Two cases of neural tube defects with dolutegravir use at conception in south Brazil

ABSTRACT Dolutegravir (DTG) is amongst the most prescribed antiretrovirals worldwide and is recommended as first line regimen in most HIV treatment guidelines. Its use, although infrequently, had been associated to an increased chance of neural tube defects (NTD) in Botswana, Africa. Herein we describe two cases of NTD in women who conceived while taking DTG as part of their antiretroviral treatment in the city of Porto Alegre, Brazil.

Which antiretroviral regimen is associated with higher adherence in Brazil? A comparison of single, multi, and dolutegravir-based regimens / Qual esquema antirretroviral está associado à maior adesão no Brasil? Uma comparação dos esquemas de comprimido único, múltiplos comprimidos e com dolutegravir / ¿Qué tratamiento antirretroviral está asociado con adherencia más alta en Brasil? Una comparación de tratamientos únicos, múltiples y basados en el dolutegravir

Abstract: We evaluated adherence to highly active antiretroviral therapy (HAART) and its associated factors according to the type of regimen in patients initiating treatment in Belo Horizonte, Minas Gerais State, Brazil. We measured adherence using the eight items Morisky Therapeutic Adhesion Scale (MMAS-8) and compared the use of "backbone" tenofovir/lamivudine plus efavirenz one tablet once-daily (STR) or dolutegravir in multi-tablet once-daily (MTR-DTG), or other multi-tablet regimens (MTR-other). We conducted a multivariate logistic regression analysis to address factors associated with adherence. A total of 393 patients were included, 254 used STR, 106 MTR-DTG, and 33 MTR-other. The overall adhesion rate was 44.8% (95%CI: 39.4; 50.1), 50% for MTR-DTG, 43.3% for STR and 39.4% for MTR-other. Multivariate analysis showed a higher chance of adherence among patients using MTR-DTG, those who received and understood counseling about their treatment and with a higher quality of life. Prior use of illicit drugs in the lifetime was associated with poorer adherence. Overall adherence was low, highlighting the need for strategies focusing on counseling about medicines and substance use. Pill burden was not an issue for patients using MTR-DTG once-daily, who achieved better results.

Resumo: Avaliamos a adesão à terapia antirretroviral (TARV) e fatores associados de acordo com o tipo de esquema em pacientes no início do tratamento em Belo Horizonte, Minas Gerais, Brasil. Mensuramos a adesão com a Escala de Adesão Terapêutica de Morisky, de oito itens (MMAS-8), e comparamos o uso de tenofovir/lamivudina com efavirenz, um comprimido uma vez ao dia (STR), ou dolutegravir em múltiplos comprimidos uma vez ao dia (MTR-DTG), com outros esquemas com múltiplos comprimidos ao dia (MTR-outros). Conduzimos uma análise de regressão logística multivariada para avaliar os fatores associados à adesão. Foram incluídos 393 pacientes: 254 em uso de STR, 106 MTR-DTG e 33 MTR-outros. A taxa global de adesão foi 44,8% (IC95%: 39,4; 50,1), sendo 50% para MTR-DTG, 43,3% para STR e 39,4% para MTR-outros. A análise multivariada mostrou chances maiores de adesão em pacientes em uso de MTR-DTG, pacientes que haviam recebido e compreendido o aconselhamento sobre o tratamento e pacientes com melhor qualidade de vida. Uso anterior de drogas ilícitas em qualquer período da vida está associada à pior adesão. A adesão global foi baixa, enfatizando a necessidade de estratégias focadas no aconselhamento sobre medicamentos e uso de drogas. A quantidade de comprimidos não foi um problema para pacientes em uso de MTR-DTG uma vez ao dia, os quais alcançaram melhores taxas de adesão.

