborea (Verbenaceae), aerial part extracts of Scoparia dulcis (Scrophulariaceae), Sida alnifolia (Malvaceae), leaf extract of Coccinia grandis (Cucurbitaceae) and root extract of Languas galanga (Zingiberaceae) on oral glucose tolerance test was evaluated. A single dose of 0.25, 0.50, 0.75, 1.00, 1.25, 2.00 g/kg of plant extract was administered orally to alloxan induced (150 mg/kg, ip) diabetic Wistar rats (n = 6). Glibenclamide (0.50 mg/kg) was used as the standard drug. The acute effect was evaluated over a 4 h period using area under the oral glucose tolerance curve. Statistical Analysis: The results were evaluated by analysis of variance followed by Dunnett's test. Results: The eight plant extracts showed statistically significant dose dependent improvement on glucose tolerance (P < 0.05). The optimum effective dose on glucose tolerance for six extracts was found to be 1.00 g/kg in diabetic rats with the exception of C. grandis: 0.75 g/kg and L. galanga: 1.25 g/kg. Conclusion: The aqueous extract of G. arborea, S. pinnata, K. zeylanica, S. caryophyllatum, S. dulcis, S. alnifolia, L. galanga and C. grandis possess potent acute antihyperglycaemic activity in alloxan induced diabetic rats. PMID:24991066

Study of antihyperglycaemic activity of medicinal plant extracts in alloxan induced diabetic rats.

PubMed

Attanayake, Anoja P; Jayatilaka, Kamani A P W; Pathirana, Chitra; Mudduwa, Lakmini K B

2013-04-01

Diabetes mellitus, for a long time, has been treated with plant derived medicines in Sri Lanka. The aim of this study is to determine the efficacy and dose response of oral antihyperglycaemic activity of eight Sri Lankan medicinal plant extracts, which are used to treat diabetes in traditional medicine in diabetic rats. Medicinal plants selected for the study on the basis of documented effectiveness and wide use among traditional Ayurveda physicians in the Southern region of Sri Lanka for the treatment of diabetes mellitus. The effect of different doses of aqueous stem bark extracts of Spondias pinnata (Anacardiaceae), Kokoona zeylanica (Celastraceae), Syzygium caryophyllatum (Myrtaceae), Gmelina arborea (Verbenaceae), aerial part extracts of Scoparia dulcis (Scrophulariaceae), Sida alnifolia (Malvaceae), leaf extract of Coccinia grandis (Cucurbitaceae) and root extract of Languas galanga (Zingiberaceae) on oral glucose tolerance test was evaluated. A single dose of 0.25, 0.50, 0.75, 1.00, 1.25, 2.00 g/kg of plant extract was administered orally to alloxan induced (150 mg/kg, ip) diabetic Wistar rats (n = 6). Glibenclamide (0.50 mg/kg) was used as the standard drug. The acute effect was evaluated over a 4 h period using area under the oral glucose tolerance curve. The results were evaluated by analysis of variance followed by Dunnett's test. The eight plant extracts showed statistically significant dose dependent improvement on glucose tolerance (P < 0.05). The optimum effective dose on glucose tolerance for six extracts was found to be 1.00 g/kg in diabetic rats with the exception of C. grandis: 0.75 g/kg and L. galanga: 1.25 g/kg. The aqueous extract of G. arborea, S. pinnata, K. zeylanica, S. caryophyllatum, S. dulcis, S. alnifolia, L. galanga and C. grandis possess potent acute antihyperglycaemic activity in alloxan induced diabetic rats.

The Flavonoid Jaceosidin from Artemisia princeps Induces Apoptotic Cell Death and Inhibits the Akt Pathway in Oral Cancer Cells.

PubMed

Han, Hye-Yeon; Kim, Hyung Joon; Jeong, Seung-Hwa; Kim, Jiyeon; Jeong, Sung-Hee; Kim, Gyoo Cheon; Hwang, Dae-Seok; Kim, Uk-Kyu; Ryu, Mi Heon

2018-01-01

Jaceosidin is a single compound from the Japanese mugwort Artemisia princeps , which is used as a food and a traditional medicinal herb. A. princeps extracts and flavonoid components have been shown to have antihyperglycaemic, antioxidant, and anti-inflammatory properties. Although the anticancer properties of these extracts were recently demonstrated, the related mechanisms have not been characterised. In this study, we investigated the effects of jaceosidin in oral squamous cell carcinoma (OSCC) cells and initially showed selective suppression of proliferation (IC 50 = 82.1  μ M in HSC-3 cells and 97.5  μ M in Ca9.22 cells) and accumulation of cells at the sub-G1 stage of the cell cycle. In addition, jaceosidin increased cleavage of caspase-9 and caspase-3 in OSCC cells, although caspase-8 was not detected. In further experiments, jaceosidin downregulated Akt phosphorylation and ectopic activation of Akt blocked the antiproliferative effects of jaceosidin. Finally, we showed that jaceosidin has no effects on HaCaT normal epithelial cell viability, indicating selective chemotherapeutic potential of jaceosidin and that tumour-specific downregulation of Akt increases apoptosis and inhibits growth in OSCC cells.

The Flavonoid Jaceosidin from Artemisia princeps Induces Apoptotic Cell Death and Inhibits the Akt Pathway in Oral Cancer Cells

PubMed Central

Han, Hye-Yeon; Kim, Hyung Joon; Jeong, Seung-Hwa; Kim, Jiyeon; Jeong, Sung-Hee; Kim, Gyoo Cheon; Hwang, Dae-Seok; Kim, Uk-Kyu

2018-01-01

Jaceosidin is a single compound from the Japanese mugwort Artemisia princeps, which is used as a food and a traditional medicinal herb. A. princeps extracts and flavonoid components have been shown to have antihyperglycaemic, antioxidant, and anti-inflammatory properties. Although the anticancer properties of these extracts were recently demonstrated, the related mechanisms have not been characterised. In this study, we investigated the effects of jaceosidin in oral squamous cell carcinoma (OSCC) cells and initially showed selective suppression of proliferation (IC50 = 82.1 μM in HSC-3 cells and 97.5 μM in Ca9.22 cells) and accumulation of cells at the sub-G1 stage of the cell cycle. In addition, jaceosidin increased cleavage of caspase-9 and caspase-3 in OSCC cells, although caspase-8 was not detected. In further experiments, jaceosidin downregulated Akt phosphorylation and ectopic activation of Akt blocked the antiproliferative effects of jaceosidin. Finally, we showed that jaceosidin has no effects on HaCaT normal epithelial cell viability, indicating selective chemotherapeutic potential of jaceosidin and that tumour-specific downregulation of Akt increases apoptosis and inhibits growth in OSCC cells. PMID:29861773

Speaking Activities and Reading.

ERIC Educational Resources Information Center

Ediger, Marlow

2000-01-01

Notes that each pupil needs to receive guidance and assistance to achieve as optimally as possible in oral communication. Discusses critical listening to the spoken voice, using puppets, using role play activities, committees in the classroom, giving oral reports, oral reading to classmates, giving and following directions, extemporaneous…

Speaking Activities and Reading.

ERIC Educational Resources Information Center

Ediger, Marlow

Pupils who are far along in their speaking vocabularies tend to do well in reading. This paper includes numerous speaking activities that bolster pupils' oral communication: the including use of puppets, role playing, committee endeavors, oral reports, oral reading, extemporaneous speaking, and giving directions. Additional experiences for pupils…

Effect of oral THC pretreatment on marijuana cue-induced responses in cannabis dependent volunteers.

PubMed

Lundahl, Leslie H; Greenwald, Mark K

2015-04-01

The current study tested whether oral Δ(9)-tetrahydrocannabinol (THC: 0-, 10-, and 20-mg) pretreatment would attenuate polysensory cue-induced craving for marijuana. Cannabis dependent participants (7 males and 7 females, who smoked on average 5.4 ± 1.1 blunts daily) completed 3 experimental sessions (oral THC pretreatment dose; counterbalanced order) using a placebo-controlled within-subject crossover design. During each session, participants completed a baseline evaluation and were first exposed to neutral cues then marijuana cues while physiological measures and subjective ratings of mood, craving, and drug effect were recorded. Following placebo oral THC pretreatment, marijuana (vs. neutral) cues significantly increased ratings of marijuana craving (desire and urge to use, Marijuana Craving Questionnaire (MCQ)-Compulsivity scale), anxious mood and feeling hungry. Males also reported feeling more "Down" during marijuana cues relative to females. Pretreatment with oral THC (10-mg and/or 20-mg vs. placebo) significantly attenuated marijuana cue-induced increases in craving and anxiety but not hunger. Oral THC attenuation of the cue-induced increase in MCQ-Compulsivity ratings was observed in females only. Oral THC produced statistically (but not clinically) significant increases in heart rate and decreases in diastolic blood pressure, independent of cues. These marijuana-cue findings replicate earlier results and further demonstrate that oral THC can attenuate selected effects during marijuana multi-cue exposure, and that some of these effects may be sex-related. Results of this study suggest oral THC may be effective for reducing marijuana cue-elicited (conditioned) effects. Further study is needed to determine whether females may selectively benefit from oral THC for this purpose. Copyright © 2015. Published by Elsevier Ireland Ltd.

A Psycholinguistic Description of the Oral and Written Language of a Selected Group of Middle School Children.

ERIC Educational Resources Information Center

Martellock, Helen Anna

Six highly skilled middle school readers read aloud a story from a basal reader, then orally retold the story in their own words, wrote a version of the story, and finally read their own version aloud. Typescripts made from audio tape were compared with typescripts of the written compositions. The oral and written retellings were analyzed for…

Influence of Media in the Choice of Oral Hygiene Products Used Among the Population of Maduravoyal, Chennai, India.

PubMed

Logaranjani, Anitha; Mahendra, Jaideep; Perumalsamy, Rajapriya; Narayan, Rajeshree Rangari; Rajendran, Sathish; Namasivayam, Ambalavanan

2015-10-01

To assess the factors influencing the awareness and practice of oral hygiene among the local population Maduravoyal, Chennai, India. A cross-sectional questionnaire based study was conducted to understand the factors influencing the choice and practice of oral hygiene products among the population of Maduravoyal, Chennai, India. Data was collected by means of a self administered structured questionnaire written in English and validated through a pilot survey. One thousand two hundred and nine subjects, with an age range of 15 to 70 years, who visited the Department of Periodontology, Meenakshi Ammal Dental College, Chennai were selected for investigation. The data obtained was analyzed using the SPSS version 13.0. The frequency of distribution and percentages were calculated. The results of the study showed that tooth brush (98.5%) and toothpaste (98%) were the main products used for the maintenance of oral hygiene and around 84.6% of the population brushed once daily. Information from the media (59.4%) and decay prevention (49.7%) were the major factors that influenced the choice of toothpaste among the study population. The major factor which influenced the choice of oral hygiene products was based on information obtained from advertisements and other sources. There is a need for the dental professionals to be aware of the ever-increasing development and marketing of oral hygiene products from various databases. Hence, the education of people regarding the importance of oral hygiene maintenance, proper selection of oral hygiene products is essential.

Discovery and characterization of ACT-335827, an orally available, brain penetrant orexin receptor type 1 selective antagonist.

PubMed

Steiner, Michel A; Gatfield, John; Brisbare-Roch, Catherine; Dietrich, Hendrik; Treiber, Alexander; Jenck, Francois; Boss, Christoph

2013-06-01

Stress relief: Orexin neuropeptides regulate arousal and stress processing through orexin receptor type 1 (OXR-1) and 2 (OXR-2) signaling. A selective OXR-1 antagonist, represented by a phenylglycine-amide substituted tetrahydropapaverine derivative (ACT-335827), is described that is orally available, penetrates the brain, and decreases fear, compulsive behaviors and autonomic stress reactions in rats. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Pathogen-Selective Antibiotic Minimizes Disturbance to the Microbiome

PubMed Central

Yao, Jiangwei; Carter, Robert A.; Vuagniaux, Grégoire; Barbier, Maryse; Rosch, Jason W.

2016-01-01

Broad-spectrum antibiotic therapy decimates the gut microbiome, resulting in a variety of negative health consequences. Debio 1452 is a staphylococcus-selective enoyl-acyl carrier protein reductase (FabI) inhibitor under clinical development and was used to determine whether treatment with pathogen-selective antibiotics would minimize disturbance to the microbiome. The effect of oral Debio 1452 on the microbiota of mice was compared to the effects of four commonly used broad-spectrum oral antibiotics. During the 10 days of oral Debio 1452 treatment, there was minimal disturbance to the gut bacterial abundance and composition, with only the unclassified S24-7 taxon reduced at days 6 and 10. In comparison, broad-spectrum oral antibiotics caused ∼100- to 4,000-fold decreases in gut bacterial abundance and severely altered the microbial composition. The gut bacterial abundance and composition of Debio 1452-treated mice were indistinguishable from those of untreated mice 2 days after the antibiotic treatment was stopped. In contrast, the bacterial abundance in broad-spectrum-antibiotic-treated mice took up to 7 days to recover, and the gut composition of the broad-spectrum-antibiotic-treated mice remained different from that of the control group 20 days after the cessation of antibiotic treatment. These results illustrate that a pathogen-selective approach to antibiotic development will minimize disturbance to the gut microbiome. PMID:27161626

Potential Role for a Carbohydrate Moiety in Anti-Candida Activity of Human Oral Epithelial Cells

PubMed Central

Steele, Chad; Leigh, Janet; Swoboda, Rolf; Ozenci, Hatice; Fidel, Paul L.

2001-01-01

Candida albicans is both a commensal and a pathogen at the oral mucosa. Although an intricate network of host defense mechanisms are expected for protection against oropharyngeal candidiasis, anti-Candida host defense mechanisms at the oral mucosa are poorly understood. Our laboratory recently showed that primary epithelial cells from human oral mucosa, as well as an oral epithelial cell line, inhibit the growth of blastoconidia and/or hyphal phases of several Candida species in vitro with a requirement for cell contact and with no demonstrable role for soluble factors. In the present study, we show that oral epithelial cell-mediated anti-Candida activity is resistant to gamma-irradiation and is not mediated by phagocytosis, nitric oxide, hydrogen peroxide, and superoxide oxidative inhibitory pathways or by nonoxidative components such as soluble defensin and calprotectin peptides. In contrast, epithelial cell-mediated anti-Candida activity was sensitive to heat, paraformaldehyde fixation, and detergents, but these treatments were accompanied by a significant loss in epithelial cell viability. Treatments that removed existing membrane protein or lipid moieties in the presence or absence of protein synthesis inhibitors had no effect on epithelial cell inhibitory activity. In contrast, the epithelial cell-mediated anti-Candida activity was abrogated after treatment of the epithelial cells with periodic acid, suggesting a role for carbohydrates. Adherence of C. albicans to oral epithelial cells was unaffected, indicating that the carbohydrate moiety is exclusively associated with the growth inhibition activity. Subsequent studies that evaluated specific membrane carbohydrate moieties, however, showed no role for sulfated polysaccharides, sialic acid residues, or glucose- and mannose-containing carbohydrates. These results suggest that oral epithelial cell-mediated anti-Candida activity occurs exclusively with viable epithelial cells through contact with C. albicans by an as-yet-undefined carbohydrate moiety. PMID:11598085

Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1 ) and receptor-5 (S1P5 ) agonist with autoimmune disease-modifying activity.

PubMed

Scott, F L; Clemons, B; Brooks, J; Brahmachary, E; Powell, R; Dedman, H; Desale, H G; Timony, G A; Martinborough, E; Rosen, H; Roberts, E; Boehm, M F; Peach, R J

2016-06-01

Sphingosine1-phosphate (S1P) receptors mediate multiple events including lymphocyte trafficking, cardiac function, and endothelial barrier integrity. Stimulation of S1P1 receptors sequesters lymphocyte subsets in peripheral lymphoid organs, preventing their trafficking to inflamed tissue sites, modulating immunity. Targeting S1P receptors for treating autoimmune disease has been established in clinical studies with the non-selective S1P modulator, FTY720 (fingolimod, Gilenya™). The purpose of this study was to assess RPC1063 for its therapeutic utility in autoimmune diseases. The specificity and potency of RPC1063 (ozanimod) was evaluated for all five S1P receptors, and its effect on cell surface S1P1 receptor expression, was characterized in vitro. The oral pharmacokinetic (PK) parameters and pharmacodynamic effects were established in rodents, and its activity in three models of autoimmune disease (experimental autoimmune encephalitis, 2,4,6-trinitrobenzenesulfonic acid colitis and CD4(+) CD45RB(hi) T cell adoptive transfer colitis) was assessed. RPC1063 was specific for S1P1 and S1P5 receptors, induced S1P1 receptor internalization and induced a reversible reduction in circulating B and CCR7(+) T lymphocytes in vivo. RPC1063 showed high oral bioavailability and volume of distribution, and a circulatory half-life that supports once daily dosing. Oral RPC1063 reduced inflammation and disease parameters in all three autoimmune disease models. S1P receptor selectivity, favourable PK properties and efficacy in three distinct disease models supports the clinical development of RPC1063 for the treatment of relapsing multiple sclerosis and inflammatory bowel disease, differentiates RPC1063 from other S1P receptor agonists, and could result in improved safety outcomes in the clinic. © 2016 The British Pharmacological Society.

Ozanimod (RPC1063) is a potent sphingosine‐1‐phosphate receptor‐1 (S1P1) and receptor‐5 (S1P5) agonist with autoimmune disease‐modifying activity

PubMed Central

Clemons, B; Brooks, J; Brahmachary, E; Powell, R; Dedman, H; Desale, H G; Timony, G A; Martinborough, E; Rosen, H; Roberts, E; Boehm, M F; Peach, R J

2016-01-01

Background and Purpose Sphingosine1‐phosphate (S1P) receptors mediate multiple events including lymphocyte trafficking, cardiac function, and endothelial barrier integrity. Stimulation of S1P1 receptors sequesters lymphocyte subsets in peripheral lymphoid organs, preventing their trafficking to inflamed tissue sites, modulating immunity. Targeting S1P receptors for treating autoimmune disease has been established in clinical studies with the non‐selective S1P modulator, FTY720 (fingolimod, Gilenya™). The purpose of this study was to assess RPC1063 for its therapeutic utility in autoimmune diseases. Experimental Approach The specificity and potency of RPC1063 (ozanimod) was evaluated for all five S1P receptors, and its effect on cell surface S1P1 receptor expression, was characterized in vitro. The oral pharmacokinetic (PK) parameters and pharmacodynamic effects were established in rodents, and its activity in three models of autoimmune disease (experimental autoimmune encephalitis, 2,4,6‐trinitrobenzenesulfonic acid colitis and CD4+CD45RBhi T cell adoptive transfer colitis) was assessed. Key Results RPC1063 was specific for S1P1 and S1P5 receptors, induced S1P1 receptor internalization and induced a reversible reduction in circulating B and CCR7+ T lymphocytes in vivo. RPC1063 showed high oral bioavailability and volume of distribution, and a circulatory half‐life that supports once daily dosing. Oral RPC1063 reduced inflammation and disease parameters in all three autoimmune disease models. Conclusions and Implications S1P receptor selectivity, favourable PK properties and efficacy in three distinct disease models supports the clinical development of RPC1063 for the treatment of relapsing multiple sclerosis and inflammatory bowel disease, differentiates RPC1063 from other S1P receptor agonists, and could result in improved safety outcomes in the clinic. PMID:26990079

Dental hygiene work in a clinical trial.

PubMed

Luís, H S; Morgado, I; Assunção, V; Bernardo, M F; Leroux, B; Martin, M D; DeRouen, T A; Leitão, J

2008-08-01

Dental hygiene activities were developed as part of a randomized clinical trial designed to assess the safety of low-level mercury exposure from dental amalgam restorations. Along with dental-hygiene clinical work, a community programme was implemented after investigators noticed the poor oral hygiene habits of participants, and the need for urgent action to minimize oral health problems in the study population. Clinical and community activity goal was to promote oral health and prevent new disease. Community activities involved participants and their fellow students and were aimed at providing education on oral health in a school environment. Dental hygienists developed clinical work with prophylaxis, sealants application and topical fluoride and implemented the community programme with in-class sessions on oral health themes. Twice a month fluoride mouthrinses and bi-annual tooth brushing instructional activity took place. Participation at dental-hygiene activities, sealed teeth with no need of restoration and dental-plaque-index were measures used to evaluate success of the programme for the participants. Improvement in dental hygiene is shown by the decrease in dental plaque index scores (P < 0.0001); also sealants integrity is achieved in 86.3% of teeth. 888 (13.7%) teeth with sealants had to be restored or were lost. Children participated actively on dental hygiene activities. Teachers became aware of the problem and included oral-health in school curricula. Dental hygiene activities have shown to be helpful to promote dental hygiene, promote oral health and to provide school-age children with education on habits that will be important for their future good health.

