RESUMO
Pteropine orthoreovirus (PRV) is an emerging zoonotic respiratory virus that can be transmitted from bats to humans. In Malaysia, aside from PRV2P (Pulau virus) being isolated from Pteropus hypomelanus sampled in Tioman Island, PRV3M (Melaka virus), PRV4K (Kampar virus), and PRV7S (Sikamat virus) were all isolated from samples of patients who reported having a disease spectrum from acute respiratory distress to influenza-like illness and sometimes even with enteric symptoms such as diarrhea and abdominal pain. Screening of sera collected from human volunteers on Tioman Island in 2001-2002 demonstrated that 12.8% (14/109) were positive for PRV2P and PRV3M. Taking all these together, we aim to investigate the serological prevalence of PRV (including PRV4K and PRV7S) among Tioman Island inhabitants again with the assumption that the seroprevalence rate will remain nearly similar to the above reported if human exposure to bats is still happening in the island. Using sera collected from human volunteers on the same island in 2017, we demonstrated seroprevalence of 17.8% (28/157) against PRV2P and PRV3M, respectively. Seropositivity of 11.4% among Tioman Island inhabitants against PRV4K and PRV7S, respectively, was described in this study. In addition, the seroprevalence of 89.5% (17/19), 73.6% (14/19), 63.0% (12/19), and 73.6% (14/19) against PRV2P, PRV3M, PRV4K, and PRV7S, respectively, were observed among pteropid bats in the island. We revealed that the seroprevalence of PRV among island inhabitants remains nearly similar after nearly two decades, suggesting that potential spill-over events in bat-human interface areas in the Tioman Island. We are unclear whether such spillover was directly from bats to humans, as suspected for the PRV3M human cases, or from an intermediate host(s) yet to be identified. There is a high possibility of the viruses circulating among the bats as demonstrated by high seroprevalence against PRV in the bats.
Assuntos
Quirópteros/virologia , Orthoreovirus/genética , Orthoreovirus/fisiologia , Infecções por Reoviridae/veterinária , Zoonoses/transmissão , Adolescente , Adulto , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Quirópteros/sangue , Feminino , Voluntários Saudáveis , Humanos , Malásia , Masculino , Pessoa de Meia-Idade , Infecções por Reoviridae/virologia , Estudos Soroepidemiológicos , Adulto Jovem , Zoonoses/sangue , Zoonoses/virologiaRESUMO
Somatic mutations in key oncogenes in non-small cell lung cancer (NSCLC) and melanoma are important determinants of tumour sensitivity to targeted therapies. Molecular screening for these predictive biomarkers is routinely used to inform treatment decisions; however, little is known about how best to communicate testing and results to patients. This qualitative study aimed to explore advanced cancer patients' attitudes and experiences regarding somatic tumour screening to identify their information and support needs. Sixteen NSCLC and eight melanoma patients who had undergone screening participated in a semi-structured face-to-face or telephone interview exploring their understanding, views, preferences and needs regarding screening. Interviews were audiotaped, transcribed and analysed for thematic patterns. Participants expressed positive views and unequivocal acceptance of screening, and understood its role in guiding treatment selection. They preferred to receive information verbally through simple, non-technical language from their oncologist with additional take-home materials. Patients were interested in learning about their test results, but wanted discussion to be focused on practical matters relevant to treatment. While receiving their screening results was not considered burdensome, information overload and cancer-related distress were identified as barriers to test comprehension. Patients may benefit from information and decision-related tools to better understand genomic information and adequately support psychosocial outcomes.