Resumen: Evaluamos la adherencia a la terapia antirretroviral altamente activa (TARAA) y sus factores asociados, según el tipo de tratamiento en pacientes que comenzaron su tratamiento en Belo Horizonte, Minas Gerais, Brasil. La adherencia se mensuró por la Escala de Adhesión Terapéutica de Morisky, de ocho ítems (MMAS-8), y se comparó el uso del "eje" tenofovir/lamivudina, además de un comprimido de efavirenz una vez al día (STR) o dolutegravir con varios comprimidos una vez al día (MTR-DTG), u otros tratamientos con múltiples comprimidos (MTR-otros). Se realizó un análisis multivariado de regresión logística para evaluar los factores asociados a la adherencia. Se incluyeron un total de 393 pacientes, 254 usaron STR, 106 MTR-DTG, y 33 MTR-Otros. La tasa de adherencia general fue de un 44,8% (95%CI: 39,4; 50,1), 50% en el MTR-DTG, 43,3% en el STR y 39,4% en el MTR-otros. El análisis multivariado mostró una probabilidad más alta de adherencia entre pacientes usando MTR-DTG, quienes recibieron y comprendieron las orientaciones acerca de sus tratamientos y los que disfrutaban de una calidad mejor de vida. El consumo previo de drogas ilícitas a lo largo de la vida estuvo asociado con una adherencia más escasa. La adherencia general fue baja y resalta la necesidad de estrategias que se enfoquen en brindar orientación sobre el uso de la medicación y de sustancias. El número de comprimidos no fue un problema para los pacientes que tomaban MTR-DTG una vez al día, que obtuvieron mejores resultados.

Enhancement of botrallin and TMC-264 production in liquid culture of endophytic fungus Hyalodendriella sp. Ponipodef12 after treatments with metal ions

Background: Hyalodendriella sp. Ponipodef12, an endophytic fungus from a poplar hybrid, was a high producer of botrallin and TMC-264 with various bioactivities. In this study, the influences of eight metal ions (i.e.,Mn2+,Na+, Mg2+,Zn2+,Cu2+,Fe2+,Fe3+ and Al3+) on botrallin and TMC-264 production in liquid culture of the endophytic fungus Hyalodendriella sp. Ponipodef12 were investigated. Results: Three most effective metal ions (Zn2+,Cu2+ and Mg2+) along with their optimum concentrations were screened. The optimum addition time and concentrations of Zn2+,Cu2+ and Mg2+ were further obtained respectively for improving botrallin and TMC-264 production. The combination effects of Zn2+,Cu2+ and Mg2+ on the production of botrallin and TMC-264 by employing statistical method based on the central composite design (CCD) and response surface methodology (RSM) were evaluated, and two quadratic predictive models were developed for botrallin and TMC-264 production. The yields of botrallin and TMC-264, which were predicted as 144.12 mg/L and 36.04 mg/L respectively, were validated to be 146.51 mg/L and 36.63 mg/L accordingly with the optimum concentrations of Zn2+ at 0.81 mmol/L, Cu2+ at 0.20 mmol/L, and Mg2+ at 0.13 mmol/L in medium. Conclusion: The results indicated that the enhancement of botrallin and TMC-264 accumulation in liquid culture of the endophytic fungus Hyalodendriella sp. Ponipodef12 by the metal ions and their combination should be an effective strategy.

Antiproliferative Effect of Specific Inhibitor XAV939 for β-catenin on MCL Jeko-1 Cells / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the effect of short hairpin RNA (shRNA) and XAV939, a specific inhibitor for β-catenin, on growth and apoptosis of mantle cell lymphoma(MCL) Jeko-1 cell line.</p><p><b>METHODS</b>β-catenin shRNA eukaryotic expression vector was transfected into Jeko-1 cells, the antiproliferative effect of shRNA on Jeko-1 cells was detected by RT-PCR and Western blot. The proliferation inhibitory rate of Jeko-1 cells treated by different doses of XAV939 was assayed by MTT method; the level of apoptosis of Jeko-1 cells was detected by flow cytometry; the expression levels of apoptosis-related protein BCL-2, BAX, CyclinD1, C-MYC and Caspase-3 in Jeko-1 cells were determined by Western blot.</p><p><b>RESULTS</b>The expression of β-catenin mRNA and growth of Jeko-1 cell line were inhibited by shRNA; after Jeko-1 cells treated with 0,2 and 8 µmol/L XAV939 for 48 hours, the cell proliferation rate decreased, while the cell apoptosis rate increased, the expressions of apoptosis-related protein BCL-2, CyclinD1 and C-MYC were down-regulated, on the contrary, the expression of BAX and caspase-3 were up-regulated.</p><p><b>CONCLUSION</b>The specific inhibition of β-catenin can inhibit Jeko-1 cell proliferation and promote the cell apoptosis.</p>