Automated frame selection process for high-resolution microendoscopy

NASA Astrophysics Data System (ADS)

Ishijima, Ayumu; Schwarz, Richard A.; Shin, Dongsuk; Mondrik, Sharon; Vigneswaran, Nadarajah; Gillenwater, Ann M.; Anandasabapathy, Sharmila; Richards-Kortum, Rebecca

2015-04-01

We developed an automated frame selection algorithm for high-resolution microendoscopy video sequences. The algorithm rapidly selects a representative frame with minimal motion artifact from a short video sequence, enabling fully automated image analysis at the point-of-care. The algorithm was evaluated by quantitative comparison of diagnostically relevant image features and diagnostic classification results obtained using automated frame selection versus manual frame selection. A data set consisting of video sequences collected in vivo from 100 oral sites and 167 esophageal sites was used in the analysis. The area under the receiver operating characteristic curve was 0.78 (automated selection) versus 0.82 (manual selection) for oral sites, and 0.93 (automated selection) versus 0.92 (manual selection) for esophageal sites. The implementation of fully automated high-resolution microendoscopy at the point-of-care has the potential to reduce the number of biopsies needed for accurate diagnosis of precancer and cancer in low-resource settings where there may be limited infrastructure and personnel for standard histologic analysis.

Lethal and sub-lethal effects of select macrocyclic lactones insecticides on forager worker honey bees under laboratory experimental conditions.

PubMed

Abdu-Allah, Gamal A M; Pittendrigh, Barry R

2018-01-01

Selective insecticide application is one important strategy for more precisely targeting harmful insects while avoiding or mitigating collateral damage to beneficial insects like honey bees. Recently, macrocyclic lactone-class insecticides have been introduced into the market place as selective bio-insecticides for controlling many arthropod pests, but how to target this selectivity only to harmful insects has yet to be achieved. In this study, the authors investigated the acute toxicity of fourmacrocyclic lactone insecticides (commercialized as abamectin, emamectin benzoate, spinetoram, and spinosad) both topically and through feeding studies with adult forager honey bees. Results indicated emamectin benzoate as topically 133.3, 750.0, and 38.3-fold and orally 3.3, 7.6, and 31.7-fold more toxic, respectively than abamectin, spinetoram and spinosad. Using Hazard Quotients for estimates of field toxicity, abamectin was measured as the safest insecticide both topically and orally for honey bees. Moreover, a significant reduction of sugar solution consumption by treatment group honey bees for orally applied emamectin benzoate and spinetoram suggests that these insecticides may have repellent properties.

Effectiveness of oral health education programs: A systematic review.

PubMed

Nakre, Priya Devadas; Harikiran, A G

2013-07-01

In recent years, attention has been drawn toward assessing the effectiveness of oral health education programs. This is in line with demand for evidence based research and will help to inform policy makers on how to allocate resources. (1) Collect and collate all information on oral health education programs. (2) Assess the programs based on various coding criteria. (3) Assess effectiveness of oral health education programs on oral health status and knowledge, attitude and practice. A search of all published articles in Medline was done using the keywords "oral health education, dental health education, oral health promotion". The resulting titles and abstracts provided the basis for initial decisions and selection of articles. Out of the primary list of articles, a total number of 40 articles were selected as they fulfilled the following inclusion criteria: (1). Articles on oral health programs with an oral health education component (2). Articles published after the year 1990 (3). Articles published in English. The full text of the articles was then obtained from either the internet or libraries of dental research colleges and hospitals in and around Bangalore. A set of important variables were identified and grouped under five headings to make them amenable for coding. The coding variables were then described under various subheadings to allow us to compare the chosen articles. Oral health education is effective in improving the knowledge attitude and practice of oral health and in reducing plaque, bleeding on probing of the gingiva and caries increment. This study identifies a few important variables which contribute to the effectiveness of the programs. There is an indication in this review that the most successful oral health programs are labor intensive, involve significant others and has received funding and additional support. A balance between inputs and outputs and health care resources available will determine if the program can be recommended for general use.

Synthetic anabolic agents: steroids and nonsteroidal selective androgen receptor modulators.

PubMed

Thevis, Mario; Schänzer, Wilhelm

2010-01-01

The central role of testosterone in the development of male characteristics, as well as its beneficial effects on physical performance and muscle growth, has led to the search for synthetic alternatives with improved pharmacological profiles. Hundreds of steroidal analogs have been prepared with a superior oral bioavailability, which should also possess reduced undesirable effects. However, only a few entered the pharmaceutical market due to severe toxicological incidences that were mainly attributed to the lack of tissue selectivity. Prominent representatives of anabolic-androgenic steroids (AAS) are for instance methyltestosterone, metandienone and stanozolol, which are discussed as model compounds with regard to general pharmacological aspects of synthetic AAS. Recently, nonsteroidal alternatives to AAS have been developed that selectively activate the androgen receptor in either muscle tissue or bones. These so-called selective androgen receptor modulators (SARMs) are currently undergoing late clinical trials (IIb) and will be prohibited by the World Anti-Doping Agency from January 2008. Their entirely synthetic structures are barely related to steroids, but particular functional groups allow for the tissue-selective activation or inhibition of androgen receptors and, thus, the stimulation of muscle growth without the risk of severe undesirable effects commonly observed in steroid replacement therapies. Hence, these compounds possess a high potential for misuse in sports and will be the subject of future doping control assays.

Acute sensitivity of the oral mucosa to oncogenic K-ras

PubMed Central

van der Weyden, Louise; Alcolea, Maria P; Jones, Philip H; Rust, Alistair G; Arends, Mark J; Adams, David J

2011-01-01

Mouse models of cancer represent powerful tools for analysing the role of genetic alterations in carcinogenesis. Using a mouse model that allows tamoxifen-inducible somatic activation (by Cre-mediated recombination) of oncogenic K-rasG12D in a wide range of tissues, we observed hyperplasia of squamous epithelium located in moist or frequently abraded mucosa, with the most dramatic effects in the oral mucosa. This epithelium showed a sequence of squamous hyperplasia followed by squamous papilloma with dysplasia, in which some areas progressed to early invasive squamous cell carcinoma, within 14 days of widespread oncogenic K-ras activation. The marked proliferative response of the oral mucosa to K-rasG12D was most evident in the basal layers of the squamous epithelium of the outer lip with hair follicles and wet mucosal surface, with these cells staining positively for pAKT and cyclin D1, showing Ras/AKT pathway activation and increased proliferation with Ki-67 and EdU positivity. The stromal cells also showed gene activation by recombination and immunopositivity for pERK indicating K-Ras/ERK pathway activation, but without Ki-67 positivity or increase in stromal proliferation. The oral neoplasms showed changes in the expression pattern of cytokeratins (CK6 and CK13), similar to those observed in human oral tumours. Sporadic activation of the K-rasG12D allele (due to background spontaneous recombination in occasional cells) resulted in the development of benign oral squamous papillomas only showing a mild degree of dysplasia with no invasion. In summary, we show that oral mucosa is acutely sensitive to oncogenic K-ras, as widespread expression of activated K-ras in the murine oral mucosal squamous epithelium and underlying stroma can drive the oral squamous papilloma–carcinoma sequence. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:21381032

Clinical Drug-Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib.

PubMed

Morcos, Peter N; Cleary, Yumi; Guerini, Elena; Dall, Georgina; Bogman, Katrijn; De Petris, Luigi; Viteri, Santiago; Bordogna, Walter; Yu, Li; Martin-Facklam, Meret; Phipps, Alex

2017-05-01

The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed-sequence studies evaluating drug-drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is coadministered with CYP3A inhibitors or inducers or for coadministered CYP3A substrates. © 2016, The American College of Clinical Pharmacology.

Review of nemonoxacin with special focus on clinical development

PubMed Central

Qin, Xiaohua; Huang, Haihui

2014-01-01

Nemonoxacin is a novel C-8-methoxy nonfluorinated quinolone with remarkably enhanced in vitro activity against a wide variety of clinically relevant pathogens, especially gram-positive bacteria, including multidrug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus. It has a low propensity for selecting resistant pathogens than fluoroquinolones, since bacteria become resistant to nemonoxacin only when three different mutations occur in their quinolone resistance-determining regions. Nemonoxacin shows greater efficacy than most of the widely used fluoroquinolones in the murine model of systemic, pulmonary, or ascending urinary tract infection. Nemonoxacin has a sound PK profile in healthy volunteers. It rapidly reaches maximum concentration Cmax 1–2 hours after oral administration in the fasting state and has a relatively long elimination half-life of more than 10 hours, which is similar to fluoroquinolones. Approximately 60%–75% of the administered dose is excreted in unchanged form via kidneys over 24–72 hours. Phase II and III studies of oral nemonoxacin and Phase II studies of intravenous nemonoxacin have been completed in patients with community-acquired pneumonia (CAP), before which the Phase I studies of oral and intravenous nemonoxacin indicated sound tolerance and safety with healthy volunteers. The published results demonstrate that an oral dose of either 500 mg or 750 mg nemonoxacin once daily for 7 days is as effective and safe as levofloxacin 500 mg once daily for 7 days. Nemonoxacin is well-tolerated in patients with CAP. The most common adverse events of oral administration are observed in the gastrointestinal and nervous system, the incidence of which is similar to levofloxacin treatment. The Phase III studies of intravenous nemonoxacin for treating CAP and oral nemonoxacin for diabetic foot infection has been registered with promising outcomes to be expected. PMID:25045247

Second-Generation Non-Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis.

PubMed

Migliore, Marco; Pontis, Silvia; Fuentes de Arriba, Angel Luis; Realini, Natalia; Torrente, Esther; Armirotti, Andrea; Romeo, Elisa; Di Martino, Simona; Russo, Debora; Pizzirani, Daniela; Summa, Maria; Lanfranco, Massimiliano; Ottonello, Giuliana; Busquet, Perrine; Jung, Kwang-Mook; Garcia-Guzman, Miguel; Heim, Roger; Scarpelli, Rita; Piomelli, Daniele

2016-09-05

Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are endogenous lipid mediators that suppress inflammation. Their actions are terminated by the intracellular cysteine amidase, N-acylethanolamine acid amidase (NAAA). Even though NAAA may offer a new target for anti-inflammatory therapy, the lipid-like structures and reactive warheads of current NAAA inhibitors limit the use of these agents as oral drugs. A series of novel benzothiazole-piperazine derivatives that inhibit NAAA in a potent and selective manner by a non-covalent mechanism are described. A prototype member of this class (8) displays high oral bioavailability, access to the central nervous system (CNS), and strong activity in a mouse model of multiple sclerosis (MS). This compound exemplifies a second generation of non-covalent NAAA inhibitors that may be useful in the treatment of MS and other chronic CNS disorders. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

22 CFR 11.3 - Oral examination for appointment to class 7 or 8.

Code of Federal Regulations, 2010 CFR

2010-04-01

... oral examination will be given throughout the year at Washington and periodically in selected cities in... Government of the United States and attachment to the principles of the Constitution. (22 U.S.C. 1221 et seq...

Classroom Activities: Oral Proficiency in Action.

ERIC Educational Resources Information Center

Hahn, Sidney; Michaelis, Joyce

It is important to introduce and facilitate oral activities in the second language classroom with enthusiasm in a climate of mutual support and cooperation. Students should understand that mistakes are inevitable but not fatal, and that each attempt will build greater ease and confidence in using the language for communication. Oral proficiency…

Activation of the TREM-1 pathway in human monocytes by periodontal pathogens and oral commensal bacteria.

PubMed

Varanat, M; Haase, E M; Kay, J G; Scannapieco, F A

2017-08-01

Periodontitis is a highly prevalent disease caused in part by an aberrant host response to the oral multi-species biofilm. A balance between the oral bacteria and host immunity is essential for oral health. Imbalances in the oral microbiome lead to an uncontrolled host inflammatory response and subsequent periodontal disease (i.e. gingivitis and periodontitis). TREM-1 is a signaling receptor present on myeloid cells capable of acting synergistically with other pattern recognition receptors leading to amplification of inflammatory responses. The aim of this study was to investigate the activation of the TREM-1 pathway in the human monocyte-like cell line THP-1 exposed to both oral pathogens and commensals. The relative expression of the genes encoding TREM-1 and its adapter protein DAP12 were determined by quantitative real-time polymerase chain reaction. The surface expression of TREM-1 was determined by flow cytometry. Soluble TREM-1 and cytokines were measured by enzyme-linked immunosorbent assay. The results demonstrate that both commensal and pathogenic oral bacteria activate the TREM-1 pathway, resulting in a proinflammatory TREM-1 activity-dependent increase in proinflammatory cytokine production. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Evaluation of the Biological Activity of Opuntia ficus indica as a Tissue- and Estrogen Receptor Subtype-Selective Modulator.

PubMed

An, Byoung Ha; Jeong, Hyesoo; Zhou, Wenmei; Liu, Xiyuan; Kim, Soolin; Jang, Chang Young; Kim, Hyun-Sook; Sohn, Johann; Park, Hye-Jin; Sung, Na-Hye; Hong, Cheol Yi; Chang, Minsun

2016-06-01

Phytoestrogens are selective estrogen receptor modulators (SERMs) with potential for use in hormone replacement therapy (HRT) to relieve peri/postmenopausal symptoms. This study was aimed at elucidating the molecular mechanisms underlying the SERM properties of the extract of Korean-grown Opuntia ficus-indica (KOFI). The KOFI extract induced estrogen response element (ERE)-driven transcription in breast and endometrial cancer cell lines and the expression of endogenous estrogen-responsive genes in breast cancer cells. The flavonoid content of different KOFI preparations affected ERE-luciferase activities, implying that the flavonoid composition likely mediated the estrogenic activities in cells. Oral administration of KOFI decreased the weight gain and levels of both serum glucose and triglyceride in ovariectomized (OVX) rats. Finally, KOFI had an inhibitory effect on the 17β-estradiol-induced proliferation of the endometrial epithelium in OVX rats. Our data demonstrate that KOFI exhibited SERM activity with no uterotrophic side effects. Therefore, KOFI alone or in combination with other botanical supplements, vitamins, or minerals may be an effective and safe alternative active ingredient to HRTs, for the management of postmenopausal symptoms. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors.

PubMed

Goodman, Krista B; Cui, Haifeng; Dowdell, Sarah E; Gaitanopoulos, Dimitri E; Ivy, Robert L; Sehon, Clark A; Stavenger, Robert A; Wang, Gren Z; Viet, Andrew Q; Xu, Weiwei; Ye, Guosen; Semus, Simon F; Evans, Christopher; Fries, Harvey E; Jolivette, Larry J; Kirkpatrick, Robert B; Dul, Edward; Khandekar, Sanjay S; Yi, Tracey; Jung, David K; Wright, Lois L; Smith, Gary K; Behm, David J; Bentley, Ross; Doe, Christopher P; Hu, Erding; Lee, Dennis

2007-01-11

Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.

Changes in oral trace gas concentrations following orthognathic surgery and intermaxillary fixation: a case study using selected ion flow tube mass spectrometry

PubMed Central

Ross, Brian M

2011-01-01

Orthognathic surgery is frequently accompanied by intermaxillary fixation. Intermaxillary fixation impedes the maintenance of effective oral hygiene and prolonged fixation can result in periodontal disease. A potential shorter term effect is the generation of oral malodour. It is unclear, however, as to how the production of malodorous compounds in the oral cavity is altered post-surgery. Oral air concentration of sulphur containing compounds, short chain organic acids, ammonia, isoprene and acetone were measured using selected ion flow tube-mass spectrometry in a patient who had undergone orthognathic surgery with subsequent intermaxillary fixation. Total sulphide levels rose approximately 5-fold during fixation with metal ties, with smaller increases recorded for the other compounds measured with the exception of isoprene which remained close to baseline levels. Organic acid levels declined markedly once elastic ties had replaced metal ties, with a lesser reduction being observed in sulphide levels, with both declining further after the commencement of a chlorhexidine-containing mouthwash. These data suggest that bacterial generation of a variety of malodorous compounds increases markedly following intermaxillary fixation. This single case also suggests that the use of elastic ties and effective oral hygiene techniques, including the use of chlorhexidine mouthwash, may help ameliorate such post-surgical effects. PMID:21789965

Clinical Pharmacokinetics and Pharmacodynamics of Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor.

PubMed

Boulton, David W

2017-01-01

Saxagliptin is an orally active, highly potent, selective and competitive dipeptidyl peptidase (DPP)-4 inhibitor used in the treatment of type 2 diabetes mellitus at doses of 2.5 or 5 mg once daily. DPP-4 is responsible for degrading the intestinally derived hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP). Inhibition of DPP-4 increases intact plasma GLP-1 and GIP concentrations, augmenting glucose-dependent insulin secretion. Both saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, demonstrate high degrees of selectivity for DPP-4 compared with other DPP enzymes. Saxagliptin is orally absorbed and can be administered with or without food. The half-life of plasma DPP-4 inhibition with saxagliptin 5 mg is ~27 h, which supports a once-daily dosing regimen. Saxagliptin is metabolized by cytochrome P450 (CYP) 3A4/5 and is eliminated by a combination of renal and hepatic clearance. No clinically meaningful differences in saxagliptin or 5-hydroxy saxagliptin pharmacokinetics have been detected in patients with hepatic impairment. No clinically meaningful differences in saxagliptin or 5-hydroxy saxagliptin pharmacokinetics have been detected in patients with mild renal impairment, whereas dose reduction is recommended in patients with moderate or severe renal impairment because of greater systemic exposure [the area under the plasma concentration-time curve (AUC)] to saxagliptin total active moieties. Clinically relevant drug-drug interactions have not been detected; however, limiting the dose to 2.5 mg once daily is recommended in the USA when saxagliptin is coadministered with strong CYP inhibitors, because of increased saxagliptin exposure. In summary, saxagliptin has a predictable pharmacokinetic and pharmacodynamic profile.

Intervention to Reduce Broad-Spectrum Antibiotics and Treatment Durations Prescribed at the Time of Hospital Discharge: A Novel Stewardship Approach

PubMed Central

Yogo, Norihiro; Shihadeh, Katherine; Young, Heather; Calcaterra, Susan; Knepper, Bryan C; Burman, William J; Mehler, Philip S; Jenkins, Timothy C

2017-01-01

Objective For most common infections requiring hospitalization, antibiotic treatment is completed after hospital discharge. Post-discharge therapy is often unnecessarily broad-spectrum and prolonged. We developed an intervention to improve antibiotic selection and shorten treatment durations. Design Single center, quasi-experimental retrospective cohort study. Methods Patients prescribed oral antibiotics at hospital discharge before (July 2012 – June 2013) and after (October 2014 – February 2015) an intervention consisting of: 1) institutional guidance for oral step-down antibiotic selection and duration of therapy, and 2) pharmacy audit of discharge prescriptions with real-time prescribing recommendations to providers. The primary outcomes were total prescribed duration of therapy and use of antibiotics with broad gram-negative activity (fluoroquinolones or amoxicillin-clavulanate). Results 300 cases from the pre-intervention period and 200 from the intervention period were included. Compared with the pre-intervention period, use of antibiotics with broad gramnegative activity decreased during the intervention (51% vs 40%, p = 0.02), particularly fluoroquinolones (38% vs 25%, p = 0.002). The difference in total duration of therapy did not reach statistical significance (10 days [interquartile range (IQR) 7–13] vs 9 [IQR 6–13], p = 0.13); however, the duration prescribed at discharge declined from 6 days (IQR 4–10) to 5 (IQR 3–7) (p = 0.003). During the intervention, there was a non-significant increase in the overall appropriateness of discharge prescriptions (52% vs 66%, p = 0.15). Conclusions A multifaceted intervention to optimize antibiotic prescribing at hospital discharge was associated with less frequent use of antibiotics with broad gram-negative activity and shorter post-hospital treatment durations. PMID:28260538

[Risk factors for cervico-uterine cancer in women in Zacatecas].