Assuntos
Atitude Frente a Saúde , Carcinoma Pulmonar de Células não Pequenas/psicologia , Testes Genéticos , Neoplasias Pulmonares/psicologia , Melanoma/psicologia , Medicina de Precisão/psicologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Educação de Pacientes como Assunto , Medicina de Precisão/métodos , Pesquisa QualitativaAssuntos
Dermatologia , Currículo , Dermatologia/educação , Avaliação Educacional , Escolaridade , Humanos , EstudantesRESUMO
We covalently linked doxorubicin with a peptide that is hydrolyzable by prostate-specific antigen. In the presence of prostate tumor cells secreting prostate-specific antigen, the peptide moiety of this conjugate, L-377,202, was hydrolyzed, resulting in the release of leucine-doxorubicin and doxorubicin, which are both very cytotoxic to cancer cells. However, L-377,202 was much less cytotoxic than conventional doxorubicin to cells in culture that do not secrete prostate-specific antigen. L-377,202 was approximately 15 times more effective than was conventional doxorubicin at inhibiting the growth of human prostate cancer tumors in nude mice when both drugs were used at their maximally tolerated doses. Nude mice inoculated with human prostate tumor cells secreting prostate-specific antigen showed considerable reductions in tumor burden with minimal total body weight loss when treated with L-377, 202. This improvement in therapeutic index correlated with the selective localization of leucine-doxorubicin and free doxorubicin in tissues secreting prostate-specific antigen after exposure to L-377,202.
Assuntos
Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Oligopeptídeos/uso terapêutico , Pró-Fármacos/uso terapêutico , Antígeno Prostático Específico/fisiologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Animais , Doxorrubicina/farmacocinética , Humanos , Masculino , Camundongos , Camundongos Nus , Oligopeptídeos/farmacocinética , Pró-Fármacos/farmacocinética , Antígeno Prostático Específico/análise , Antígeno Prostático Específico/sangue , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A potent (IC50 = 30 nM), specific nonnucleoside HIV-1 reverse transcriptase (RT) inhibitor 3-[N-(phthalimidomethyl)amino]-5-ethyl-6-methylpyridin-2(1H) -one (1), was discovered through an in vitro screening program. This compound did not inhibit (IC50 > 300 microns) other DNA and RNA polymerases, including HIV-2 RT and SIV-RT. Unfortunately, hydrolytic instability of this (aminomethyl)phthalimide precluded use as an antiviral agent. In the first paper of this series, preliminary development efforts are described which produced ethylphthalimide 20, a hydrolytically stable compound with reduced (100-fold) HIV-1 RT inhibitory activity and weak (CIC95 = 40 microM) antiviral activity in H9 cells. Structure-activity studies demonstrated the importance of the 5-ethyl, 6-methyl substituent pattern on the pyridinone ring and the need for a flexible two-atom linker between the pyridinone and phthalimide heterocycles. These leads, 1 and 20, provided a basis for the further development of this structural class of inhibitors from which several compounds, the subject of accompanying reports, were selected for clinical evaluation.
Assuntos
Antivirais/farmacologia , HIV-1/enzimologia , Ftalimidas/farmacologia , Piridonas/farmacologia , Inibidores da Transcriptase Reversa , Antivirais/química , Células Cultivadas , Transcriptase Reversa do HIV , HIV-2/enzimologia , Hidrólise , Espectroscopia de Ressonância Magnética , Ftalimidas/síntese química , Ftalimidas/química , Piridonas/síntese química , Piridonas/química , Vírus da Imunodeficiência Símia/enzimologiaRESUMO
A series of nonnucleoside 3-aminopyridin-2(1H)-one derivatives was synthesized and evaluated for HIV-1 RT inhibitory properties. Several analogs proved to be potent and highly selective antagonists with in vitro IC50 values as low as 19 nM in the enzyme assay using rC.dG as template-primer. Two compounds from this series, 3-[[(4,7-dimethylbenzoxazol-2-yl)methyl]-amino]-5-ethyl-6-methy lpyridin-2(1H)-one (34, L-697,639) and the corresponding 4,7-dichloro analogue (37, L-697,661) inhibited the spread of HIV-1 IIIb infection by 95% in MT4 cell culture at concentrations of 25-50 nM and were selected for clinical trials as antiviral agents.