The in vitro HAART pharmacodynamics study with dolutegravir as the "anchor" / 药学学报

This study is to evaluate the HAART pharmacodynamics with dolutegravir as the "anchor" in vitro. A nucleoside reverse transcriptase inhibitors (NRTIs) resistant recombinant virus model (VSVG/HIV-1(RT-D67N,K70R,T215F)) and an integrase inhibitors (INIs) resistant recombinant virus model (VSVG/HIV-1(IN-G140S,QI48H)) were constructed and established. The anti-viral pharmacodynamics was evaluated with drug combinations including two NRTIs along with one INI or one NNRTI. The results showed that the combination with an INI gave a stronger synergism on wild type HIV-1 replication comparing to that with an NNRTI. Comparing the two INIs as the "anchor" for HAART, DTG exhibited an equivalent CI to that of RAL on wild type HIV-1 replication; but a greater synergy than RAL on INI-resistant HIV-1 replication. Besides of the pharmacodynamics results of DTG-based drug combination, the results may contribute to clinical antiviral therapy.

Inducing Effect of Akt Kinase Inhibitor MK2206 on Apoptosis in U937 Cells and RS4;11 Cells, and Its Mechanism / 中国实验血液学杂志

<p><b>OBJECTIVE</b>This study was purposed to investigate the effect of Akt kinase inhibitor MK2206 on proliferation and apoptosis of U937 cells and RS4;11 cells, and to explore its possible mechanism.</p><p><b>METHODS</b>U937 and RS4;11 cells were cultured with different concentrations of MK2206 for 24 h and 48 h, and cell growth curve was analyzed by CCK-8; cell apoptosis was analyzed by Annexin V/7-AAD double labeling; cell cycle changes were analyzed by flow cytometry. The BAX, BCL-2, XIAP, CDK1, caspase-3 mRNA expressions were determined by real time PCR.</p><p><b>RESULTS</b>MK2206 significantly inhibited the growth of U937 and RS4;11 cells in a time-and dose-dependent manner, and the IC50 values of U937 cells for 24 h and 48 h were (0.48±0.15) µmol/L and (0.09±0.01) µmol/L respectively, while IC50 values of RS4;11 cells for 24 h and 48 h were (0.91±0.02) µmol/L and (0.68±0.11) µmol/L respectively. U937 were cultured with 0.5 µmol/L MK2206 and RS4;11 cells were cultured with 1.0 µmol/L MK2206 for 24 h and 48 h, and the both apoptosis rates were higher for 24 h or 48 h than that in control group (P<0.05), meanwhile the apoptosis rates for 48 h were higher than 24 h. The results of cell cycle detection showed that the both cells were arrested in G2/M phase compared with control group. The real time PCR assay revealed that the expressions of BAX, caspase-3 mRNA in cells treated with MK2206 were increased, while BCL-2, XIAP, CDK1 were reduced compared with control group.</p><p><b>CONCLUSION</b>MK2206 can inhibit proliferation and induce apoptosis of U937 and RS4;11 cells, and the both cells are arrested in G2/M phase. The mechanism of promoting apoptosis may be related with up-regulating BAX, caspase-3 and down-regulating BCL-2, XIAP, meanwhile the cell cycle arrested in G2/M phase may be associated with down-regulating CDK1.</p>

Haplophytin B from Maclurodendron porteri

An alkaloid from Maclurodendron porteri has been isolated and characterized. Extraction process was conducted by acid-base extraction method followed by column chromatography. The structure was established by nuclear magnetic resonance spectroscopy and mass spectrometry. The compound was identified as haplophytin B which occurs commonly in the Rutaceae family. However, this is the first time this alkaloid was isolated and reported from the species. The compound showed no inhibition against Staphylococus aureus, Pseudomonas aeruginosa, Bacillus cereus and Escherichia coli and no cytotoxic activity against H199 and A549 cell lines.