PubMed

Castañeda-Iñiguez, M S; Toledo-Cisneros, R; Aguilera-Delgadillo, M

1998-01-01

To determine the sociodemographic characteristics and the reproductive and sexual behavior of participants in the Cervical Cancer Prevention and Control Program and to identify the risk factors for this neoplasm. A case control study was performed among participants in the Cervical Cancer Prevention and Control Program in the state of Zacatecas. The cases consisted of all patients diagnosed and corroborated by histopathology with CIN III and invasive carcinoma of the uterine cervix (251) who were referred to the Dysplasia Clinic (within the same program), during 1993-1995. Controls were women randomly selected from the population which participates in this program, who had negative cervical cytology. One control was selected for each case and paired by age and date, simultaneous to the cervical cytology. Risk of cervical cancer was higher in women with greater number of pregnancies (more than 12 pregnancies) than in women with less than 3 (OR 5.2, CI 95% 2.6-10.5). This is also true of women with greater number of births (12 or more) who have a risk five times higher than women with less than 3. Beginning sexual activity at an early age was associated to the risk of cervical cancer; women who began their sexual activity after the age of 19 had a risk two times lower than those who started before the age of 15. The use of oral contraceptives increased the risk of cervical cancer in relation to the use of non-hormonal contraceptives (OR 1.9, CI 95% 1.3-3.4). In the present study, the risk factors for cervical cancer in the population participating in the prevention and control program were higher in women with high parity, who began sexual activity at an early age and/or who consumed oral contraceptives.

Comparison of Tooth Color Change After Bleaching With Conventional and Different Light-Activated Methods.

PubMed

Shahabi, Sima; Assadian, Hadi; Mahmoudi Nahavandi, Alireza; Nokhbatolfoghahaei, Hanieh

2018-01-01

Introduction: The demand for esthetic dental treatments is increasing in recent years mainly due to improved oral hygiene and better maintenance of oral health and teeth in older individuals. Bleaching of discolored anterior teeth is the most popular among esthetic dental treatments. Even individuals with sound teeth and adequate esthetics seek to have whiter teeth in the anterior region. The aim of this study was to evaluate tooth color changes following conventional in-office bleaching techniques compared to light-activated methods using different light sources. Methods: Seventy sound anterior teeth (devoided of caries and/or fracture), extracted for periodontal and orthodontic reasons were selected and allocated to 7 groups: (A) control, (B) conventional bleaching (C) LED-activated bleaching, (D) KTP laser-activated bleaching, (E) diode laser-activated bleaching, (F) Nd:YAG laser-activated bleaching and (G) CO2 laser-activated bleaching. Colorimetric evaluation was carried out before and after treatment using a spectrophotoradiometer. Data were analyzed by one- and two-way analysis of variance (ANOVA) as well as multiple comparison methods. Results: The results showed that all bleaching procedures were effective in reducing the yellowness index. However, the KTP laser-activated bleaching was significantly more effective than the other techniques in 95% confidence level. It was also seen that CO2 laser activated method has outperformed groups E, F and G and the conventional bleaching without light activation was not effective at all and represented similar results with the control group. Furthermore, the groups E and G had almost the same results in decreasing the yellowness index. Conclusion: The results showed that all bleaching techniques were effective however, the KTP laser-activated bleaching was significantly more efficient, closely followed by the CO2 laser-activated bleaching technique.

Antimicrobial Activity of Seven Essential Oils From Iranian Aromatic Plants Against Common Causes of Oral Infections

PubMed Central

Zomorodian, Kamiar; Ghadiri, Pooria; Saharkhiz, Mohammad Jamal; Moein, Mohammad Reza; Mehriar, Peiman; Bahrani, Farideh; Golzar, Tahereh; Pakshir, Keyvan; Fani, Mohammad Mehdi

2015-01-01

Background: Over the past two decades, there has been a growing trend in using oral hygienic products originating from natural resources such as essential oils (EOs) and plant extracts. Seven aromatic plants used in this study are among popular traditional Iranian medicinal plants with potential application in modern medicine as anti-oral infectious diseases. Objectives: This study was conducted to determine the chemical composition and antimicrobial activities of essential oils from seven medicinal plants against pathogens causing oral infections. Materials and Methods: The chemical compositions of EOs distilled from seven plants were analyzed by gas chromatography/mass spectrometry (GC/MS). These plants included Satureja khuzestanica, S. bachtiarica, Ocimum sanctum, Artemisia sieberi, Zataria multiflora, Carum copticum and Oliveria decumbens. The antimicrobial activity of the essential oils was evaluated by broth micro-dilution in 96 well plates as recommended by the Clinical and Laboratory Standards Institute (CLSI) methods. Results: The tested EOs inhibited the growth of examined oral pathogens at concentrations of 0.015-16 µL/mL. Among the examined oral pathogens, Enterococcus faecalis had the highest Minimum Inhibitory Concentrations (MICs) and Minimum Microbicidal Concentrations (MMCs). Of the examined EOs, S. khuzestanica, Z. multiflora and S. bachtiarica, showed the highest antimicrobial activities, respectively, while Artemisia sieberi exhibited the lowest antimicrobial activity. Conclusions: The excellent antimicrobial activities of the tested EOs might be due to their major phenolic or alcoholic monoterpenes with known antimicrobial activities. Hence, these EOs can be possibly used as an antimicrobial agent in treatment and control of oral pathogens. PMID:25793100

Human Cadaver Material in Preclinical Oral Surgery.

ERIC Educational Resources Information Center

Barber, H. Dexter; And Others

1993-01-01

A University of Michigan dental school curriculum for oral surgery that uses human cadaver heads is described. Selection, preparation, and laboratory use of the materials are outlined. Faculty and students have received the sequence well and found it prepared them for clinical rotation. (MSE)

Expression of granulocyte colony-stimulating factor receptor correlates with prognosis in oral and mesopharyngeal carcinoma.

PubMed

Tsuzuki, H; Fujieda, S; Sunaga, H; Noda, I; Saito, H

1998-02-15

Granulocyte colony-stimulating factor receptors (G-CSFRs) have been observed on the surface of not only hematopoietic cells but also several cancer cells. The stimulation of G-CSF has been demonstrated to induce proliferation and activation of G-CSFR-positive cells. In this study, we investigated the expression of G-CSFR on the surface of tumor cells and G-CSF production in oral and mesopharyngeal squamous cell carcinoma (SCC) by an immunohistochemical approach. Of 58 oral and mesopharyngeal SCCs, 31 cases (53.4%) and 36 cases (62.1%) were positive for G-CSFR and G-CSF, respectively. There was no association between G-CSFR expression and G-CSF staining. In the group positive for G-CSFR expression, relapse was significantly more likely after primary treatment (P = 0.0069), whereas there was no association between G-CSFR expression and age, sex, tumor size, lymph node metastasis, and clinical stage. Also, the G-CSFR-positive groups had a significantly lower disease-free and overall survival rate than the G-CSFR-negative groups (P = 0.0172 and 0.0188, respectively). However, none of the clinical markers correlated significantly with G-CSF staining, nor did the status of G-CSF production influence the overall survival. The results imply that assessment of G-CSFR may prove valuable in selecting patients with oral and mesopharyngeal SCC for aggressive therapy.

Novel technology to prepare oral formulations for preclinical safety studies.

PubMed

Niwa, Toshiyuki; Hashimoto, Naofumi

2008-02-28

A novel method to prepare oral formulations, normally suspended dosage form, for preclinical safety studies in animals has been developed using a rotation/revolution mixer. Small hard balls made of zirconia were added to the mixing process to evaluate effectiveness in making a high quality suspension. The driving with balls loaded in the cylindrical container (vessel) of the mixer was quite efficient in dispersing and milling the particles of the active pharmaceutical ingredient (API) in an aqueous medium. The API powder and a small amount of oral aqueous medium (vehicle) were successfully mixed by the spinning motion of the balls in the vessel as though the paste-like suspension was kneaded with a mortar and pestle. It was found that the milled suspension with the mean size of 10-20microm could be prepared, in addition finer milling of less than 10microm could be achieved by selecting the material of vessel. Optimum driving conditions including mixing time, size and quantity of balls, and the standard operational procedure was established using compounds varying in physicochemical properties. The particle size and quantitative analysis by HPLC showed that the resultant suspension was well-milled and highly homogeneous with the nearly intended concentration of API. The proposed method established by this experiment could be applied to the actual safety studies in the real preparation scale of oral suspension.

Impact of nonsynonymous mutations of factor X on the functions of factor X and anticoagulant activity of edoxaban.

PubMed

Noguchi, Kengo; Morishima, Yoshiyuki; Takahashi, Shinichi; Ishihara, Hiroaki; Shibano, Toshiro; Murata, Mitsuru

2015-03-01

Edoxaban is an oral direct factor Xa (FXa) inhibitor and its efficacy as an oral anticoagulant is less subject to drug-food and drug-drug interaction than existing vitamin K antagonists. Although this profile of edoxaban suggests it is well suited for clinical use, it is not clear whether genetic variations of factor X influence the activity of edoxaban. Our aim was to investigate a possible impact of single-nucleotide polymorphisms (SNPs) in the factor X gene on the functions of factor X and the activity of edoxaban. Two nonsynonymous SNPs within mature factor X, Ala152Thr and Gly192Arg, were selected as possible candidates that might affect the functions of FXa and the activity of edoxaban. We measured catalytic activities of wild type and mutant FXas in a chromogenic assay using S-2222 and coagulation times including prothrombin time (PT) and activated partial thrombin time (aPTT) of plasma-containing recombinant FXs in the presence and absence of edoxaban. Michaelis-Menten kinetic parameters of FXas, Km and Vmax values, PT and aPTT were not influenced by either mutation indicating these mutations do not affect the FXa catalytic and coagulation activities. The Ki values of edoxaban for the FXas and the concentrations of edoxaban required to double PT and aPTT were not different between wild type and mutated FXas indicating that both mutations have little impact on the activity of edoxaban. In conclusion, these data suggest that edoxaban has little interpatient variability stemming from SNPs in the factor X gene.

An endostatin-derived peptide orally exerts anti-fibrotic activity in a murine pulmonary fibrosis model.

PubMed

Nishimoto, Tetsuya; Mlakar, Logan; Takihara, Takahisa; Feghali-Bostwick, Carol

2015-10-01

Pulmonary fibrosis causes high morbidity and mortality in affected individuals. Recently, we showed that parenteral or intratracheal administration of a peptide derived from endostatin, called E4, prevents and ameliorates fibrosis using different models of dermal and pulmonary disease. No marketed orally delivered peptide drugs are currently available for progressive pulmonary fibrosis; however oral delivery of drugs is the preferred route for treating most chronic diseases. Thus, we investigated whether oral administration of E4 peptide exerted anti-fibrotic activity in a murine pulmonary fibrosis model. Bleomycin (1.2mU/g body weight) was intratracheally administrated to male 6-8-week-old C57BL/6J mice. E4 peptide (20, 10, 5, and 1 μg/mouse) or scrambled control peptide (20 μg/mouse) was orally administered on the same day as bleomycin. In some experiments, E4 peptide (10 and 5 μg/mouse) was orally administered three times on days 0, 3, and 6 post-bleomycin treatment. Lungs were harvested on day 21 for histological analysis and hydroxyproline assay. Histological analysis and hydroxyproline assay revealed that bleomycin successfully induced pulmonary fibrosis, and that 20 μg of oral E4 peptide ameliorated the fibrosis. The lower doses of E4 peptide (10, 5, and 1 μg) were insufficient to exert anti-fibrotic activity when given as a single dose. Multiple doses of E4 peptide efficiently exerted anti-fibrotic activity even at lower doses. E4 peptide shows oral bioavailability and exerts anti-fibrotic activity in a bleomycin-induced pulmonary fibrosis model. We suggest that E4 peptide is a novel oral drug for fibroproliferative disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

An endostatin-derived peptide orally exerts anti-fibrotic activity in a murine pulmonary fibrosis model

PubMed Central

Nishimoto, Tetsuya; Mlakar, Logan; Takihara, Takahisa; Feghali-Bostwick, Carol

2016-01-01

Objective Pulmonary fibrosis causes high morbidity and mortality in affected individuals. Recently, we showed that parenteral or intratracheal administration of a peptide derived from endostatin, called E4, prevents and ameliorates fibrosis using different models of dermal and pulmonary disease. No marketed orally delivered peptide drugs are currently available for progressive pulmonary fibrosis; however oral delivery of drugs is the preferred route for treating most chronic diseases. Thus, we investigated whether oral administration of E4 peptide exerted anti-fibrotic activity in a murine pulmonary fibrosis model. Methods Bleomycin (1.2mU/g body weight) was intratracheally administrated to male 6–8-week-old C57BL/6J mice. E4 peptide (20, 10, 5, and 1 μg/mouse) or scrambled control peptide (20 μg/mouse) were orally administered on the same day as bleomycin. In some experiments, E4 peptide (10 and 5 μg/mouse) was orally administered three times on days 0, 3, and 6 post-bleomycin treatment. Lungs were harvested on day 21 for histological analysis and hydroxyproline assay. Results Histological analysis and hydroxyproline assay revealed that bleomycin successfully induced pulmonary fibrosis, and that 20μg of oral E4 peptide ameliorated the fibrosis. The lower doses of E4 peptide (10, 5, and 1 μg) were insufficient to exert anti-fibrotic activity when given as a single dose. Multiple doses of E4 peptide efficiently exerted anti-fibrotic activity even at lower doses. Conclusion E4 peptide shows oral bioavailability and exerts anti-fibrotic activity in a bleomycin-induced pulmonary fibrosis model. We suggest that E4 peptide is a novel oral drug for fibroproliferative disorders. PMID:26315492

Development of Self Emulsifying Formulations of Poorly Soluble Naproxen for Enhanced Drug Delivery.

PubMed

Penjuri, Subhash C B; Saritha, Damineni; Ravouru, Nagaraju; Poreddy, Srikanth R

2016-01-01

The objective of this investigation was to develop a self emulsifying drug delivery system (SEDDS) of naproxen, a poorly water soluble drug, which could improve its solubility and oral bioavailability. The recent patents on SEDDS of abiraterone acetate (WO2014/009434 A1) and tamoxifen (WO2013/0080083) helped in selecting the naproxen and excipients. Phase diagrams were constructed and the formulations were taken from the micro emulsion region. Formulations were subjected to thermodynamic stability, dispersibility and precipitation tests for optimization. Physico chemical characterization was carried out by FTIR and DSC studies. The selected SEDDS consisted of IPM+labrafac lipophile WL 1349, tween 80, PEG 400 and naproxen. The optimized formulation has globule size- 187.6 nm, zeta potential- -9.81 mv, viscosity- 1.772 cps and infinite dilution ability. In vitro drug release was 98.21% and was found to be significantly different from the marketed product and plain drug. After oral administration in rats the SEDDS of naproxen showed anti inflammatory activity (69.82%) which was much improved as compared to the marketed formulation. The Cmax, AUC0t of naproxen was boosted with SEDDS to 133.63 g/ml and 698.29 hr. g/ml respectively. The optimized formulation was found to be stable for 6 months during stability studies conducted according to the ICH Q1A (R2) guidelines. Thus this developed self emulsifying drug delivery system may be a useful tool to enhance the solubility of oral poorly water soluble drug naproxen. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Clinical Efficacy of a Specifically Targeted Antimicrobial Peptide Mouth Rinse: Targeted Elimination of Streptococcus mutans and Prevention of Demineralization

PubMed Central

Sullivan, R.; Santarpia, P.; Lavender, S.; Gittins, E.; Liu, Z.; Anderson, M.H.; He, J.; Shi, W.; Eckert, R.

2011-01-01

Background/Aims Streptococcus mutans, the major etiological agent of dental caries, has a measurable impact on domestic and global health care costs. Though persistent in the oral cavity despite conventional oral hygiene, S. mutans can be excluded from intact oral biofilms through competitive exclusion by other microorganisms. This suggests that therapies capable of selectively eliminating S. mutans while limiting the damage to the normal oral flora might be effective long-term interventions to fight cariogenesis. To meet this challenge, we designed C16G2, a novel synthetic specifically targeted antimicrobial peptide with specificity for S. mutans. C16G2 consists of a S. mutans-selective ‘targeting region’ comprised of a fragment from S. mutans competence stimulation peptide (CSP) conjoined to a ‘killing region’ consisting of a broad-spectrum antimicrobial peptide (G2). In vitro studies have indicated that C16G2 has robust efficacy and selectivity for S. mutans, and not other oral bacteria, and affects targeted bacteria within seconds of contact. Methods In the present study, we evaluated C16G2 for clinical utility in vitro, followed by a pilot efficacy study to examine the impact of a 0.04% (w/v) C16G2 rinse in an intra-oral remineralization/demineralization model. Results and Conclusions C16G2 rinse usage was associated with reductions in plaque and salivary S. mutans, lactic acid production, and enamel demineralization. The impact on total plaque bacteria was minimal. These results suggest that C16G2 is effective against S. mutans in vivo and should be evaluated further in the clinic. PMID:21860239

The relationship between patient activation, confidence to self-manage side effects, and adherence to oral oncolytics: a pilot study with Michigan oncology practices.

PubMed

Salgado, Teresa M; Mackler, Emily; Severson, Jane A; Lindsay, Jamie; Batra, Peter; Petersen, Laura; Farris, Karen B

2017-06-01

The Michigan Oncology Quality Consortium (MOQC) is a continuous quality improvement collaborative seeking to improve oncology care in Michigan, including for patients taking oral chemotherapy. The aim of this study was to assess the relationship between patient activation, confidence to self-manage side effects, and adherence to oral oncolytics to inform future oncology care. A multicenter cross-sectional observational study was conducted using an online survey to examine patient activation (patient activation measure, PAM), health literacy, symptom burden (Edmonton Symptom Assessment System, ESAS), confidence to self-manage side effects (fatigue, nausea, and diarrhea), and adherence to oral oncolytics. Inclusion criteria were patients taking an oral oncolytic for at least 1 month. Bivariate analyses and logistic regression were performed to evaluate relationships between the variables. A total of 125 respondents, mean (SD) age 66.2 (13.6), 57.7% female, and 95.1% Caucasian completed the survey. The mean (SD) PAM score was 65.0 (18.0). Confidence to manage fatigue, nausea, and diarrhea was associated with higher activation, and confidence to self-manage fatigue and diarrhea were associated with higher health literacy. About 30% of participants reported some level of non-adherence to oral oncolytics, and those who experienced side effects (Fisher's exact test p = 0.033) and with shorter length of therapy (t test p = 0.027) were significantly more likely to be non-adherent. These findings show that there is room for improvement across practices involved with MOQC with regard to supporting patients taking oral oncolytics. Patients will need to improve their activation levels, and oncology clinics will need to create new workflows in order to enhance self-care management ability for patients taking oral oncolytics.

Salivary flow and alpha-amylase: collection technique, duration, and oral fluid type.

PubMed

Beltzer, Emilie K; Fortunato, Christine K; Guaderrama, Melissa M; Peckins, Melissa K; Garramone, Bianca M; Granger, Douglas A

2010-09-01

There has been renewed interest in salivary alpha-amylase (sAA), a surrogate marker of autonomic/sympathetic activity, in biosocial research on stress vulnerability, reactivity, and recovery. This study explored the impact of saliva flow rate on sAA measurement by examining the influence of (1) the technique used to collect oral fluid-synthetic swab, cotton pledget, hydrocellulose microsponge, or passive drool; (2) collection point duration--the length of time the technique is employed (1-5min); and (3) oral fluid type--whole unstimulated saliva (not absorbed by any material) or oral fluid sampled from areas near the parotid, submandibular, or sublingual salivary glands. sAA activity (U/mL) was the highest in oral fluid collected from the parotid and submandibular gland areas. The volume (mL) of oral fluid collected increased, and the activity of sAA (U/mL) decreased, as collection point duration lengthened. The magnitude of these effects varied according to collection technique and oral fluid type. Across all conditions, there were positive correlations (range .70-.88) between sAA activity (U/mL) and sAA output (U/min). Management of these potential sources of measurement error will be essential to ensuring the success of future research on the correlates and concomitants of sAA activity, stress-related reactivity and recovery, and diurnal variation. Copyright 2010 Elsevier Inc. All rights reserved.

Systems Biological Approach of Molecular Descriptors Connectivity: Optimal Descriptors for Oral Bioavailability Prediction

PubMed Central

Ahmed, Shiek S. S. J.; Ramakrishnan, V.