Assuntos
Aminopiridinas/farmacologia , Antivirais/farmacologia , Benzoxazóis/farmacologia , HIV-1/efeitos dos fármacos , Piridonas/farmacologia , Inibidores da Transcriptase Reversa , Aminopiridinas/química , Antivirais/síntese química , Benzoxazóis/síntese química , Células Cultivadas , Transcriptase Reversa do HIV , HIV-1/enzimologia , Piridonas/síntese química , Piridonas/química , Relação Estrutura-AtividadeRESUMO
A series of HIV-1 protease inhibitors containing a novel hydroxyethyl secondary amine transition state isostere has been synthesized. The compounds exhibit a strong preference for the (R) stereochemistry at the transition state hydroxyl group. Molecular modeling studies with the prototype compound 11 have provided important insights into the structural requirements for good inhibitor-active site binding interaction. N-Terminal extension of 11 into the P2-P3 region led to the discovery of 19, the most potent enzyme inhibitor in the series (IC50 = 5.4 nM). 19 was shown to have potent antiviral activity in cultured MT-4 human T-lymphoid cells. Comparison of analogs of 19 with analogs of 1 (Ro31-8959) demonstrates that considerably different structure-activity relationships exist between these two subclasses of hydroxyethylamine HIV-protease inhibitors.
Assuntos
Antivirais/síntese química , Etilaminas/farmacologia , Inibidores da Protease de HIV , HIV-1/enzimologia , Inibidores de Proteases/síntese química , Sequência de Aminoácidos , Antivirais/farmacologia , Sítios de Ligação , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Etilaminas/química , Proteína do Núcleo p24 do HIV/análise , Protease de HIV/metabolismo , Humanos , Espectrometria de Massas , Modelos Moleculares , Dados de Sequência Molecular , Inibidores de Proteases/farmacologiaRESUMO
A new series of potent specific 2-pyridinone reverse transcriptase (RT) inhibitors was developed based on the preliminary development lead 3-[(phthalmido)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (3), a non-nucleoside derivative which exhibited weak antiviral activity in cell culture against HIV-1 strain IIIB. One compound, 3-[(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (9,L-696,229), which was a highly selective antagonist of the RT enzyme (IC50 = 23 nM) and which inhibited the spread of HIV-1 IIIB infection by > 95% in MT4 human T-lymphoid cell culture (CIC95 = 50-100 nM), was selected for clinical evaluation as an antiviral agent.
Assuntos
Antivirais/síntese química , Benzoxazóis/síntese química , Piridonas/síntese química , Inibidores da Transcriptase Reversa , Antivirais/química , Antivirais/farmacologia , Benzoxazóis/química , Benzoxazóis/farmacologia , Proteínas Sanguíneas/metabolismo , Células Cultivadas , Avaliação de Medicamentos , Transcriptase Reversa do HIV , Humanos , Piridonas/química , Piridonas/farmacologia , Relação Estrutura-AtividadeRESUMO
In an ongoing effort to develop novel nonnucleoside, specific human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitors, a series of 3-[(pyridylmethyl)amino]- and 3-[(phenylmethyl)amino]-2-pyridinone derivatives was synthesized and tested for HIV-1 RT inhibitory activity. The more potent compounds have a 2'-methoxy group and 4'- and/or 5'-aliphatic substituents on the pyridyl and phenyl rings. Several of the more potent compounds were also evaluated for antiviral activity in MT-4 cell culture. From this series of compounds, 3-[N-[(5-ethyl-2-methoxy-6-methyl-3-pyridyl)methyl]amino]-5-ethyl-6- methylpyridin-2(1H)-one (6) was selected for clinical evaluation.
Assuntos
Aminopiridinas/síntese química , Antivirais/síntese química , Piridonas/síntese química , Inibidores da Transcriptase Reversa , Aminopiridinas/química , Aminopiridinas/farmacologia , Animais , Antivirais/química , Antivirais/farmacologia , Células Cultivadas , Transcriptase Reversa do HIV , Haplorrinos , Piridonas/química , Piridonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
We have observed a high correlation between the intermolecular interaction energy (Einter) calculated for HIV-1 protease inhibitor complexes and the observed in vitro enzyme inhibition. A training set of 33 inhibitors containing modifications in the P1' and P2' positions was used to develop a regression equation which relates Einter and pIC50. This correlation was subsequently employed to successfully predict the activity of proposed HIV-1 protease inhibitors in advance of synthesis in a structure-based design program. This included a precursor, 47, to the current phase II clinical candidate, L-735,524 (51). The development of the correlation, its applications, and its limitations are discussed, and the force field (MM2X) and host molecular mechanics program (OPTIMOL) used in this work are described.