2012-01-01

Background Poor oral bioavailability is an important parameter accounting for the failure of the drug candidates. Approximately, 50% of developing drugs fail because of unfavorable oral bioavailability. In silico prediction of oral bioavailability (%F) based on physiochemical properties are highly needed. Although many computational models have been developed to predict oral bioavailability, their accuracy remains low with a significant number of false positives. In this study, we present an oral bioavailability model based on systems biological approach, using a machine learning algorithm coupled with an optimal discriminative set of physiochemical properties. Results The models were developed based on computationally derived 247 physicochemical descriptors from 2279 molecules, among which 969, 605 and 705 molecules were corresponds to oral bioavailability, intestinal absorption (HIA) and caco-2 permeability data set, respectively. The partial least squares discriminate analysis showed 49 descriptors of HIA and 50 descriptors of caco-2 are the major contributing descriptors in classifying into groups. Of these descriptors, 47 descriptors were commonly associated to HIA and caco-2, which suggests to play a vital role in classifying oral bioavailability. To determine the best machine learning algorithm, 21 classifiers were compared using a bioavailability data set of 969 molecules with 47 descriptors. Each molecule in the data set was represented by a set of 47 physiochemical properties with the functional relevance labeled as (+bioavailability/−bioavailability) to indicate good-bioavailability/poor-bioavailability molecules. The best-performing algorithm was the logistic algorithm. The correlation based feature selection (CFS) algorithm was implemented, which confirms that these 47 descriptors are the fundamental descriptors for oral bioavailability prediction. Conclusion The logistic algorithm with 47 selected descriptors correctly predicted the oral bioavailability, with a predictive accuracy of more than 71%. Overall, the method captures the fundamental molecular descriptors, that can be used as an entity to facilitate prediction of oral bioavailability. PMID:22815781

Systems biological approach of molecular descriptors connectivity: optimal descriptors for oral bioavailability prediction.

PubMed

Ahmed, Shiek S S J; Ramakrishnan, V

2012-01-01

Poor oral bioavailability is an important parameter accounting for the failure of the drug candidates. Approximately, 50% of developing drugs fail because of unfavorable oral bioavailability. In silico prediction of oral bioavailability (%F) based on physiochemical properties are highly needed. Although many computational models have been developed to predict oral bioavailability, their accuracy remains low with a significant number of false positives. In this study, we present an oral bioavailability model based on systems biological approach, using a machine learning algorithm coupled with an optimal discriminative set of physiochemical properties. The models were developed based on computationally derived 247 physicochemical descriptors from 2279 molecules, among which 969, 605 and 705 molecules were corresponds to oral bioavailability, intestinal absorption (HIA) and caco-2 permeability data set, respectively. The partial least squares discriminate analysis showed 49 descriptors of HIA and 50 descriptors of caco-2 are the major contributing descriptors in classifying into groups. Of these descriptors, 47 descriptors were commonly associated to HIA and caco-2, which suggests to play a vital role in classifying oral bioavailability. To determine the best machine learning algorithm, 21 classifiers were compared using a bioavailability data set of 969 molecules with 47 descriptors. Each molecule in the data set was represented by a set of 47 physiochemical properties with the functional relevance labeled as (+bioavailability/-bioavailability) to indicate good-bioavailability/poor-bioavailability molecules. The best-performing algorithm was the logistic algorithm. The correlation based feature selection (CFS) algorithm was implemented, which confirms that these 47 descriptors are the fundamental descriptors for oral bioavailability prediction. The logistic algorithm with 47 selected descriptors correctly predicted the oral bioavailability, with a predictive accuracy of more than 71%. Overall, the method captures the fundamental molecular descriptors, that can be used as an entity to facilitate prediction of oral bioavailability.

Midwestern Rural Adolescents' Oral Sex Experience

ERIC Educational Resources Information Center

Dake, Joseph A.; Price, James H.; Ward, Britney L.; Welch, Philip J.

2011-01-01

Background: This study examined the prevalence of oral sexual activity in rural Midwestern adolescents. We also examined the correlates of a series of risk behaviors with oral sexual activity. Methods: A questionnaire based on the Youth Risk Behavior Surveillance System was distributed to 2121 rural middle and high school students in grades 6-12…

Evaluation of Student Reflection as a Route to Improve Oral Communication

ERIC Educational Resources Information Center

Mineart, Kenneth P.; Cooper, Matthew E.

2016-01-01

This study describes the use of guided self-reflection and peer feedback activities to improve student oral communication in a large ChE class (n ~ 100) setting. Student performance tracked throughout an experimental semester indicated both reflection activities accelerated improvement in oral communication over control; student perception of the…

Preoperative fluid and electrolyte management with oral rehydration therapy.

PubMed

Taniguchi, Hideki; Sasaki, Toshio; Fujita, Hisae; Takamori, Mina; Kawasaki, Rieko; Momiyama, Yukinori; Takano, Osami; Shibata, Toshinari; Goto, Takahisa

2009-01-01

We hypothesized that oral rehydration therapy using an oral rehydration solution may be effective for preoperative fluid and electrolyte management in surgical patients before the induction of general anesthesia, and we investigated the safety and effectiveness of oral rehydration therapy as compared with intravenous therapy. Fifty female patients who underwent breast surgery were randomly allocated to two groups. Before entry to the operation room and the induction of general anesthesia, 25 patients drank 1000 ml of an oral rehydration solution ("oral group") and 25 patients were infused with 1000 ml of an intravenous electrolyte solution ("intravenous group"). Parameters such as electrolyte concentrations in serum and urine, urine volume, vital signs, vomiting and aspiration, volumes of esophageal-pharyngeal fluid and gastric fluid (EPGF), and patient satisfaction with the therapy (as surveyed by a questionnaire) were assessed. After treatment, the serum sodium concentration and the hematocrit value, which both declined within the normal limits, were significantly higher in the oral group than in the intravenous group (sodium, 140.8 +/- 2.9 mEq x l(-1) in the oral group and 138.7 +/- 1.9 mEq x l(-1) in the intravenous group; P = 0.005; hematocrit, 39.03 +/- 4.16% in the oral group and 36.15 +/- 3.41% in the intravenous group; P = 0.01). No significant difference was observed in serum glucose values. Urine volume was significantly larger in the oral group (864.9 +/- 211.5 ml) than in the intravenous group (561.5 +/- 216.0 ml; P < 0.001). The fractional excretion of sodium (FENa), as an index of renal blood flow, was increased in both groups following treatment (0.8 +/- 0.5 in the oral group and 0.8 +/- 0.3 in the intravenous group). Patient satisfaction with the therapy favored the oral rehydration therapy, as judged by factors such as "feeling of hunger", "occurrence of dry mouth", and "less restriction in physical activity". The volume of EPGF collected following the induction of anesthesia was significantly smaller in the oral group than in the intravenous group (6.03 +/- 9.14 ml in the oral group and 21.76 +/- 30.56 ml in the intravenous group; P < 0.001). No adverse events or adverse reactions were observed in either group. The results suggest that the oral rehydration therapy with an oral rehydration solution before surgery is superior to the current preoperative intravenous therapy for the provision of water, electrolytes, and carbohydrates, and this therapy should be considered as an alternative to the intravenous therapy for preoperative fluid and electrolyte management in selected surgical patients in whom there is no reason to suspect delayed gastric emptying.

Retro-binding thrombin active site inhibitors: identification of an orally active inhibitor of thrombin catalytic activity.

PubMed

Iwanowicz, Edwin J; Kimball, S David; Lin, James; Lau, Wan; Han, W-C; Wang, Tammy C; Roberts, Daniel G M; Schumacher, W A; Ogletree, Martin L; Seiler, Steven M

2002-11-04

A series of retro-binding inhibitors of human alpha-thrombin was prepared to elucidate structure-activity relationships (SAR) and optimize in vivo performance. Compounds 9 and 11, orally active inhibitors of thrombin catalytic activity, were identified to be efficacious in a thrombin-induced lethality model in mice.

Interpretation of Oral Fluid Tests for Drugs of Abuse

PubMed Central

CONE, EDWARD J.; HUESTIS, MARILYN A.

2009-01-01

Oral fluid testing for drugs of abuse offers significant advantages over urine as a test matrix. Collection can be performed under direct observation with reduced risk of adulteration and substitution. Drugs generally appear in oral fluid by passive diffusion from blood, but also may be deposited in the oral cavity during oral, smoked, and intranasal administration. Drug metabolites also can be detected in oral fluid. Unlike urine testing, there may be a close correspondence between drug and metabolite concentrations in oral fluid and in blood. Interpretation of oral fluid results for drugs of abuse should be an iterative process whereby one considers the test results in the context of program requirements and a broad scientific knowledge of the many factors involved in determining test outcome. This review delineates many of the chemical and metabolic processes involved in the disposition of drugs and metabolites in oral fluid that are important to the appropriate interpretation of oral fluid tests. Chemical, metabolic, kinetic, and analytic parameters are summarized for selected drugs of abuse, and general guidelines are offered for understanding the significance of oral fluid tests. PMID:17332074

Antimicrobial efficacy of 3 oral antiseptics containing octenidine, polyhexamethylene biguanide, or Citroxx: can chlorhexidine be replaced?

PubMed

Rohrer, Nadine; Widmer, Andreas F; Waltimo, Tuomas; Kulik, Eva M; Weiger, Roland; Filipuzzi-Jenny, Elisabeth; Walter, Clemens

2010-07-01

Use of oral antiseptics decreases the bacterial load in the oral cavity. To compare the antimicrobial activity of 3 novel oral antiseptics with that of chlorhexidine, which is considered the "gold standard" of oral hygiene. Comparative in vitro study. Four common oral microorganisms (Streptococcus sanguinis, Streptococcus mutans, Candida albicans, and Fusobacterium nucleatum) were tested under standard conditions and at different concentrations, by use of a broth dilution assay and an agar diffusion assay and by calculating the log10 reduction factor (RF). The antimicrobial activity of each antiseptic was assessed by counting the difference in bacterial densities (ie, the log10 number of colony-forming units of bacteria) before and after the disinfection process. The oral antiseptics containing octenidine (with an RF in the range of 7.1-8.24 CFU/mL) and polyhexamethylene biguanide (with an RF in the range of 7.1-8.24 CFU/mL) demonstrated antimicrobial activity comparable to that of chlorhexidine (with an RF in the range of 1.03-8.24 CFU/mL), whereas the mouth rinse containing Citroxx (Citroxx Biosciences; with an RF in the range of 0.22-1.36 CFU/mL) showed significantly weaker antimicrobial efficacy. Overall, octenidine and polyhexamethylene biguanide were more active at lower concentrations.conclusion. Oral antiseptics containing the antimicrobial agent octenidine or polyhexamethylene biguanide may be considered as potent alternatives to chlorhexidine-based preparations.

An oral form of methylglyoxal-bis-guanylhydrazone reduces monocyte activation and traffic to the dorsal root ganglia in a primate model of HIV-peripheral neuropathy.

PubMed

Lakritz, Jessica R; Yalamanchili, Samshita; Polydefkis, Michael J; Miller, Andrew D; McGrath, Michael S; Williams, Kenneth C; Burdo, Tricia H

2017-08-01

Peripheral neuropathy (PN) is a major comorbidity of HIV infection that is caused in part by chronic immune activation. HIV-PN is associated with infiltration of monocytes/macrophages to the dorsal root ganglia (DRG) causing neuronal loss and formation of Nageotte nodules. Here, we used an oral form of methylglyoxal-bis-guanylhydrazone (MGBG), a polyamine biosynthesis inhibitor, to specifically reduce activation of myeloid cells. MGBG is selectively taken up by monocyte/macrophages in vitro and inhibits HIV p24 expression and DNA viral integration in macrophages. Here, MGBG was administered to nine SIV-infected, CD8-depleted rhesus macaques at 21 days post-infection (dpi). An additional nine SIV-infected, CD8-depleted rhesus macaques were used as untreated controls. Cell traffic to tissues was measured by in vivo BrdU pulse labeling. MGBG treatment significantly diminished DRG histopathology and reduced the number of CD68+ and CD163+ macrophages in DRG tissue. The number of recently trafficked BrdU+ cells in the DRG was significantly reduced with MGBG treatment. Despite diminished DRG pathology, intraepidermal nerve fiber density (IENFD) did not recover after treatment with MGBG. These data suggest that MGBG alleviated DRG pathology and inflammation.

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

PubMed Central

Neumann, Susanne; Huang, Wenwei; Titus, Steve; Krause, Gerd; Kleinau, Gunnar; Alberobello, Anna Teresa; Zheng, Wei; Southall, Noel T.; Inglese, James; Austin, Christopher P.; Celi, Francesco S.; Gavrilova, Oksana; Thomas, Craig J.; Raaka, Bruce M.; Gershengorn, Marvin C.

2009-01-01

Seven-transmembrane-spanning receptors (7TMRs) are prominent drug targets. However, small-molecule ligands for 7-transmembrane-spanning receptors for which the natural ligands are large, heterodimeric glycoprotein hormones, like thyroid-stimulating hormone (TSH; thyrotropin), have only recently been reported, and none are approved for human use. We have used quantitative high-throughput screening to identify a small-molecule TSH receptor (TSHR) agonist that was modified to produce a second agonist with increased potency. We show that these agonists are highly selective for human TSHR versus other glycoprotein hormone receptors and interact with the receptor's serpentine domain. A binding pocket within the transmembrane domain was defined by docking into a TSHR homology model and was supported by site-directed mutagenesis. In primary cultures of human thyrocytes, both TSH and the agonists increase mRNA levels for thyroglobulin, thyroperoxidase, sodium iodide symporter, and deiodinase type 2, and deiodinase type 2 enzyme activity. Moreover, oral administration of the agonist stimulated thyroid function in mice, resulting in increased serum thyroxine and thyroidal radioiodide uptake. Thus, we discovered a small molecule that activates human TSHR in vitro, is orally active in mice, and could be a lead for development of drugs to use in place of recombinant human TSH in patients with thyroid cancer. PMID:19592511

An orally effective dihydropyrimidone (DHPM) analogue induces apoptosis-like cell death in clinical isolates of Leishmania donovani overexpressing pteridine reductase 1.

PubMed

Singh, Neeloo; Kaur, Jaspreet; Kumar, Pranav; Gupta, Swati; Singh, Nasib; Ghosal, Angana; Dutta, Avijit; Kumar, Ashutosh; Tripathi, Ramapati; Siddiqi, Mohammad Imran; Mandal, Chitra; Dube, Anuradha

2009-10-01

The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis. The enzyme pteridine reductase 1 (PTR1) of L. donovani acts as a metabolic bypass for drugs targeting dihydrofolate reductase (DHFR); therefore, for successful antifolate chemotherapy to be developed against Leishmania, it must target both enzyme activities. Leishmania cells overexpressing PTR1 tagged at the N-terminal with green fluorescent protein were established to screen for proprietary dihydropyrimidone (DHPM) derivatives of DHFR specificity synthesised in our laboratory. A cell-permeable molecule with impressive antileishmanial in vitro and in vivo oral activity was identified. Structure activity relationship based on homology model drawn on our recombinant enzyme established the highly selective inhibition of the enzyme by this analogue. It was seen that the leishmanicidal effect of this analogue is triggered by programmed cell death mediated by the loss of plasma membrane integrity as detected by binding of annexin V and propidium iodide (PI), loss of mitochondrial membrane potential culminating in cell cycle arrest at the sub-G0/G1 phase and oligonucleosomal DNA fragmentation. Hence, this DHPM analogue [(4-fluoro-phenyl)-6-methyl-2-thioxo-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester] is a potent antileishmanial agent that merits further pharmacological investigation.

Discovery of BI 135585, an in vivo efficacious oxazinanone-based 11β hydroxysteroid dehydrogenase type 1 inhibitor.

PubMed

Zhuang, Linghang; Tice, Colin M; Xu, Zhenrong; Zhao, Wei; Cacatian, Salvacion; Ye, Yuan-Jie; Singh, Suresh B; Lindblom, Peter; McKeever, Brian M; Krosky, Paula M; Zhao, Yi; Lala, Deepak; Kruk, Barbara A; Meng, Shi; Howard, Lamont; Johnson, Judith A; Bukhtiyarov, Yuri; Panemangalore, Reshma; Guo, Joan; Guo, Rong; Himmelsbach, Frank; Hamilton, Bradford; Schuler-Metz, Annette; Schauerte, Heike; Gregg, Richard; McGeehan, Gerard M; Leftheris, Katerina; Claremon, David A

2017-07-15

A potent, in vivo efficacious 11β hydroxysteroid dehydrogenase type 1 (11β HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11β HSD1 activity in human adipocytes with an IC 50 of 4.3nM and in primary human adipose tissue with an IC 80 of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11β HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthesis, in vitro and in vivo antimalarial assessment of sulfide, sulfone and vinyl amide-substituted 1,2,4-trioxanes prepared via thiol-olefin co-oxygenation (TOCO) of allylic alcohols.

PubMed

Amewu, Richard; Gibbons, Peter; Mukhtar, Amira; Stachulski, Andrew V; Ward, Stephen A; Hall, Charlotte; Rimmer, Karen; Davies, Jill; Vivas, Livia; Bacsa, John; Mercer, Amy E; Nixon, Gemma; Stocks, Paul A; O'Neill, Paul M

2010-05-07

Thiol-Olefin Co-Oxygenation (TOCO) methodology has been applied to the synthesis of a small library of weak base and polar 1,2,4-trioxanes. The 1,2,4-trioxane units synthesised exhibit remarkable stability as they survive base catalysed hydrolysis and mixed anhydride/amine coupling reactions. This unique stability feature has enabled a range of novel substitution patterns to be incorporated within the spiro 1,2,4-trioxane unit. Selected analogues express potent in vitro nM antimalarial activity, low cytotoxicity and oral activity in the Plasmodium berghei mouse model of malaria.

Potential benefits of chewing gum for the delivery of oral therapeutics and its possible role in oral healthcare.

PubMed

Wessel, Stefan W; van der Mei, Henny C; Maitra, Amarnath; Dodds, Michael W J; Busscher, Henk J

2016-10-01

Over the years, chewing gum has developed from a candy towards an oral health-promoting nutraceutical. This review summarizes evidence for the oral health benefits of chewing gum, emphasizing identification of active ingredients in gum that facilitate prevention and removal of oral biofilm. Chewing of sugar-free gum yields oral health benefits that include clearance of food debris, reduction in oral dryness, increase of biofilm pH and remineralization of enamel. These basic effects of chewing gum are attributed to increased mastication and salivation. Active ingredients incorporated in chewing gums aim to expand these effects to inhibition of extrinsic tooth stain and calculus formation, enhanced enamel remineralization, reduction of the numbers of bacteria in saliva and amount of oral biofilm, neutralization of biofilm pH, and reduction of volatile sulfur compounds. Evidence for oral-health benefits of chewing gum additives is hard to obtain due to their relatively low concentrations and rapid wash-out. Clinical effects of gum additives are overshadowed by effects of increased mastication and salivation due to the chewing of gum and require daily chewing of gum for prolonged periods of time. Future studies on active ingredients should focus on specifically targeting pathogenic bacteria, whilst leaving the healthy microbiome unaffected.

Chronic administration of aripiprazole activates GSK3β-dependent signalling pathways, and up-regulates GABAA receptor expression and CREB1 activity in rats.

PubMed

Pan, Bo; Huang, Xu-Feng; Deng, Chao

2016-07-20

Aripiprazole is a D2-like receptor (D2R) partial agonist with a favourable clinical profile. Previous investigations indicated that acute and short-term administration of aripiprazole had effects on PKA activity, GSK3β-dependent pathways, GABAA receptors, NMDA receptor and CREB1 in the brain. Since antipsychotics are used chronically in clinics, the present study investigated the long-term effects of chronic oral aripiprazole treatment on these cellular signalling pathways, in comparison with haloperidol (a D2R antagonist) and bifeprunox (a potent D2R partial agonist). We found that the Akt-GSK3β pathway was activated by aripiprazole and bifeprunox in the prefrontal cortex; NMDA NR2A levels were reduced by aripiprazole and haloperidol. In the nucleus accumbens, all three drugs increased Akt-GSK3β signalling; in addition, both aripiprazole and haloperidol, but not bifeprunox, increased the expression of Dvl-3, β-catenin and GABAA receptors, NMDA receptor subunits, as well as CREB1 phosphorylation levels. The results suggest that chronic oral administration of aripiprazole affects schizophrenia-related cellular signalling pathways and markers (including Akt-GSK3β signalling, Dvl-GSK3β-β-catenin signalling, GABAA receptor, NMDA receptor and CREB1) in a brain-region-dependent manner; the selective effects of aripiprazole on these signalling pathways might be associated with its unique clinical effects.

Double-edged swords as cancer therapeutics: novel, orally active, small molecules simultaneously inhibit p53-MDM2 interaction and the NF-κB pathway.