Assuntos
Inibidores da Protease de HIV/química , Protease de HIV/química , Sítios de Ligação , Desenho Assistido por Computador , Desenho de Fármacos , Protease de HIV/ultraestrutura , Modelos Moleculares , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , TermodinâmicaRESUMO
A series of protease inhibitors bearing constrained unnatural amino acids at the P2-position and novel heterocycles at the P3-position of compound 1 (Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral activities were evaluated. Replacement of P2-asparagine of compound 1 with (2S,3'R)-tetrahydrofuranylglycine resulted in improvement in enzyme inhibitory as well as antiviral potencies (compound 23). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylglycine at the P2-position proved to be less effective. The resulting compound 24 was 100-fold less potent than the 2S,3R-isomer (compound 23). This stereochemical preference indicated a hydrogen-bonding interaction between the tetrahydrofuranyl oxygen and the residues of the S2-region of the enzyme active site. Furthermore, replacement of P3-quinolinoyl ligand of 1 with various novel heterocycles resulted in potent inhibitors of HIV proteases. Of particular interest, compound 2 with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine derivative at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compound 27 in which the P2-P3-amide carbonyl has been removed. The resulting compound 27 has exhibited improvement in antiviral potency while retaining the enzyme inhibitory potency similar to compound 1.
Assuntos
Inibidores da Protease de HIV/síntese química , Antivirais/metabolismo , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/metabolismoRESUMO
Doxorubicin (Dox) can provide some stabilization in prostate cancer; however, its use is limited because of systemic toxicities, primarily cardiotoxicity and immunosuppression. The administration of a prodrug of doxorubicin, designed to permit selective activation by the tumor, would reduce general systemic exposure to the active drug and would thereby increase the therapeutic index. Prostate specific antigen (PSA) is a serine protease with chymotrypsin-like activity that is a member of the kallikrein gene family. PSA's putative physiological role is the liquefaction of semen by virtue of its ability to cleave the seminal fluid proteins semenogelins I and II. Serum PSA levels have been found to correlate well with the number of malignant prostate cells. The use of a prodrug which is cleaved by the enzyme PSA in the prostate should in principle produce high localized concentrations of the cytotoxic agent at the tumor site while limiting systemic exposure to the active drug. Cleavage maps following PSA treatment of human semenogelin were constructed. Systematic modification of the amino acid residues flanking the primary cleavage site led to the synthesis of a series of short peptides which were efficiently hydrolyzed by PSA. Subsequent coupling of selected peptides to doxorubicin provided a series of doxorubicin-peptide conjugates which were evaluated in vitro and in vivo as targeted prodrugs for PSA-secreting tumor cells. From these studies we selected Glutaryl-Hyp-Ala-Ser-Chg-Gln-Ser-Leu-Dox, 27, as the peptide-doxorubicin conjugate with the best profile of physical and biological properties. Compound 27 has a greater than 20-fold selectivity against human prostate PSA-secreting LNCaP cells relative to the non-PSA-secreting DuPRO cell line. In nude mouse xenograft studies, 27 reduced PSA levels by 95% and tumor weight by 87% at a dose below its MTD. Both doxorubicin and Leu-Dox (13) were ineffective in reducing circulating PSA and tumor burden at their maximum tolerated doses. On the basis of these results, we selected 27 for further study to assess its ability to inhibit human prostate cancer cell growth and tumorigenesis.