PubMed

Zhuang, Chunlin; Miao, Zhenyuan; Wu, Yuelin; Guo, Zizhao; Li, Jin; Yao, Jianzhong; Xing, Chengguo; Sheng, Chunquan; Zhang, Wannian

2014-02-13

Simultaneous inactivation of p53 and hyperactivation of nuclear factor-κB (NF-κB) is a common occurrence in human cancer. Currently, antitumor agents are being designed to selectively activate p53 or inhibit NF-κB. However, there is no concerted effort yet to deliberately design inhibitors that can simultaneously do both. This paper provided a proof-of-concept study that p53-MDM2 interaction and NF-κB pathway can be simultaneously targeted by a small-molecule inhibitor. A series of pyrrolo[3,4-c]pyrazole derivatives were rationally designed and synthesized as the first-in-class inhibitors of p53-MDM2 interaction and NF-κB pathway. Most of the compounds were identified to possess nanomolar p53-MDM2 inhibitory activity. Compounds 5q and 5s suppressed NF-κB activation through inhibition of IκBα phosphorylation and elevation of the cytoplasmic levels of p65 and phosphorylated IKKα/β. Biochemical assay for the kinases also supported the fact that pyrrolo[3,4-c]pyrazole compounds directly targeted the NF-κB pathway. In addition, four compounds (5j, 5q, 5s, and 5u) effectively inhibited tumor growth in the A549 xenograft model. Further pharmacokinetic study revealed that compound 5q exhibited excellent oral bioavailability (72.9%).

Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor.

PubMed

Mulvihill, Mark J; Cooke, Andrew; Rosenfeld-Franklin, Maryland; Buck, Elizabeth; Foreman, Ken; Landfair, Darla; O'Connor, Matthew; Pirritt, Caroline; Sun, Yingchaun; Yao, Yan; Arnold, Lee D; Gibson, Neil W; Ji, Qun-Sheng

2009-09-01

The IGF-1 receptor (IGF-1R) has been implicated in the promotion of tumorigenesis, metastasis and resistance to cancer therapies. Therefore, this receptor has become a major focus for the development of anticancer agents. Our lead optimization efforts that blended structure-based design and empirical medicinal chemistry led to the discovery of OSI-906, a novel small-molecule dual IGF-1R/insulin receptor (IR) kinase inhibitor. OSI-906 potently and selectively inhibits autophosphorylation of both human IGF-1R and IR, displays in vitro antiproliferative effects in a variety of tumor cell lines and shows robust in vivo anti-tumor efficacy in an IGF-1R-driven xenograft model when administered orally once daily. OSI-906 is a novel, potent, selective and orally bioavailable dual IGF-1R/IR kinase inhibitor with favorable preclinical drug-like properties, which has demonstrated in vivo efficacy in tumor models and is currently in clinical testing.

Effect of an oxygenating agent on oral bacteria in vitro and on dental plaque composition in healthy young adults

PubMed Central

Fernandez y Mostajo, Mercedes; van der Reijden, Wil A.; Buijs, Mark J.; Beertsen, Wouter; van der Weijden, Fridus; Crielaard, Wim; Zaura, Egija

2014-01-01

Oral bacteria live in symbiosis with the host. Therefore, when mouthwashes are indicated, selective inhibition of taxa contributing to disease is preferred instead of broad-spectrum antimicrobials. The potential selectivity of an oxygenating mouthwash, Ardox-X® (AX), has not been assessed. The aim of this study was to determine the antimicrobial potential of AX and the effects of a twice-daily oral rinse on dental plaque composition. Material and methods: In vitro, 16 oral bacterial strains were tested using agar diffusion susceptibility, minimum inhibitory and minimum bactericidal concentration tests. A pilot clinical study was performed with 25 healthy volunteers. Clinical assessments and microbiological sampling of supragingival plaque were performed at 1 month before the experiment (Pre-exp), at the start of the experiment (Baseline) and after the one-week experimental period (Post-exp). During the experiment individuals used AX mouthwash twice daily in absence of other oral hygiene measures. The microbiological composition of plaque was assessed by 16S rRNA gene amplicon sequencing. Results: AX showed high inter-species variation in microbial growth inhibition. The tested Prevotella strains and Fusobacterium nucleatum showed the highest sensitivity, while streptococci and Lactobacillus acidophilus were most resistant to AX. Plaque scores at Pre-exp and Baseline visits did not differ significantly (p = 0.193), nor did the microbial composition of plaque. During a period of 7-days non-brushing but twice daily rinsing plaque scores increased from 2.21 (0.31) at Baseline to 2.43 (0.39) Post-exp. A significant microbial shift in composition was observed: genus Streptococcus and Veillonella increased while Corynebacterium, Haemophilus, Leptotrichia, Cardiobacterium and Capnocytophaga decreased (p ≤ 0.001). Conclusion: AX has the potential for selective inhibition of oral bacteria. The shift in oral microbiome after 1 week of rinsing deserves further research. PMID:25101249

A genetic programming approach to oral cancer prognosis

PubMed Central

Tan, Mei Sze; Tan, Jing Wei; Yap, Hwa Jen; Abdul Kareem, Sameem; Zain, Rosnah Binti

2016-01-01

Background The potential of genetic programming (GP) on various fields has been attained in recent years. In bio-medical field, many researches in GP are focused on the recognition of cancerous cells and also on gene expression profiling data. In this research, the aim is to study the performance of GP on the survival prediction of a small sample size of oral cancer prognosis dataset, which is the first study in the field of oral cancer prognosis. Method GP is applied on an oral cancer dataset that contains 31 cases collected from the Malaysia Oral Cancer Database and Tissue Bank System (MOCDTBS). The feature subsets that is automatically selected through GP were noted and the influences of this subset on the results of GP were recorded. In addition, a comparison between the GP performance and that of the Support Vector Machine (SVM) and logistic regression (LR) are also done in order to verify the predictive capabilities of the GP. Result The result shows that GP performed the best (average accuracy of 83.87% and average AUROC of 0.8341) when the features selected are smoking, drinking, chewing, histological differentiation of SCC, and oncogene p63. In addition, based on the comparison results, we found that the GP outperformed the SVM and LR in oral cancer prognosis. Discussion Some of the features in the dataset are found to be statistically co-related. This is because the accuracy of the GP prediction drops when one of the feature in the best feature subset is excluded. Thus, GP provides an automatic feature selection function, which chooses features that are highly correlated to the prognosis of oral cancer. This makes GP an ideal prediction model for cancer clinical and genomic data that can be used to aid physicians in their decision making stage of diagnosis or prognosis. PMID:27688975

Influence of Media in the Choice of Oral Hygiene Products Used Among the Population of Maduravoyal, Chennai, India

PubMed Central

Logaranjani, Anitha; Perumalsamy, Rajapriya; Narayan, Rajeshree Rangari; Rajendran, Sathish; Namasivayam, Ambalavanan

2015-01-01

Background and Aims To assess the factors influencing the awareness and practice of oral hygiene among the local population Maduravoyal, Chennai, India. Materials and Methods A cross-sectional questionnaire based study was conducted to understand the factors influencing the choice and practice of oral hygiene products among the population of Maduravoyal, Chennai, India. Data was collected by means of a self administered structured questionnaire written in English and validated through a pilot survey. One thousand two hundred and nine subjects, with an age range of 15 to 70 years, who visited the Department of Periodontology, Meenakshi Ammal Dental College, Chennai were selected for investigation. The data obtained was analyzed using the SPSS version 13.0. The frequency of distribution and percentages were calculated. Results The results of the study showed that tooth brush (98.5%) and toothpaste (98%) were the main products used for the maintenance of oral hygiene and around 84.6% of the population brushed once daily. Information from the media (59.4%) and decay prevention (49.7%) were the major factors that influenced the choice of toothpaste among the study population. Conclusion The major factor which influenced the choice of oral hygiene products was based on information obtained from advertisements and other sources. There is a need for the dental professionals to be aware of the ever-increasing development and marketing of oral hygiene products from various databases. Hence, the education of people regarding the importance of oral hygiene maintenance, proper selection of oral hygiene products is essential. PMID:26557606

Lapatinib nano-delivery systems: a promising future for breast cancer treatment.

PubMed

Bonde, Gunjan Vasant; Yadav, Sarita Kumari; Chauhan, Sheetal; Mittal, Pooja; Ajmal, Gufran; Thokala, Sathish; Mishra, Brahmeshwar

2018-05-01

Breast cancer stands the second prominent cause of death among women. For its efficient treatment, Lapatinib (LAPA) was developed as a selective tyrosine kinase inhibitor of receptors, overexpressed by breast cancer cells. Various explored delivery strategies for LAPA indicated its controlled release with enhanced aqueous solubility, improved bioavailability, decreased plasma protein binding, reduced dose and toxicity to the other organs with maximized clinical efficacy, compared to its marketed tablet formulation. Areas covered: This comprehensive review deals with the survey, performed through different electronic databases, regarding various challenges and their solutions attained by fabricating delivery systems like nanoparticles, micelle, nanocapsules, nanochannels, and liposomes. It also covers the synthesis of novel LAPA-conjugates for diagnostic purpose. Expert opinion: Unfortunately, clinical use of LAPA is restricted because of its extensive albumin binding capacity, poor oral bioavailability, and poor aqueous solubility. LAPA is marketed as the oral tablet only. Therefore, it becomes imperative to formulate alternate efficient multiparticulate or nano-delivery systems for administration through non-oral routes, for active/passive targeting, and to scale-up by pharmaceutical scientists followed by their clinical trials by clinical experts. LAPA combinations with capecitabine and letrozole should also be tried for breast cancer treatment.

Successful Doxycycline Therapy in a Patient With Escherichia coli and Multidrug-Resistant Klebsiella pneumoniae Urinary Tract Infection.

PubMed

White, Cassandra R; Jodlowski, Tomasz Z; Atkins, Dylan T; Holland, Nicole G

2017-08-01

To report on a patient with a symptomatic, polymicrobial Escherichia coli and multidrug-resistant (MDR), extended-spectrum β-lactamase (ESBL)-positive Klebsiella pneumoniae urinary tract infection (UTI) who was successfully treated with oral doxycycline hyclate. A 70-year-old white male inpatient with a history of recurrent UTI, type 2 diabetes, hypertension, obesity, and diverticular disease was diagnosed with UTI and empirically treated with oral ciprofloxacin. Symptoms persisted 2 days later, and the patient was transitioned to amoxicillin/clavulanate by a different provider. The next day, upon receipt of the urine culture and susceptibility panel revealing E coli and MDR, ESBL-positive K pneumoniae infection, treatment was switched to doxycycline hyclate, which resulted in clinical improvement. Complicated UTI involving multiple pathogens requires careful clinical judgment to select the appropriate antimicrobial agent, improve clinical outcomes, and prevent resistance. Treatment with doxycycline was based on the susceptibility panel and local resistance patterns. Advantages of doxycycline for UTI include its oral formulation, wide spectrum of activity, ability to achieve high concentration in the urine, and low toxicity. Doxycycline hyclate may be an effective treatment option for patients with susceptible MDR UTI.

Neural network pattern recognition of lingual-palatal pressure for automated detection of swallow.

PubMed

Hadley, Aaron J; Krival, Kate R; Ridgel, Angela L; Hahn, Elizabeth C; Tyler, Dustin J

2015-04-01

We describe a novel device and method for real-time measurement of lingual-palatal pressure and automatic identification of the oral transfer phase of deglutition. Clinical measurement of the oral transport phase of swallowing is a complicated process requiring either placement of obstructive sensors or sitting within a fluoroscope or articulograph for recording. Existing detection algorithms distinguish oral events with EMG, sound, and pressure signals from the head and neck, but are imprecise and frequently result in false detection. We placed seven pressure sensors on a molded mouthpiece fitting over the upper teeth and hard palate and recorded pressure during a variety of swallow and non-swallow activities. Pressure measures and swallow times from 12 healthy and 7 Parkinson's subjects provided training data for a time-delay artificial neural network to categorize the recordings as swallow or non-swallow events. User-specific neural networks properly categorized 96 % of swallow and non-swallow events, while a generalized population-trained network was able to properly categorize 93 % of swallow and non-swallow events across all recordings. Lingual-palatal pressure signals are sufficient to selectively and specifically recognize the initiation of swallowing in healthy and dysphagic patients.

Orally disintegrating dosage forms and taste-masking technologies; 2010.

PubMed

Douroumis, Dennis

2011-05-01

In the last decade the development of orally disintegrating tablets (ODTs) and thin-film platforms has grown enormously in the field of pharmaceutical industry. A wide variety of new masking technologies combined with the aforementioned platforms have been developed in order to mask the taste of bitter active substances and achieve patient compliance. The commercial success and viability of such products requires the development of robust formulations with excellent palatability, disintegration times, physicochemical stability and pharmacokinetic profiles. In this review, emerging taste-masking technologies applied to solid dosage form manufacturing are summarized. The unique features and principles of taste-masking approaches used with ODT platforms are discussed, including the advantages and limitations of each technology. A brief discussion is also included on the taste masking of thin-film technologies, owing to their similar applications and requirements. This review elucidates the unique features of current commercially available or highly promising ODT and thin-film technologies, along with taste-masking approaches used in the manufacturing of oral solid dosage forms. A better understanding of these drug delivery approaches will help researchers to select the appropriate platform, or to develop innovative products with improved safety, compliance and clinical value.

Assessment of cold-chain maintenance in vaccine carriers during Pulse Polio National Immunization Day in a rural block of India.

PubMed

Pakhare, Abhijit P; Bali, Surya; Pawar, Radhakishan B; Lokhande, Ganesh S

2014-01-01

India was certified polio free on 27 March 2014. Supplementary immunization activities, in the form of national immunization days, is one of the core strategies for eradication, where oral polio vaccine is administered to children aged under 5 years throughout the country. Oral polio vaccine is heat sensitive and requires maintenance of a stringent cold chain. Therefore, vaccine carriers with ice packs are used in the Pulse Polio Immunization (PPI) programme. This study assessed whether the cold chain is maintained during National Immunization Day in Beed district. A cross-sectional study was conducted at six randomly selected booths, one each from six primary health centres in Georai block of Beed district in Maharashtra. Electronic data loggers, configured to measure half-hourly temperatures, were kept in vaccine carriers throughout the day of PPI. The vaccine carrier temperature was below 8 °C at all six booths; minimum temperature recorded was -9.5 °C, while the maximum was 4.5 °C. The vaccine vial monitor did not reach discard point in any booth. A vaccine carrier with four ice packs very effectively maintains the cold chain required for oral polio vaccine.

Investigating Socioeconomic Position in Dental Caries and Traumatic Dental Injury among Children in Quebec.

PubMed

Da Rosa, P; Rousseau, Marie-Claude; Edasseri, A; Henderson, M; Nicolau, B

2017-12-01

Socioeconomic position (SEP) is inversely associated with most oral health outcomes, but the patterns of association may vary depending on the specific outcome. We estimated associations between SEP and two oral health outcomes, dental caries and traumatic dental injuries (TDI), in Quebec children. We used data from the baseline visit of the QUALITY (QUebec Adipose and Lifestyle Investigation in Youth) Cohort, an ongoing study in Montreal and Quebec, Canada. The analytical sample included 590 children aged 8-10 years. Data on parents' SEP (household income, education) and children's health behaviours and involvement in sports were obtained through questionnaires and interviews. Oral health outcomes (dental caries and TDI in permanent teeth) were assessed by clinical oral exam. Negative binomial regression was used to model dental caries (DMFS index) and number of teeth with TDI adjusting for selected covariates. The mean (SD) DMFS and number of TDI were 0.61 (1.43) and 0.12 (0.43), respectively. Compared to the upper quartile of income, children in the lower quartile had a DMFS approximately 3 times higher (PRR=2.68, 95% CI: 1.43, 5.04). Adjusting for oral health and nutritional behaviours had no effect. Conversely, children in the highest income quartile had a 3 times higher number of teeth with TDI compared to the lowest quartile (PRR=3.14, 95% CI: 1.22, 8.08). Physical activity did not explain this relationship. Parents' education was not associated with dental caries or TDI. SEP seems to play a different role in the cause of dental caries and TDI. Copyright© 2017 Dennis Barber Ltd.

Expression of GLUT-1 in oral squamous cell carcinoma in tobacco and non-tobacco users

PubMed Central

Azad, Neha; Kumari Maurya, Malti; Kar, Meenakshi; Goel, Madhu Mati; Singh, Ajay Kumar; Sagar, Mala; Mehrotra, Divya; Kumar, Vijay

2016-01-01

Background GLUTs are a family of proteins that mediate glucose transport through the membrane, expressed in head and neck squamous cell carcinoma. GLUT-1 positivity in malignant cells indicates increased proliferative activity, energy requirements, aggressive behaviour and poor radiation response. Aim To observe the expression of GLUT-1 protein in oral squamous cell carcinoma in tobacco and non-tobacco users and to correlate the expression with histopathological grading and pathological staging. Methods 50 cases (25 tobacco and 25 non-tobacco) of oral squamous cell carcinoma, selected during period of August 2014 to July 2015. Histopathological grading, TNM and staging were done. Immunohistochemical staining was performed using standard protocol for paraffin embedded sections. Analysis was performed on SPSS software (Windows version 17.0). Results Significant association of GLUT-1 expression was found with history of tobacco (p < 0.001), Bryne's grade (p < 0.001), tumour size (p = 0.001), nodal metastasis (p = 0.022) and stage (p < 0.001). Higher GLUT-1 expression in stage II, stage III and stage IV was found as compared to stage I. GLUT-1 immunoexpression also shows progressive switch from membranous to cytoplasmic to combined location correlating with histopathologic grade and pTNM stage. Conclusion GLUT-1 expression correlates significantly with histological grade and pTNM staging of oral squamous cell carcinoma. It also significantly correlates with tobacco addiction. Thus, GLUT-1 expression may serve as a biomarker for patients of oral squamous cell carcinoma. PMID:26937365

Oral candidiasis in systemic lupus erythematosus.

PubMed

Fangtham, M; Magder, L S; Petri, M A

2014-06-01

We assessed the frequency of oral candidiasis and the association between demographic variables, disease-related variables, corticosteroid treatment, other treatments and the occurrence of oral candidiasis in the Hopkins Lupus Cohort. In this large prospective cohort study of 2258 patients with systemic lupus erythematosus (SLE), demographic and clinical associates of oral candidiasis were estimated by univariate, multivariate and within-person regression models. There were 53,548 cohort visits. Oral candidiasis was diagnosed at 675 visits (1.25%) in 325 (14%) of the patients. In the multivariate analyses, oral candidiasis was associated with African-American ethnicity, SELENA-SLEDAI disease activity, high white blood cell count, a history of bacterial infection, prednisone use and immunosuppressive use. The urine protein by urine dip stick was higher in SLE patients with oral candidiasis. Considering only patients who had candidiasis at some visits in a 'within-person' analysis, candidiasis was more frequent in visits with higher SELENA-SLEDAI disease activity, high white blood cell count, proteinuria by urine dip stick, a history of bacterial infection and prednisone use. The use of hydroxychloroquine was associated with a lower risk of oral candidiasis, but was not statistically significant (p = 0.50) in the within-person analysis models. This study identified multiple risk factors for oral candidiasis in SLE. Inspection of the oral cavity for signs of oral candidiasis is recommended especially in SLE patients with active disease, proteinuria, high white blood cell count, taking prednisone, immunosuppressive drugs or antibiotics. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Oral lipase activities and fat-taste receptors for fat-taste sensing in chickens.

PubMed

Kawabata, Yuko; Kawabata, Fuminori; Nishimura, Shotaro; Tabata, Shoji

2018-01-01

It has been reported that a functional fat-taste receptor, GPR120, is present in chicken oral tissues, and that chickens can detect fat taste in a behavioral test. However, although triglycerides need to be digested to free fatty acids to be recognized by fat-taste receptors such as GPR120, it remains unknown whether lipase activities exist in chicken oral tissues. To examine this question, we first cloned another fat-taste receptor candidate gene, CD36, from the chicken palate. Then, using RT-PCR, we determined that GPR120 and CD36 were broadly expressed in chicken oral and gastrointestinal tissues. Also by RT-PCR, we confirmed that several lipase genes were expressed in both oral and gastrointestinal tissues. Finally, we analyzed the lipase activities of oral tissues by using a fluorogenic triglyceride analog as a lipase substrate. We found there are functional lipases in oral tissues as well as in the stomach and pancreas. These results suggested that chickens have a basic fat-taste reception system that incorporates a triglycerides/oral-lipases/free fatty acids/GPR120 axis and CD36 axis. Copyright © 2017 Elsevier Inc. All rights reserved.

Oral Health Disparities as Determined by Selected Healthy People 2020 Oral Health Objectives for the United States, ...

MedlinePlus

... status of the civilian noninstitutionalized U.S. population. The survey consists of interviews conducted in participants' homes and standardized physical examinations in mobile examination centers. The sample design includes oversampling to obtain reliable estimates of health ...

[Anti-Candida activity of aroma candy and its protective activity against murine oral candidiasis].

PubMed

Hayama, Kazumi; Takahashi, Miki; Suzuki, Motofumi; Ezawa, Kunio; Yamazaki, Masatoshi; Matsukawa, Taiji; Kishi, Akinobu; Sato, Nobuya; Abe, Shigeru

2015-01-01

A daily eatable candy that has possible protective activity against oral candidiasis was experimentally produced. The candy was made from reduced-maltose as main constituent and from several natural products, such as oligonol (depolymerized polyphenols derived from lychee), cinnamon (cassia), citral, and capric acid, which are known to have anti-Candida activity in vitro and in vivo. The candy effectively inhibited the mycelial growth of C. albicans, even when it was diluted 1,000 times with culture media. We assessed the protective activity of the candy against murine candidiasis. When 50μl of candy dissolved and diluted 4 times with water was administered 3 times into the oral cavity of Candida infected mice, the score of lesions on the Candida-infected tongues improved on day 2. These findings suggest that this candy has potential as food that provides protective activity against oral candidiasis.

The scorpion venom peptide BmKn2 induces apoptosis in cancerous but not in normal human oral cells.

PubMed

Satitmanwiwat, Saranya; Changsangfa, Chinarat; Khanuengthong, Anuson; Promthep, Kornkanok; Roytrakul, Sittiruk; Arpornsuwan, Teerakul; Saikhun, Kulnasan; Sritanaudomchai, Hathaitip

2016-12-01

This study aimed to investigate the mechanism of the induction of apoptosis of human oral cancer cells by the scorpion venom peptide BmKn2. Human oral squamous carcinoma cells (HSC4), mouth epidermoid carcinoma cells (KB), human normal gingival cells (HGC) and dental pulp cells (DPC) were treated with BmKn-2 peptide for 24h. Cell viability was determined by the MTT assay. Apoptosis was assessed using phase contrast microscopy, by propidium iodide (PI) staining to assess nuclear morphology and by Annexin V staining. Apoptotic signaling pathways were investigated by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and Western blotting. BmKn-2 showed potent cytotoxic effects towards both HSC4 and KB cells with the associated induction of apoptosis. The cells showed distinct morphological changes, nuclear disintegration and an increase in the number of Annexin V-positive cells. Interestingly, at concentrations which kill cancerous cells, BmKn-2 did not affect cell viability or mediate the induction of apoptosis in normal HGC or DPC. Induction of apoptosis by BmKn-2 in HSC4 and KB cells was associated with the activation of tumor suppress p53. Pro-apoptotic BAX expression was increased, whereas antiapoptotic BCL-2 expression was decreased in BmKn-2 exposed HSC4 and KB cells. BmKn-2 treated-oral cancer cells showed distinct upregulation of initiator caspase-9, with no effect on caspase-8 expression. Increased expression levels of executor caspases-3 and -7 were also found in treated cells for both oral cancers. This study has suggested for the first time that BmKn-2 exerts selective cytotoxic effects on human oral cancer cells by inducting apoptosis via a p53-dependent intrinsic apoptotic pathway. BmKn-2 peptide originally derived from a natural source shows great promise as a candidate treatment for oral cancer, with minimal effects on healthy tissue. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

A role for CFTR in the elevation of glutathione levels in the lung by oral glutathione administration

PubMed Central

Kariya, Chirag; Leitner, Heather; Min, Elysia; van Heeckeren, Christiaan; van Heeckeren, Anna; Day, Brian J.

2014-01-01

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is the only known apical glutathione (GSH) transporter in the lung. The purpose of these studies was to determine whether oral GSH or glutathione disulfide (GSSG) treatment could increase lung epithelial lining fluid (ELF) GSH levels and whether CFTR plays a role in this process. The pharmacokinetic profile of an oral bolus dose of GSH (300 mg/kg) was determined in mice. Plasma, ELF, bronchoalveolar lavage (BAL) cells, and lung tissue were analyzed for GSH content. There was a rapid elevation in the GSH levels that peaked at 30 min in the plasma and 60 min in the lung, ELF, and BAL cells after oral GSH dosing. Oral GSH treatment produced a selective increase in the reduced and active form of GSH in all lung compartments examined. Oral GSSG treatment (300 mg/kg) resulted in a smaller increase of GSH levels. To evaluate the role of CFTR in this process, Cftr knockout (KO) mice and gut-corrected Cftr KO-transgenic (Tg) mice were given an oral bolus dose of GSH (300 mg/kg) and compared with wild-type mice for changes in GSH levels in plasma, lung, ELF, and BAL cells. There was a twofold increase in plasma, a twofold increase in lung, a fivefold increase in ELF, and a threefold increase in BAL cell GSH levels at 60 min in wild-type mice; however, GSH levels only increased by 40% in the plasma, 60% in the lung, 50% in the ELF, and twofold in the BAL cells within the gut-corrected Cftr KO-Tg mice. No change in GSH levels was observed in the uncorrected Cftr KO mice. These studies suggest that CFTR plays an important role in GSH uptake from the diet and transport processes in the lung. PMID:17369290

Curcumin attenuates collagen-induced inflammatory response through the "gut-brain axis".

PubMed

Dou, Yannong; Luo, Jinque; Wu, Xin; Wei, Zhifeng; Tong, Bei; Yu, Juntao; Wang, Ting; Zhang, Xinyu; Yang, Yan; Yuan, Xusheng; Zhao, Peng; Xia, Yufeng; Hu, Huijuan; Dai, Yue

2018-01-06

Previous studies have demonstrated that oral administration of curcumin exhibited an anti-arthritic effect despite its poor bioavailability. The present study aimed to explore whether the gut-brain axis is involved in the therapeutic effect of curcumin. The collagen-induced arthritis (CIA) rat model was induced by immunization with an emulsion of collagen II and complete Freund's adjuvant. Sympathetic and parasympathetic tones were measured by electrocardiographic recordings. Unilateral cervical vagotomy (VGX) was performed before the induction of CIA. The ChAT, AChE activities, and serum cytokine levels were determined by ELISA. The expression of the high-affinity choline transporter 1 (CHT1), ChAT, and vesicular acetylcholine transporter (VAChT) were determined by real-time PCR and immunohistochemical staining. The neuronal excitability of the vagus nerve was determined by whole-cell patch clamp recording. Oral administration of curcumin restored the imbalance between the sympathetic and parasympathetic tones in CIA rats and increased ChAT activity and expression of ChAT and VAChT in the gut, brain, and synovium. Additionally, VGX eliminated the effects of curcumin on arthritis and ACh biosynthesis and transport. Electrophysiological data showed that curcumin markedly increased neuronal excitability of the vagus nerve. Furthermore, selective α7 nAChR antagonists abolished the effects of curcumin on CIA. Our results demonstrate that curcumin attenuates CIA through the "gut-brain axis" by modulating the function of the cholinergic system. These findings provide a novel approach for mechanistic studies of anti-arthritic compounds with low oral absorption and bioavailability.

Update on Janus Kinase Antagonists in Inflammatory Bowel Disease

PubMed Central

Boland, Brigid S.; Sandborn, William J.; Chang, John T.

2014-01-01

Janus kinase (JAK) inhibitors have emerged as a novel orally administered small molecule therapy for the treatment of ulcerative colitis and possibly Crohn’s disease. These molecules are designed to selectively target the activity of specific JAKs and offer a targeted mechanism of action without risk of immunogenicity. Based on data from clinical trials in rheumatoid arthritis and phase 2 studies in inflammatory bowel disease, tofacitinib and other JAK inhibitors are likely to become a new form of medical therapy for the treatment of inflammatory bowel disease. PMID:25110261

Rapid Screening and Characterization of Acetylcholinesterase Inhibitors from Yinhuang Oral Liquid Using Ultrafiltration-liquid Chromatography-electrospray Ionization Tandem Mass Spectrometry

PubMed Central

Zhang, Haomin; Guo, Yinan; Meng, Lingwen; Sun, Hui; Yang, Yinping; Gao, Ying; Sun, Jiaming

2018-01-01

Background: At present, approximately 17–25 million people in the world suffer from Alzheimer's disease (AD). The most efficacious and acceptable therapeutic drug clinically are the acetylcholinesterase inhibitors (AChEIs). Yinhuang oral liquid is a Chinese medicine preparation which contains AChEIs according to the literatures. However, no strategy has been presented for rapid screening and identification of AChEIs from Yinhuang oral liquid. Objective: To develop a method for rapid screening and identification of AChEIs from Yinhuang oral liquid using ultrafiltration–liquid chromatography–electrospray ionization tandem mass spectrometry (UF-LC-ESI-MS/MS). Materials and Methods: In this study, UF incubation conditions such as enzyme concentration, incubation time, and incubation temperature were optimized so as to get better screening results. The AChEIs from Yinhuang oral liquid were identified by high-performance liquid chromatography-ESI-MS and the improved Ellman method was used for the AChE inhibitory activity test in vitro. Results: The results showed that Yinhuang oral liquid can inhibit the activity of AChE. We screened and identified seven compounds with potential AChE inhibitory activity from Yinhuang oral liquid, which provided experimental basis for the treatment and prevention of AD. Conclusion: The current technique was used to directly screen the active ingredients with acetylcholinesterase inhibition from complex traditional Chinese medicine, which was simple, rapid, accurate, and suitable for high-throughput screening of AChEI from complex systems. SUMMARY A UF-LC-ESI-MS/MS method for rapid screening and identification of AChEIs from Yinhuang oral liquid was developedSeven compounds were screened and identified with potential AChE inhibitory activity from Yinhuang oral liquidIt provided experimental basis of Yinhuang oral liquid for the treating and preventing AD. Abbreviations used: (AD): Alzheimer's disease; (UF-LC-ESI-MS/MS): ultrafiltration–liquid chromatography–electrospray ionization tandem mass spectrometry; (AChEIs): acetylcholinesterase inhibitors. PMID:29720840

How Should an Efficient Oral History Interview Process Be Conducted According to the Views of Pre-Service Teachers?

ERIC Educational Resources Information Center

Dogan, Yasin

2015-01-01

Oral history is a type of history arising from using the memories of people and listening to what they narrate. Oral history is a kind of history established around people. It introduces life into the history, and extends its scope. It selects its heroes among the majority of people who have not been known up to that time not only among the…

Minimal and moderate oral sedation in the adult special needs patient.

PubMed

Coke, John M; Edwards, Michael D

2009-04-01

Oral minimal/moderate sedation can be an effective tool to aid in the dental management of adult special needs patients. Specific sedative drugs must be chosen by the dentist that can be used safely and effectively on these patients. This article focuses on a select number of these drugs, specific medical and pharmacologic challenges presented by adult special needs patients, and techniques to safely administer oral minimal and moderate sedation.

Oral therapies for pulmonary arterial hypertension: endothelin receptor antagonists and phosphodiesterase-5 inhibitors.

PubMed

Channick, Richard; Preston, Iona; Klinger, James R

2013-12-01

The development of orally active pulmonary vasodilators has been a major breakthrough in the treatment of pulmonary arterial hypertension (PAH). Orally active medications greatly enhanced patient access to PAH treatment and increased an interest in the diagnosis and treatment of this disease that still continues. Four different orally active drugs are currently available for the treatment of PAH and several more are undergoing evaluation. This article discusses the mechanisms by which endothelin receptor antagonists and phosphodiesterase-5 inhibitors mitigate pulmonary hypertensive responses, and reviews the most recent data concerning their efficacy and limitations in the treatment of PAH. Copyright © 2013 Elsevier Inc. All rights reserved.

Evidence that formulations of the selective MAO-B inhibitor, selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human brain

DOE PAGES

Fowler, Joanna S.; Logan, Jean; Volkow, Nora D.; ...

2015-10-29

Selegiline (L-deprenyl) is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B) at the conventional dose (10 mg/day oral) that is used in the treatment of Parkinson’s disease. However, controlled studies have demonstrated antidepressant activity for high doses of oral selegiline and for transdermal selegiline suggesting that when plasma levels of selegiline are elevated, brain MAO-A might also be inhibited. Zydis selegiline (Zelapar®) is an orally disintegrating formulation of selegiline, which is absorbed through the buccal mucosa producing higher plasma levels of selegiline and reduced amphetamine metabolites compared to equal doses of conventional selegiline. Although there is indirect evidence thatmore » Zydis selegiline at high doses loses its selectivity for MAO-B, there is no direct evidence that it also inhibits brain MAO-A in humans. We measured brain MAO-A in 18 healthy men after a 28-day treatment with Zydis selegiline (2.5, 5.0, or 10 mg/day) and in 3 subjects receiving the selegiline transdermal system (Emsam patch, 6 mg/day) using PET and the MAO-A radiotracer [¹¹C]clorgyline. We also measured dopamine transporter (DAT) availability in three subjects from the 10 mg group. The 10 mg Zydis selegiline dose significantly inhibited MAO-A (36.9 ± 19.7%, range 11–70%, p<0.007)) but not DAT; and while Emsam also inhibited MAO-A (33.2 ± 28.9 (range 9-68%) the difference did not reach significance (p=0.10)) presumably because of the small sample size. Our results provide the first direct evidence of brain MAO-A inhibition in humans by formulations of selegiline, which are currently postulated but not verified to target brain MAO-A in addition to MAO-B.« less

Evidence that formulations of the selective MAO-B inhibitor, selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fowler, Joanna S.; Logan, Jean; Volkow, Nora D.

Selegiline (L-deprenyl) is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B) at the conventional dose (10 mg/day oral) that is used in the treatment of Parkinson’s disease. However, controlled studies have demonstrated antidepressant activity for high doses of oral selegiline and for transdermal selegiline suggesting that when plasma levels of selegiline are elevated, brain MAO-A might also be inhibited. Zydis selegiline (Zelapar®) is an orally disintegrating formulation of selegiline, which is absorbed through the buccal mucosa producing higher plasma levels of selegiline and reduced amphetamine metabolites compared to equal doses of conventional selegiline. Although there is indirect evidence thatmore » Zydis selegiline at high doses loses its selectivity for MAO-B, there is no direct evidence that it also inhibits brain MAO-A in humans. We measured brain MAO-A in 18 healthy men after a 28-day treatment with Zydis selegiline (2.5, 5.0, or 10 mg/day) and in 3 subjects receiving the selegiline transdermal system (Emsam patch, 6 mg/day) using PET and the MAO-A radiotracer [¹¹C]clorgyline. We also measured dopamine transporter (DAT) availability in three subjects from the 10 mg group. The 10 mg Zydis selegiline dose significantly inhibited MAO-A (36.9 ± 19.7%, range 11–70%, p<0.007)) but not DAT; and while Emsam also inhibited MAO-A (33.2 ± 28.9 (range 9-68%) the difference did not reach significance (p=0.10)) presumably because of the small sample size. Our results provide the first direct evidence of brain MAO-A inhibition in humans by formulations of selegiline, which are currently postulated but not verified to target brain MAO-A in addition to MAO-B.« less

Chilean patients’ perception of oral health-related quality of life after third molar surgery

PubMed Central

Aravena, Pedro Christian; Delgado, Felipe; Olave, Hugo; Ulloa-Marin, Carolina; Perez-Rojas, Francisco

2016-01-01

Objective To describe the perception of the quality of life in oral health based on the Health-Related Quality of Life instrument in its Spanish version (HRQOL-sp) in Chilean patients with third molar extraction surgery. Patients and methods A cross-sectional study. The HRQOL-sp was administered to dental patients at the Public Hospital in Rio Bueno in southern Chile treated for unilateral third molar extraction between March and June 2014. The instrument was applied by phone survey on the first, third, fifth, and seventh days after surgery. For the ordinal scale, the response was considered interference in the quality of life when patients selected the options “quite a bit of trouble” or “lots of trouble” for oral function and general activity; and selected complications-related signs and symptoms, a pain level score with a Verbal Rating Scale (range 0 to 7), and worst pain perceived. The patient’s sociodemographic data, type of surgery, and the quality of life level were analyzed according to the domains of the HRQOL-sp instrument. Results A total of 106 patients were selected (age: 20.4±7.39 years; 71.7% women) and a total of 127 extracted third molars. On the first day of follow-up, most patients reported interference in their quality of life. The main problems were difficulty opening the mouth (50.94%) and swelling (83.02%). The worst symptom perceived was “bad breath” (>31%) and the worst pain felt was a mean of 4.31±1.62 on the Verbal Rating Scale. All items gradually reduced until the seventh day. Conclusion The HRQOL-sp revealed substantial interference in the quality of life on the first postoperative day. It is suggested that the risk factors associated with quality of life be analyzed and the instrument in Spanish be validated. PMID:27660421

Activation of Toll-like receptor-9 promotes cellular migration via up-regulating MMP-2 expression in oral squamous cell carcinoma.

PubMed

Ruan, Min; Zhang, Zun; Li, Siyi; Yan, Min; Liu, Shengwen; Yang, Wenjun; Wang, Lizheng; Zhang, Chenping

2014-01-01

Activation of Toll like receptors (TLRs) signaling has been implicated in promoting malignant cell invasion and metastatic potential. Previously we demonstrated that increased TLR-9 expression predicted poor survival in oral cancer patients. The objective of this study is to further investigate the roles and potential molecular mechanisms of TLR-9 signaling in human oral cancer cell invasion. Cell migration, invasion and protein expression were detected by wound healing assay, Transwell chambers model and western blot. The secretion and activity levels of metalloproteinases-2/9 were quantified by ELISA and Gelatin zymography. EMSA and ChIP assays were employed to detect the activity of AP-1signal pathway. TLR-9 siRNA transfection was used to regulate the expression and activity of TLR-9 in oral cancer cell line HB cells. The results of both wound healing assay and in vitro Transwell assay revealed that activation of TLR-9 induced dose- and time- dependent migration and invasion of HB cells. An increased expression, secretion and activity of MMP-2 were observed upon the treatment of CpG-ODN. The TLR-9 signaling-mediated MMP-2 expression appeared to be a consequence of AP-1 activation, because that their DNA binding activity was enhanced by CpG-ODN treatment. All these influences were efficiently repressed by the knockdown of TLR-9 through siRNA or pretreatment of an AP-1 inhibitor. Activation of TLR-9 signaling could promote human oral cancer HB cells invasion with the induction of MMP-2 presentation by attenuating AP-1 binding activity, suggesting a novel anti-metastatic application for TLR-9 targeted therapy in oral cancer in the future.

New treatment options for inflammatory bowel diseases.

PubMed

Verstockt, Bram; Ferrante, Marc; Vermeire, Séverine; Van Assche, Gert

2018-05-01

The advent of anti-TNF agents has dramatically changed the treatment algorithms for IBD in the last 15 years, but primarily and more importantly secondary loss of response is often observed. Fortunately , new treatment options have been actively explored and some have already entered our clinical practice. In the class of anti-cytokine agents, the anti-IL12/IL23 monoclonal antibodies (mAbs) have entered clinical practice with the anti-p40 mAb ustekinumab in Crohn's disease (CD). Also, more selective anti-IL23 agents (anti-p19) have shown efficacy and are being further developed, in contrast to agents inhibiting IL-17 downstream which have failed in clinical trials despite their clear efficacy in psoriasis (Verstockt et al. in Expert Opin Biol Ther 17(1):31-47, 2017; Verstockt et al. in Expert Opin Drug Saf 16(7):809-821, 2017). Following up on the efficacy of the anti-adhesion molecule vedolizumab, etrolizumab (anti-beta-7 integrin) and PF-00547659, an anti-MadCam mAb, are being developed (Lobaton et al. in Aliment Pharmacol Ther 39(6):579-594, 2014). Oral anti-trafficking agents, such as ozanimod, targeting the S1P receptor responsible for the efflux of T-cells from the lymph nodes, have also shown efficacy in patients with ulcerative colitis (UC) (Sandborn et al. in N Engl J Med 374(18):1754-1762, 2016). Oral agents inhibiting cell signaling have been explored successfully in IBD. Tofacitinib, a non-selective oral Janus kinase (JAK) inhibitor, is effective in patients with UC and several other more or less selective Jak1, 2 and 3 inhibitors are being developed for the treatment of CD and UC (Sandborn et al. in N Engl J Med 376(18):1723-1736, 2017; Vermeire et al. in Lancet 389(10066):266-275, 2017; De Vries et al. in J Crohns Colitis 11(7):885-93, 2017). Finally, despite initial disappointing results with systemic administration of mesenchymal stem cells, Alofisel, adipose tissue derived, allogeneic mesenchymal stem cells, locally injected in perianal fistula tracts, induce long-lasting beneficial effects and the drug has been approved in Europe (Panes et al. in Gastroenterology, 2017). In summary, the quest for new treatment options in IBD is very active and justified by the high medical need and unresolved problems patients are facing.