Assuntos
Antibióticos Antineoplásicos/química , Antineoplásicos/química , Doxorrubicina/química , Oligopeptídeos/química , Fragmentos de Peptídeos/química , Pró-Fármacos/química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/toxicidade , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Doxorrubicina/síntese química , Doxorrubicina/farmacologia , Doxorrubicina/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Espectrometria de Massas , Camundongos , Camundongos Nus , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Oligopeptídeos/toxicidade , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Pró-Fármacos/toxicidade , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
Methyl substitution at the 2-position of the imidazole ring greatly improved drug metabolism profiles, in human liver microsomes, of ras farnesyl-protein transferase inhibitor (FTI) candidates for drug development. Methyl substitution markedly reduced the P450 inhibitory potency of non-substituted FTIs for CYP3A4 (by a factor of 12-403) and 2C9 (by a factor of 4.2-28), while it had little effect on the CYP2D6 enzyme. An immunochemical inhibition study demonstrated that CYP3A4 plays a predominant role in the metabolism of both non-substituted and 2-methyl-substituted imidazole-containing FTI candidates. Very strong type II binding spectra with human liver microsomes were observed for all non-substituted FTIs, while methyl substitution markedly weakened type II spectra or shifted the type of spectra from II to I. This indicated that methyl substitution on the imidazole moiety interfered with the substrate-P450 heme interaction, likely due to a steric effect caused by the methyl group. A kinetics study revealed that the methyl substitution increased V(max) and K(m) values to the same extent. These studies suggested that the 2-methyl substitution on the imidazole ring improved its drug metabolism profile by reducing the potential to inhibit CYP3A4-mediated metabolism without affecting intrinsic metabolic clearance (V(max)/K(m)).
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Oxigenases de Função Mista/antagonistas & inibidores , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Imidazóis/química , Imidazóis/metabolismo , Técnicas In Vitro , Microssomos Hepáticos/enzimologia , Oxigenases de Função Mista/metabolismo , Análise EspectralRESUMO
OBJECTIVE: To understand the chemical changes in the decocting process of Radix et Rhizoma Rhei. METHOD: Comparing the contents of many kinds of anthraquinones in the crude drug, decoction and drug sediments of Radix et Rhizoma Rhei by HPLC. RESULT: The contents of combined and free anthraquinones changed after the crude drug was decocted. CONCLUSION: These changes may be related to the hydrolysis of combined anthraquinones, the decomposition of free anthraquinones, and the inter-transition among anthraquinones.
Assuntos
Antraquinonas/análise , Medicamentos de Ervas Chinesas/química , Plantas Medicinais/química , Rheum/química , Emodina/análise , Temperatura Alta , Oxigenases de Função Mista/análise , Raízes de Plantas/química , Rizoma/químicaRESUMO
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease, and the incidence increases year by year. The pathogenesis of NAFLD is correlated with insulin resistant (IR), and oxidative stress which induces varied inflammatory cytokines (TNF-α, IL-1, IL-6, etc). Different signal transductions such as MAPK, NF-κB, AMPK, JAK2/STAT3, PPAR, PI3K/Akt, TLR were activated by the pathogenic factors to regulate correlative reactions. Thus, in-depth study of the signal transductions will probably provide new suitable solutions for the prevention and therapy of NAFLD.
RESUMO
Incorrect patellar resection during total knee arthroplasty can lead to anterior knee pain, patellar maltracking, patellofemoral impingement, patellar fracture, component loosening and reduced range of motion. A computer-assisted surgery (CAS) system was developed to improve the accuracy of the patellar cut. Twelve cadaveric knee specimens (6 pairs) were surgically prepared and the patella resected by two senior orthopaedic residents using either a conventional sawguide technique (right knee) or a computer-assisted sawguide technique (left knee). Multiple cuts and measurements were permitted for the conventional technique, to reflect the clinical situation, whereas only a single cut was permitted for the CAS technique. Prior training had been provided on artificial bones for both techniques. Custom marker arrays were mounted on the sawguide and patella. The user positioned the sawguide based on a real-time display that compared the current sawguide plane to the ideal resection. The resulting mediolateral and superoinferior resection angles and central thickness were measured from CT scans of the specimens, relative to the anterior surface of the patella. Both techniques resulted in symmetric cuts (<7°). Repeatability in the mediolateral direction was better for the CAS technique than for the conventional technique (p<0.01). This study demonstrated that computer-assisted patellar resection is a feasible approach that can produce results equal to or better than those obtained with conventional techniques, even when the experimental conditions favor the conventional technique. Improvements in the CAS hardware could further improve the accuracy and usability of the system, resulting in reductions in postoperative complications. Patellar CAS could also serve as a valuable tool for feedback and training.