Nonpeptidic angiotensin II AT₁ receptor antagonists derived from 6-substituted aminocarbonyl and acylamino benzimidazoles.

PubMed

Zhang, Jun; Wang, Jin-Liang; Yu, Wei-Fa; Zhou, Zhi-Ming; Tao, Wen-Chang; Wang, Yi-Cheng; Xue, Wei-Zhe; Xu, Di; Hao, Li-Ping; Han, Xiao-Feng; Fei, Fan; Liu, Ting; Liang, Ai-Hua

2013-11-01

Both 6-substituted aminocarbonyl and acylamino benzimidazole derivatives were designed and synthesized as nonpeptidic angiotensin II AT₁ receptor antagonists. Compounds 6f, 6g, 11e, 11f, 11g, and 12 showed nanomolar AT₁ receptor binding affinity and high AT₁ receptor selectivity over AT₂ receptor in a preliminary pharmacological evaluation. Among them, the two most active compounds 6f (AT₁ IC₅₀ = 3 nM, AT₂ IC₅₀ > 10,000 nM, PA₂ = 8.51) and 11g (AT₁ IC₅₀ = 0.1 nM, AT₂ IC₅₀ = 149 nM, PA₂ = 8.43) exhibited good antagonistic activity in isolated rabbit aortic strip functional assay. In addition, they were orally active AT₁ receptor antagonists in spontaneous hypertensive rats. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

[Brazilian bibliographical output on public oral health in public health and dentistry journals].

PubMed

Celeste, Roger Keller; Warmling, Cristine Maria

2014-06-01

The scope of this paper is to describe characteristics of the scientific output in the area of public oral health in journals on public health and dentistry nationwide. The Scopus database of abstracts and quotations was used and eight journals in public health, as well as ten in dentistry, dating from 1947 to 2011 were selected. A research strategy using key words regarding oral health in public health and key words about public health in dentistry was used to locate articles. The themes selected were based on the frequency of key words. Of the total number of articles, 4.7% (n = 642) were found in oral health journals and 6.8% (n = 245) in public health journals. Among the authors who published most, only 12% published in both fields. There was a percentile growth of public oral health publications in dentistry journals, though not in public health journals. In dentistry, only studies indexed as being on the topic of epidemiology showed an increase. In the area of public health, planning was predominant in all the phases studied. Research to evaluate the impact of research and postgraduate policies in scientific production is required.

Screening and referral of oral mucosal pathology: a check-up of Australian dentists.

PubMed

Allen, K; Farah, C S

2015-03-01

Oral squamous cell carcinomas and potentially malignant oral disorders can be detected early by visually inspecting the oral soft tissues. This study aimed to determine Australian dentists' opinions and practices regarding oral mucosal screening, referral and oral cancer prevention. Nine hundred and ninety-nine randomly selected general dentists were mailed a questionnaire. The questionnaire queried practitioners' opinions and perceptions of oral mucosal screening, their referral practices and their beliefs regarding detection and prevention of oral cancer. A total of n=640 individuals responded, yielding a response rate of 70.2%. Most Australian dentists reported to routinely perform oral mucosal screening. Lack of training, confidence, time and financial incentives were seen as barriers to performing mucosal screening to at least some degree by participants in this study. Most dentists manage referrals for oral mucosal pathology appropriately; however, only about half believe in following up with referred patients. Only half of dentists surveyed believed that they could influence a patient to quit smoking. Australian dentists place importance on oral mucosal screening. Some changes to dental education and training could be made to further improve confidence and ability of dentists in detecting and referring oral mucosal pathology. © 2015 Australian Dental Association.

Suppression of NLRP3 inflammasome by oral treatment with sulforaphane alleviates acute gouty inflammation.

PubMed

Yang, Gabsik; Yeon, Sang Hyeon; Lee, Hye Eun; Kang, Han Chang; Cho, Yong Yeon; Lee, Hye Suk; Lee, Joo Young

2018-04-01

The aetiology of gout is closely linked to the deposition of monosodium uric acid (MSU) crystals and the consequent activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. In this study, we investigated whether oral administration of an NLRP3 inhibitor would be effective to attenuate the symptoms of gout. The effects of oral administration with sulforaphane (SFN) were examined in two mouse models of acute gout induced by injection of MSU crystals into footpads or air pouch. The production of caspase-1 (p10) and IL-1β was examined by immunoblotting and ELISA as hallmarks of NLRP3 inflammasome activation. Oral administration of SFN attenuated MSU crystal-induced swelling and neutrophil recruitment in a mouse foot acute gout model, correlating with the suppression of the NLRP3 inflammasome activation in foot tissues. Consistently, oral administration of SFN blocked MSU-crystal-induced activation of the NLRP3 inflammasome in a mouse air pouch gout model. SFN suppressed NLRP3 inflammasome activation induced by MSU crystals, adenosine triphosphate and nigericin but not by poly(dA:dT) in primary mouse macrophages, independent of the reactive oxygen species pathway. SFN inhibited ligand-independent activation of the NLRP3 inflammasome, suggesting that SFN may act directly on the NLRP3 inflammasome complex. Oral administration of SFN effectively alleviated acute gouty inflammation by suppression of the NLRP3 inflammasome. Our results provide a novel strategy in which oral treatment with SFN may be beneficial in preventing acute attacks of gout.

[Effects of traditional Chinese medicine on oral bacteria biofilm].

PubMed

Zhao, Jin; Li, Ji-yao; Zhu, Bing; Zhou, Xue-dong

2007-10-01

To investigate the effects of compounds of Galla chinensis extract (GCE) and Nidus vespae extract-1 (WVE1) on oral bacteria biofilm structure and activity and to determine the possibility of caries prevention by the compounds. The morphology and activity of treated-oral bacterial biofilm and untreated-oral bacterial biofilm were observed by using fluorescence microscope in combination of idio-fluorochrome to label the died and living bacteria. The visible light semiquantitative method was used to measure biomass glucosyltransferase (GTF, A620) values and to determine the effects of active compounds of GCE and NVE1 on GTF of oral bacteria biofilm. The living bacteria in the untreated 24 h bacterial biofilm was dominant, and only a small number of died bacteria were found, the biofilm structure was regular and clear. GCE, GCE-B and NVE1 could inhibit the bacteria in the dental biofilm, which showed significant difference with the negative control. GCE and NVE1 could also inhibit GTF activity of 24 h bacterial biofilm in comparison with the negative control. The traditional Chinese medicine Galla chinensis and Nidus vespae could not only inhibit bacteria growth on oral bacterial biofilm, but also function by adjusting biofilm structure, composition and GTF activity of 24 h bacterial biofilm.

Innovation of natural essential oil-loaded Orabase for local treatment of oral candidiasis

PubMed Central

Labib, Gihan S; Aldawsari, Hibah

2015-01-01

Purpose Oral candidiasis may be manifested in the oral cavity as either mild or severe oral fungal infection. This infection results from the overgrowth of Candida species normally existing in the oral cavity in minute amounts based on many predisposing factors. Several aspects have spurred the search for new strategies in the treatment of oral candidiasis, among which are the limited numbers of new antifungal drugs developed in recent years. Previous studies have shown that thyme and clove oils have antimycotic activities and have suggested their incorporation into pharmaceutical preparations. This study aimed to investigate the possibility of the incorporation and characterization of essential oils or their extracted active ingredients in Orabase formulations. Methods Orabase loaded with clove oil, thyme oil, eugenol, and thymol were prepared and evaluated for their antifungal activities, pH, viscosity, erosion and water uptake characteristics, mechanical properties, in vitro release behavior, and ex vivo mucoadhesion properties. Results All prepared bases showed considerable antifungal activity and acceptable physical characteristics. The release pattern from loaded bases was considerably slow for all oils and active ingredients. All bases showed appreciable adhesion in the in vitro and ex vivo studies. Conclusion The incorporation of essential oils in Orabase could help in future drug delivery design, with promising outcomes on patients’ well-being. PMID:26170621

Innovation of natural essential oil-loaded Orabase for local treatment of oral candidiasis.

PubMed

Labib, Gihan S; Aldawsari, Hibah

2015-01-01

Oral candidiasis may be manifested in the oral cavity as either mild or severe oral fungal infection. This infection results from the overgrowth of Candida species normally existing in the oral cavity in minute amounts based on many predisposing factors. Several aspects have spurred the search for new strategies in the treatment of oral candidiasis, among which are the limited numbers of new antifungal drugs developed in recent years. Previous studies have shown that thyme and clove oils have antimycotic activities and have suggested their incorporation into pharmaceutical preparations. This study aimed to investigate the possibility of the incorporation and characterization of essential oils or their extracted active ingredients in Orabase formulations. Orabase loaded with clove oil, thyme oil, eugenol, and thymol were prepared and evaluated for their antifungal activities, pH, viscosity, erosion and water uptake characteristics, mechanical properties, in vitro release behavior, and ex vivo mucoadhesion properties. All prepared bases showed considerable antifungal activity and acceptable physical characteristics. The release pattern from loaded bases was considerably slow for all oils and active ingredients. All bases showed appreciable adhesion in the in vitro and ex vivo studies. The incorporation of essential oils in Orabase could help in future drug delivery design, with promising outcomes on patients' well-being.

Buccal swab, a minimally invasive method for the screening of oral cancer in active smokers

NASA Astrophysics Data System (ADS)

Suyatmi; Subiyantoro, P.; Indrakila, S.

2018-05-01

Smoking is the main risk factor for developing oral cancer. The previous study showed that there was a strong correlation between the length of smoking with the risk to develop oral cancer. Early detection of epithelial changes of oral mucosa will be a good prevention of the incidence of oral cancer among active smokers. This study evaluated the potential use of buccal swab for the screening of early signs of malignancy in active smokers. This study involved 80 participants including those who were smokers and non smokers. The buccal swab was conducted using sterile cytobrush. An epithelial smear was made from the buccal swab and stained with Papanicolaou’s technique. An cytomorphometric analysis was conducted by comparing the ratio of nuclear cell to cytoplasmic diameter (ND/CD) between the two groups. The mean of ND observed in this study were 8.963µ for active smokers and 7.991µ for non smokers groups. While the mean of CD were 58.249µ and 63.473µ for active smoker and non-smoker respectively. The mean of ND/CD ratio were 0.156 for active smokers and 0.129 for non smokers groups. This study detected a significant difference on the ND/CD ratio among active smokers vs non smokers (p<0.0001 95% CI = -0.040 – -0.014). In conclusion buccal swab could be a routine procedure to obtain sample for identification of changes in cells morphology to screen an early development of oral cancer.

Oral health status, salivary factors and microbial analysis in patients with active gastro-oesophageal reflux disease.

PubMed

Filipi, Kristina; Halackova, Zdenka; Filipi, Vladimir

2011-08-01

To present a complex oral health status including salivary factors, microbial analysis and periodontal and hygiene indices in patients with active gastro-oesophageal reflux disease (GORD). Return of stomach contents is quite common in cases of gastro-oesophageal reflux. Pathological acid movement from the stomach into the oesophagus and oral cavity may lead to a development of dental erosion. Long-lasting untreated GORD may damage hard dental and periodontal tissues and alter the oral microbial environment. The quality and amount of the saliva play an important role in hard and soft oral tissues changes. Fifty patients with diagnosed GORD using 24-hour pH manometry underwent dental examination; 24 patients had active GORD and had been waiting for surgical therapy. In this patient group oral health status and salivary analysis were evaluated. Indicated low salivary flow rates and buffering capacity with a low caries risk but a high risk for dental erosion progression. © 2011 FDI World Dental Federation.

Association of Psychosocial Conditions, Oral Health, and Dietary Variety with Intellectual Activity in Older Community-Dwelling Japanese Adults.

PubMed

Tomioka, Kimiko; Okamoto, Nozomi; Kurumatani, Norio; Hosoi, Hiroshi

2015-01-01

This study examined the factors related to intellectual activity in community-dwelling elderly persons. Self-administered questionnaires mailed to all people aged ≥65 years in a dormitory suburb in Japan (n = 15,210). The response rate was 72.2%. Analytical subjects (n = 8,910) were those who lived independently and completely answered questions about independent and dependent variables and covariates. Independent variables included psychosocial conditions (i.e., social activities, hobbies, and a sense that life is worth living (ikigai)), oral health (i.e., dental health behaviors and oral function evaluated by chewing difficulties, swallowing difficulties, and oral dryness), and dietary variety measured using the dietary variety score (DVS). A dependent variable was intellectual activity measured using the Tokyo Metropolitan Institute of Gerontology Index of Competence. Covariates included age, gender, family structure, pensions, body mass index, alcohol, smoking, medical history, self-rated health, medications, cognitive function, depression, and falling. Logistic regression was used to estimate the odds ratio (OR) for poor intellectual activity. Poor intellectual activity was reported by 28.9% of the study population. After adjustment for covariates and independent variables, poor intellectual activity was significantly associated with nonparticipation in social activities (OR = 1.90, 95%CI = 1.61-2.24), having neither hobbies nor ikigai (3.13, 2.55-3.84), having neither regular dental visits nor daily brushing (1.70, 1.35-2.14), the poorest oral function (1.61, 1.31-1.98), and the lowest DVS quartile (1.96, 1.70-2.26). These results indicate that psychosocial conditions, oral health, and dietary variety are independently associated with intellectual activity in elderly persons. The factors identified in this study may be used in community health programs for maintaining the intellectual activity ability of the elderly.

Intestinal absorption and activation of decitabine amino acid ester prodrugs mediated by peptide transporter PEPT1 and enterocyte enzymes.

PubMed

Tao, Wenhui; Zhao, Dongyang; Sun, Mengchi; Wang, Ziyu; Lin, Bin; Bao, Yu; Li, Yingying; He, Zhonggui; Sun, Yinghua; Sun, Jin

2018-04-25

Decitabine (DAC), a potent DNA methyltransferase (DNMT) inhibitor, has a limited oral bioavailability. Its 5'-amino acid ester prodrugs could improve its oral delivery but the specific absorption mechanism is not yet fully understood. The aim of this present study was to investigate the in vivo absorption and activation mechanism of these prodrugs using in situ intestinal perfusion and pharmacokinetics studies in rats. Although PEPT1 transporter is pH dependent, there appeared to be no proton cotransport in the perfusion experiment with a preferable transport at pH 7.4 rather than pH 6.5. This suggested that the transport was mostly dependent on the dissociated state of the prodrugs and the proton gradient might play only a limited role. In pH 7.4 HEPES buffer, an increase in P eff was observed for L-val-DAC, D-val-DAC, L-phe-DAC and L-trp-DAC (2.89-fold, 1.2-fold, 2.73-fold, and 1.90-fold, respectively), compared with the parent drug. When co-perfusing the prodrug with Glysar, a known substrate of PEPT1, the permeabilities of the prodrugs were significantly inhibited compared with the control. To further investigate the absorption of the prodrugs, L-val-DAC was selected and found to be concentration-dependent and saturable, suggesting a carrier-mediated process (intrinsic K m : 7.80 ± 2.61 mM) along with passive transport. Determination of drug in intestinal homogenate after perfusion further confirmed that the metabolic activation mainly involved an intestinal first-pass effect. In a pharmacokinetic evaluation, the oral bioavailability of L-val-DAC, L-phe-DAC and L-trp-DAC were nearly 1.74-fold, 1.69-fold and 1.49-fold greater than that of DAC. The differences in membrane permeability and oral bioavailability might be due to the different stability in the intestinal lumen and the distinct PEPT1 affinity which is mainly caused by the stereochemistry, hydrophobicity and steric hindrance of the side chains. In summary, the detailed investigation of the absorption mechanism by in vivo intestinal perfusion and pharmacokinetic studies showed that the prodrugs of DAC exhibited excellent permeability and oral bioavailability, which might be attributed to a hybrid (partly PEPT1-mediated and partly passive) transport mode and a rapid activation process in enterocytes. Copyright © 2018 Elsevier B.V. All rights reserved.

Mature leaf concentrate of Sri Lankan wild type Carica papaya Linn. modulates nonfunctional and functional immune responses of rats.

PubMed

Jayasinghe, Chanika Dilumi; Gunasekera, Dinara S; De Silva, Nuwan; Jayawardena, Kithmini Kawya Mandakini; Udagama, Preethi Vidya

2017-04-26

The leaf concentrate of Carica papaya is a traditionally acclaimed immunomodulatory remedy against numerous diseases; nonetheless comprehensive scientific validation of this claim is limited. The present study thus investigated the immunomodulatory potential of Carica papaya mature leaf concentrate (MLCC) of the Sri Lankan wild type cultivar using nonfunctional and functional immunological assays. Wistar rats (N = 6/ group) were orally gavaged with 3 doses (0.18, 0.36 and 0.72 ml/100g body weight) of the MLCC once daily for 3 consecutive days. Selected nonfunctional (enumeration of immune cells and cytokine levels) and functional (cell proliferation and phagocytic activity) immunological parameters, and acute toxic effects were determined using standard methods. Effect of the MLCC (31.25, 62.5, 125, 250, 500 and 1000 μg/ml) on ex vivo proliferation of bone marrow cells (BMC) and splenocytes (SC), and in vitro phagocytic activity of peritoneal macrophages (PMs), and their corresponding cytokine responses were evaluated. The phytochemical profile of the MLCC was established using liquid chromatography-mass spectrometry (LS-MS) and Gas chromatography-mass spectrometry (GC-MS). Counts of rat platelets, total leukocytes, lymphocyte and monocyte sub populations, and BMCs were significantly augmented by oral gavage of the MLCC (p < 0.05). The highest MLCC dose tested herein significantly reduced pro inflammatory cytokines, Interleukin 6 (IL-6) and Tumor Necrosis Factor α (TNF α) levels of rats (p < 0.05). The in vivo phagocytic index of rat PMs significantly increased by oral gavage of all three doses of the MLCC (p < 0.05). In vitro phagocytic activity of rat PMs were enhanced by the MLCC and triggered a Th1 biased cytokine response. The MLCC at low concentrations elicited ex vivo proliferation of BMC (31.25 μg/ml) and SC (31.25 and 62.5 μg/ml) respectively. Conversely, high concentrations (500 and 1000 μg/ml) exhibited cytotoxicity of both BMC and SC with significant modulation of cytokines. Chemical profile of the MLCC revealed the presence of several immunomodulatory compounds. The oral gavage of the MLCC was found to be safe in terms of both hepatic and renal toxicities. The present study established that the mature leaf concentrate (MLCC) of Carica papaya Sri Lankan wild type cultivar is orally active, safe and effectively modulates nonfunctional and functional immunological parameters of rats that unequivocally corroborate the traditional medical claims.

Oral health conditions and frailty in Mexican community-dwelling elderly: a cross sectional analysis

PubMed Central

2012-01-01

Background Oral health is an important component of general well-being for the elderly. Oral health-related problems include loss of teeth, nonfunctional removable dental prostheses, lesions of the oral mucosa, periodontitis, and root caries. They affect food selection, speaking ability, mastication, social relations, and quality of life. Frailty is a geriatric syndrome that confers vulnerability to negative health-related outcomes. The association between oral health and frailty has not been explored thoroughly. This study sought to identify associations between the presence of some oral health conditions, and frailty status among Mexican community-dwelling elderly. Methods Analysis of baseline data of the Mexican Study of Nutritional and Psychosocial Markers of Frailty, a cohort study carried out in a representative sample of people aged 70 and older residing in one district of Mexico City. Frailty was defined as the presence of three or more of the following five components: weight loss, exhaustion, slowness, weakness, and low physical activity. Oral health variables included self-perception of oral health compared with others of the same age; utilization of dental services during the last year, number of teeth, dental condition (edentate, partially edentate, or completely dentate), utilization and functionality of removable partial or complete dentures, severe periodontitis, self-reported chewing problems and xerostomia. Covariates included were gender, age, years of education, cognitive performance, smoking status, recent falls, hospitalization, number of drugs, and comorbidity. The association between frailty and dental variables was determined performing a multivariate logistic regression analysis. Final models were adjusted by socio-demographic and health factors Results Of the 838 participants examined, 699 had the information needed to establish the criteria for diagnosis of frailty. Those who had a higher probability of being frail included women (OR = 1.9), those who reported myocardial infarction (OR = 3.8), urinary incontinence (OR = 2.7), those who rated their oral health worse than others (OR = 3.2), and those who did not use dental services (OR = 2.1). For each additional year of age and each additional drug consumed, the probability of being frail increased 10% and 30%, respectively. Conclusions Utilization of dental services and self-perception of oral health were associated with a higher probability of being frail. PMID:22971075

Size-dependent antibacterial activities of silver nanoparticles against oral anaerobic pathogenic bacteria.

PubMed

Lu, Zhong; Rong, Kaifeng; Li, Ju; Yang, Hao; Chen, Rong

2013-06-01

Dental caries and periodontal disease are widespread diseases for which microorganism infections have been identified as the main etiology. Silver nanoparticles (Ag Nps) were considered as potential control oral bacteria infection agent due to its excellent antimicrobial activity and non acute toxic effects on human cells. In this work, stable Ag Nps with different sizes (~5, 15 and 55 nm mean values) were synthesized by using a simple reduction method or hydrothermal method. The Nps were characterized by powder X-ray diffraction, transmission electron microscopy and UV-vis absorption spectroscopy. The antibacterial activities were evaluated by colony counting assay and growth inhibition curve method, and corresponding minimum inhibitory concentration (MIC) against five anaerobic oral pathogenic bacteria and aerobic bacteria E. coli were determined. The results showed that Ag Nps had apparent antibacterial effects against the anaerobic oral pathogenic bacteria and aerobic bacteria. The MIC values of 5-nm Ag against anaerobic oral pathogenic bacteria A. actinomycetemcomitans, F. nuceatum, S. mitis, S. mutans and S. sanguis were 25, 25, 25, 50 and 50 μg/mL, respectively. The aerobic bacteria were more susceptible to Ag NPs than the anaerobic oral pathogenic bacteria. In the mean time, Ag NPs displayed an obvious size-dependent antibacterial activity against the anaerobic bacteria. The 5-nm Ag presents the highest antibacterial activity. The results of this work indicated a potential application of Ag Nps in the inhibition of oral microorganism infections.

Oral nano-delivery of anticancer ginsenoside 25-OCH3-PPD, a natural inhibitor of the MDM2 oncogene: Nanoparticle preparation, characterization, in vitro and in vivo anti-prostate cancer activity, and mechanisms of action.

PubMed

Voruganti, Sukesh; Qin, Jiang-Jiang; Sarkar, Sushanta; Nag, Subhasree; Walbi, Ismail A; Wang, Shu; Zhao, Yuqing; Wang, Wei; Zhang, Ruiwen

2015-08-28

The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progression through p53-dependent and p53-independent mechanisms. Both natural and synthetic MDM2 inhibitors have been shown anticancer activity against several human cancers. We have recently identified a novel ginsenoside, 25-OCH3-PPD (GS25), one of the most active anticancer ginsenosides discovered thus far, and have demonstrated its MDM2 inhibition and anticancer activity in various human cancer models, including prostate cancer. However, the oral bioavailability of GS25 is limited, which hampers its further development as an oral anticancer agent. The present study was designed to develop a novel nanoparticle formulation for oral delivery of GS25. After GS25 was successfully encapsulated into PEG-PLGA nanoparticles (GS25NP) and its physicochemical properties were characterized, the efficiency of MDM2 targeting, anticancer efficacy, pharmacokinetics, and safety were evaluated in in vitro and in vivo models of human prostate cancer. Our results indicated that, compared with the unencapsulated GS25, GS25NP demonstrated better MDM2 inhibition, improved oral bioavailability and enhanced in vitro and in vivo activities. In conclusion, the validated nano-formulation for GS25 oral delivery improves its molecular targeting, oral bioavailability and anticancer efficacy, providing a basis for further development of GS25 as a novel agent for cancer therapy and prevention.

Effect of oral administration of unfractionated heparin (UFH) on coagulation parameters in plasma and levels of urine and fecal heparin in dogs

PubMed Central

Erickson, Malathi; Hiebert, Linda M.; Carr, Anthony P.; Stickney, Jocelyn D.

2014-01-01

The effects of heparin administration, by the oral route, were evaluated in dogs. In single and multiple dose studies (single 7.5 mg/kg, multiple 3 × 7.5 mg/kg per 48 h), plasma, urine, and fecal samples were collected at various times up to 120 h after oral administration of unfractionated heparin. Changes in plasma and urine anti-Xa activity, plasma and urine anti-IIa activity, plasma activated partial thromboplastin time (APTT) and antithrombin (ATIII), and chemical heparin in urine and feces were examined with time. There was support for heparin absorption, with significant differences in APTT, heparin in plasma as determined by anti-Xa activity (Heptest) in the single dose study and plasma anti-Xa activity, anti-IIa activity and ATIII; and chemical heparin in urine in the multiple dose study. No clinical evidence of bleeding was detected in any dog during the studies. Oral heparin therapy may be applicable for thromboembolic disease in animals. Further studies are warranted to determine the effects of oral heparin at the endothelial level in the dog. PMID:24982550

Dihydrobenz[e][1,4]oxazepin-2(3H)-ones, a new anthelmintic chemotype immobilising whipworm and reducing infectivity in vivo

PubMed Central

Bataille, Carole J. R.; Forman, Ruth; Heyer-Chauhan, Narinder; Marinič, Bruno; Sowood, Daniel J. C.; Wynne, Graham M.; Else, Kathryn J.; Russell, Angela J.

2017-01-01

Trichuris trichiura is a human parasitic whipworm infecting around 500 million people globally, damaging the physical growth and educational performance of those infected. Current drug treatment options are limited and lack efficacy against the worm, preventing an eradication programme. It is therefore important to develop new treatments for trichuriasis. Using Trichuris muris, an established model for T. trichiura, we screened a library of 480 novel drug-like small molecules for compounds causing paralysis of the ex vivo adult parasite. We identified a class of dihydrobenz[e][1,4]oxazepin-2(3H)-one compounds with anthelmintic activity against T. muris. Further screening of structurally related compounds and resynthesis of the most potent molecules led to the identification of 20 active dihydrobenzoxazepinones, a class of molecule not previously implicated in nematode control. The most active immobilise adult T. muris with EC50 values around 25–50μM, comparable to the existing anthelmintic levamisole. The best compounds from this chemotype show low cytotoxicity against murine gut epithelial cells, demonstrating selectivity for the parasite. Developing a novel oral pharmaceutical treatment for a neglected disease and deploying it via mass drug administration is challenging. Interestingly, the dihydrobenzoxazepinone OX02983 reduces the ability of embryonated T. muris eggs to establish infection in the mouse host in vivo. Complementing the potential development of dihydrobenzoxazepinones as an oral anthelmintic, this supports an alternative strategy of developing a therapeutic that acts in the environment, perhaps via a spray, to interrupt the parasite lifecycle. Together these results show that the dihydrobenzoxazepinones are a new class of anthelmintic, active against both egg and adult stages of Trichuris parasites. They demonstrate encouraging selectivity for the parasite, and importantly show considerable scope for further optimisation to improve potency and pharmacokinetic properties with the aim of developing a clinical agent. PMID:28182663

Dihydrobenz[e][1,4]oxazepin-2(3H)-ones, a new anthelmintic chemotype immobilising whipworm and reducing infectivity in vivo.

PubMed

Partridge, Frederick A; Murphy, Emma A; Willis, Nicky J; Bataille, Carole J R; Forman, Ruth; Heyer-Chauhan, Narinder; Marinič, Bruno; Sowood, Daniel J C; Wynne, Graham M; Else, Kathryn J; Russell, Angela J; Sattelle, David B

2017-02-01

Trichuris trichiura is a human parasitic whipworm infecting around 500 million people globally, damaging the physical growth and educational performance of those infected. Current drug treatment options are limited and lack efficacy against the worm, preventing an eradication programme. It is therefore important to develop new treatments for trichuriasis. Using Trichuris muris, an established model for T. trichiura, we screened a library of 480 novel drug-like small molecules for compounds causing paralysis of the ex vivo adult parasite. We identified a class of dihydrobenz[e][1,4]oxazepin-2(3H)-one compounds with anthelmintic activity against T. muris. Further screening of structurally related compounds and resynthesis of the most potent molecules led to the identification of 20 active dihydrobenzoxazepinones, a class of molecule not previously implicated in nematode control. The most active immobilise adult T. muris with EC50 values around 25-50μM, comparable to the existing anthelmintic levamisole. The best compounds from this chemotype show low cytotoxicity against murine gut epithelial cells, demonstrating selectivity for the parasite. Developing a novel oral pharmaceutical treatment for a neglected disease and deploying it via mass drug administration is challenging. Interestingly, the dihydrobenzoxazepinone OX02983 reduces the ability of embryonated T. muris eggs to establish infection in the mouse host in vivo. Complementing the potential development of dihydrobenzoxazepinones as an oral anthelmintic, this supports an alternative strategy of developing a therapeutic that acts in the environment, perhaps via a spray, to interrupt the parasite lifecycle. Together these results show that the dihydrobenzoxazepinones are a new class of anthelmintic, active against both egg and adult stages of Trichuris parasites. They demonstrate encouraging selectivity for the parasite, and importantly show considerable scope for further optimisation to improve potency and pharmacokinetic properties with the aim of developing a clinical agent.

Crystal violet stain as a selective stain for the assessment of mitotic figures in oral epithelial dysplasia and oral squamous cell carcinoma.

PubMed

Jadhav, Kiran B; Ahmed Mujib, B R; Gupta, Nidhi

2012-01-01

Assessment of mitotic figures (MFs) is routinely practiced as prognostic indicator in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC), but identification of MFs poses a problem in terms of staining characteristics. To evaluate effectiveness of crystal violet stain for staining of MFs and its comparison with hematoxylin and eosin (H and E) stain. Study sample includes archival tissues embedded in paraffin blocks diagnosed as OED (n = 30) and OSCC (n = 30). The control group comprised of tissue specimen from oral mucosa of healthy volunteers (n = 30). Two serial sections of each tissue specimen were stained separately with H and E stain and 1% crystal violet stain. The stained sections were observed under microscope for identification and counting of MFs. Data obtained was statistically analyzed by using the Man-Whitney U test. A significant increase in number of MFs was observed in OED and OSCC in comparison with normal oral mucosa. There was a highly significant increase in number of MFs in crystal violet stained tissue sections when compared with H and E stain. Metaphase is the most commonly observed phase of mitosis in crystal violet stain when compared with H and E stain for all three groups. Crystal violet stain can be considered as selective stain for mitotic figures.

Consensus Modeling of Oral Rat Acute Toxicity

EPA Science Inventory

An acute toxicity dataset (oral rat LD50) with about 7400 compounds was compiled from the ChemIDplus database. This dataset was divided into a modeling set and a prediction set. The compounds in the prediction set were selected so that they were present in the modeling set used...

Some Influences of Greek and Roman Rhetoric on Early Letter Writing.

ERIC Educational Resources Information Center

Hildebrandt, Herbert W.

1988-01-01

Describes how letter writing, especially business letters, was influenced by Greek and Roman oral rhetoricians. Discusses three precepts of oral rhetoric--inventio, dispositio, and style--and notes that the classical theories' reflection in written communication can be seen in selected Italian, German, and English epistolographic works. (MM)

Autism Developmental Profiles and Cooperation with Oral Health Screening

ERIC Educational Resources Information Center

Du, Rennan Y.; Yiu, Cynthia C. Y.; Wong, Virginia C. N.; McGrath, Colman P.

2015-01-01

To determine the associations between autism developmental profiles and cooperation with an oral health screening among preschool children with autism spectrum disorders (ASDs). A random sample of Special Child Care Centres registered with the Government Social Welfare Department in Hong Kong was selected (19 out of 37 Centres). All preschool…

40 CFR 795.228 - Oral/dermal pharmacokinetics.

Code of Federal Regulations, 2010 CFR

2010-07-01

... CONTROL ACT (CONTINUED) PROVISIONAL TEST GUIDELINES Provisional Health Effects Guidelines § 795.228 Oral... laboratory. The animals shall be selected at random for the test groups and any animal showing signs of ill health shall not be used. In all studies, unless otherwise specified, each test group shall contain at...

40 CFR 795.228 - Oral/dermal pharmacokinetics.

Code of Federal Regulations, 2012 CFR

2012-07-01

... CONTROL ACT (CONTINUED) PROVISIONAL TEST GUIDELINES Provisional Health Effects Guidelines § 795.228 Oral... laboratory. The animals shall be selected at random for the test groups and any animal showing signs of ill health shall not be used. In all studies, unless otherwise specified, each test group shall contain at...

40 CFR 795.228 - Oral/dermal pharmacokinetics.

Code of Federal Regulations, 2011 CFR

2011-07-01

... CONTROL ACT (CONTINUED) PROVISIONAL TEST GUIDELINES Provisional Health Effects Guidelines § 795.228 Oral... laboratory. The animals shall be selected at random for the test groups and any animal showing signs of ill health shall not be used. In all studies, unless otherwise specified, each test group shall contain at...

40 CFR 795.228 - Oral/dermal pharmacokinetics.

Code of Federal Regulations, 2013 CFR

2013-07-01

... CONTROL ACT (CONTINUED) PROVISIONAL TEST GUIDELINES Provisional Health Effects Guidelines § 795.228 Oral... laboratory. The animals shall be selected at random for the test groups and any animal showing signs of ill health shall not be used. In all studies, unless otherwise specified, each test group shall contain at...

40 CFR 795.228 - Oral/dermal pharmacokinetics.

Code of Federal Regulations, 2014 CFR

2014-07-01

... CONTROL ACT (CONTINUED) PROVISIONAL TEST GUIDELINES Provisional Health Effects Guidelines § 795.228 Oral... laboratory. The animals shall be selected at random for the test groups and any animal showing signs of ill health shall not be used. In all studies, unless otherwise specified, each test group shall contain at...

32 CFR 1633.8 - Basis of classification.

Code of Federal Regulations, 2011 CFR

2011-07-01

... of the official forms of the Selective Service System and other written information in his file, oral statements, if made by the registrant at his personal appearance before the board, and oral statements, if made by the registrant's witnesses at his personal appearance. Any information in any written summary...

32 CFR 1633.8 - Basis of classification.

Code of Federal Regulations, 2010 CFR

2010-07-01

... of the official forms of the Selective Service System and other written information in his file, oral statements, if made by the registrant at his personal appearance before the board, and oral statements, if made by the registrant's witnesses at his personal appearance. Any information in any written summary...

A Report on IRI Scoring and Interpretation.

ERIC Educational Resources Information Center

Anderson, Betty

Noting that most classroom teachers use informal reading inventories (IRI) as diagnostic instruments, a study examined what oral reading accuracy level is most appropriate for the instructional level and whether repetitions should be counted as oral reading errors. Randomly selected students from the second through fifth grades at two elementary…

Relationship between Chemical Structure and Antimicrobial Activities of Isothiocyanates from Cruciferous Vegetables against Oral Pathogens.

PubMed

Ko, Mi-Ok; Kim, Mi-Bo; Lim, Sang-Bin

2016-12-28

We evaluated the potentials of 10 isothiocyanates (ITCs) from cruciferous vegetables and radish root hydrolysate for inhibiting the growth of oral pathogens, with an emphasis on assessing any structure-function relationship. Structural differences in ITCs impacted their antimicrobial activities against oral pathogens differently. The indolyl ITC (indol-3-carbinol) was the most potent inhibitor of the growth of oral pathogens, followed by aromatic ITCs (benzyl ITC (BITC) and phenylethyl ITC (PEITC)) and aliphatic ITCs (erucin, iberin, and sulforaphene). Sulforaphene, which is similar in structure, but has one double bond, showed higher antimicrobial activity than sulforaphane. Erucin, which has a thiol group, showed higher antimicrobial activity than sulforaphane, which has a sulfinyl group. BITC and iberin with a short chain exhibited higher antimicrobial potential than PEITC and sulforaphane with a longer chain, respectively. ITCs have strong antimicrobial activities and may be useful in the prevention and management of dental caries.

Ecological Effect of Arginine on Oral Microbiota.

PubMed

Zheng, Xin; He, Jinzhi; Wang, Lin; Zhou, Shuangshuang; Peng, Xian; Huang, Shi; Zheng, Liwei; Cheng, Lei; Hao, Yuqing; Li, Jiyao; Xu, Jian; Xu, Xin; Zhou, Xuedong

2017-08-03

Dental caries is closely associated with the microbial dybiosis between acidogenic/aciduric pathogens and alkali-generating commensal bacteria colonized in the oral cavity. Our recent studies have shown that arginine may represent a promising anti-caries agent by modulating microbial composition in an in vitro consortium. However, the effect of arginine on the oral microbiota has yet to be comprehensively delineated in either clinical cohort or in vitro biofilm models that better represent the microbial diversity of oral cavity. Here, by employing a clinical cohort and a saliva-derived biofilm model, we demonstrated that arginine treatment could favorably modulate the oral microbiota of caries-active individuals. Specifically, treatment with arginine-containing dentifrice normalized the oral microbiota of caries-active individuals similar to that of caries-free controls in terms of microbial structure, abundance of typical species, enzymatic activities of glycolysis and alkali-generation related enzymes and their corresponding transcripts. Moreover, we found that combinatory use of arginine with fluoride could better enrich alkali-generating Streptococcus sanguinis and suppress acidogenic/aciduric Streptococcus mutans, and thus significantly retard the demineralizing capability of saliva-derived oral biofilm. Hence, we propose that fluoride and arginine have a potential synergistic effect in maintaining an eco-friendly oral microbial equilibrium in favor of better caries management.

Impact of Sense of Coherence on Oral Health among Bus Drivers: A Cross-Sectional Study

PubMed Central

Ahmed, Shaik Ijaz; Sudhir, Kudlur Maheswarappa; Reddy, V. Chandra Sekhara; Kumar, R. V. S. Krishna; Srinivasulu, G.; Deepthi, Athuluru

2018-01-01

Aim and Objectives: To assess the sense of coherence (SOC) and the impact of SOC on oral hygiene behaviors and oral health status among bus drivers in Nellore district, Andhra Pradesh. Materials and Methods: A descriptive cross-sectional study was conducted during August–September 2017. Cluster random sampling methodology was used for the selection of drivers. Five depots were randomly selected from the list of various Andhra Pradesh State Road Transport Corporation depots in Nellore district. The estimated sample size was proportionately divided among these five depots of Nellore district (n = 120). The SOC-related data were obtained using short version of Antonovsky's SOC scale. Every item was scored on a Likert scale ranging from 1 to 7. The sum of the scores for SOC was 13–91. A high score indicates a strong SOC. Clinical examination was done for recording oral health status using Oral Hygiene Index-simplified (OHI-S), dental caries, periodontal status, and oral mucosal lesions were recorded according to the WHO criteria 1997. Data were entered and analyzed using SPSS ver. 22 (SPSS Inc., Chicago, IL, USA). Results: Majority of the bus drivers who participated in the study had a low SOC (60%). A significant (P < 0.05) positive correlation was observed with age (r = 0.1420), socioeconomic status (r = 0.1467), and visit to dentist (r = 0.1912). A nonsignificant negative correlation was observed with habits (r = −0.0681), OHI-S (r = −0.0772), dental caries (r = −0.0874), Community Periodontal Index (r = −0.0642), loss of attachment (r = −0.0650), and oral mucosal lesions (r = −0.0542). Conclusion: Strong SOC was associated with increase in age, better socioeconomic status, good habits, increased frequency of dental visits, and a good oral health.

Melatonin Inhibits Reactive Oxygen Species-Driven Proliferation, Epithelial-Mesenchymal Transition, and Vasculogenic Mimicry in Oral Cancer

PubMed Central

Liu, Rui; Wang, Hui-li; Deng, Man-jing; Wen, Xiu-jie; Mo, Yuan-yuan; Chen, Fa-ming; Zou, Chun-li; Duan, Wei-feng

2018-01-01

Globally, oral cancer is the most common type of head and neck cancers. Melatonin elicits inhibitory effects on oral cancer; however, the biological function of melatonin and underlying mechanisms remain largely unknown. In this study, we found that melatonin impaired the proliferation and apoptosis resistance of oral cancer cells by inactivating ROS-dependent Akt signaling, involving in downregulation of cyclin D1, PCNA, and Bcl-2 and upregulation of Bax. Melatonin inhibited the migration and invasion of oral cancer cells by repressing ROS-activated Akt signaling, implicating with the reduction of Snail and Vimentin and the enhancement of E-cadherin. Moreover, melatonin hampered vasculogenic mimicry of oral cancer cells through blockage of ROS-activated extracellular-regulated protein kinases (ERKs) and Akt pathways involving the hypoxia-inducible factor 1α. Consistently, melatonin retarded tumorigenesis of oral cancer in vivo. Overall, these findings indicated that melatonin exerts antisurvival, antimotility, and antiangiogenesis effects on oral cancer partly by suppressing ROS-reliant Akt or ERK signaling. PMID:29725496