Further casbane-type diterpenes from the soft coral Sinularia depressa / 中国天然药物

AIM@#To study the minor diterpenes from the soft coral Sinularia depressa@*METHOD@#The chemical constituents were isolated and purified by various chromatographic techniques, and the chemical structures, including absolute configuration, were established on the basis of detailed analysis of spectroscopic data and by literature comparison with the data of related known compounds.@*RESULTS@#A new casbane-type diterpene, 2-epi-10-hydroxydepressin (1), was isolated and identified.@*CONCLUSION@#Compound 1 is a new casbane-type diterpene.

Research progress of selective mGluR1 antagonists / 药学学报

As an important member of metabotropic glutamate receptors (mGluR), metabotropic glutamate receptor 1 (mGluR1) plays an important role in the signal transduction of central nervous system. Selective mGluR1 antagonists can block the signaling pathway activated by mGluR1 and exert a series of physiological actions including analgesia, antianxiety, antidepression, etc. Currently, the discovery and modification of selective mGluR1 antagonists have become a hot research focus. This paper reviews the structural catalogs of selective mGluR1 antagonists and their structure-activity relationships in the last decade.

Pharmacokinetics of hylotelephin in Beagle dogs / 药学学报

<p><b>AIM</b>To investigate the pharmacokinetics of hylotelephin in Beagle dogs and obtain the main pharmacokinetic parameters.</p><p><b>METHODS</b>An HPLC method with UV detection was developed to study the pharmacokinetics of hylotelephin in dogs by joining an internal standard (anthracene). Benzoyl chloride was used to the pre-column derivatization of hylotelephin and methanol-water (64:36) was used as the mobile phase. According to the 3P97 pharmacokinetic program, the main parameters were calculated.</p><p><b>RESULTS</b>The hylotelephin pharmacokinetics conforms to a two-compartment open model after a single iv dose of hylotelephin 10.6 or 21.3 mg x kg(-1) in Beagle dogs. The parameters of two groups were as follows: T(1/2) alpha were 2.3 and 2.1 min, T(1/2) beta were 1.9 and 2.0 h, K12 were 0. 12 and 0.11 min, K21 were 0.17 and 0.21 min, K10 were 0.011 and 0.0094 min, Vc were 0.54 and 0.54 L x kg(-1), AUC were 1.8 and 4.1 g x min x L(-1), CL were 0.0048 and 0.0056 L x kg(-1) x min(-1), MRT were 2.10 and 2.4 h, respectively.</p><p><b>CONCLUSION</b>The pharmacokinetics of hylotelephin after iv administration showed a rapid distribution and elimination process in Beagle dogs and was of first order kinetics.</p>

Studies on the chemical constituents from the roots of Chloranthus henryi / 药学学报

<p><b>AIM</b>To study the chemical constituents of the roots of Chloranthus henryi.</p><p><b>METHODS</b>The constituents of Chloranthus henryi were separated with various chromatographic techniques. structures were elucidated by physico-chemical properties and spectral data.</p><p><b>RESULTS</b>Eight compounds were isolated from Chloranthus henryi. They were identified as curcolonol (I), zedoarofuran (II), shizukanolide E (III) , skimmin (IV), calucanthoside (V), chloracoumarin (VI), beta-sitosterol (VII), daucosterin (VIII).</p><p><b>CONCLUSION</b>Chloracoumarin (VI) is a new compound and characterized as 6,8-dimethoxy-7-O-[beta-D-apiofunanosyl(l --> 3 )-D-glucopyranosyl]-2H-benzopyran-2-one. Compounds I, II were isolated from Chloranthus henryi for the first time.</p>

A novel phlegmariurine type alkaloid from Huperzia serrata (Thunb.) Trev / 药学学报

<p><b>AIM</b>To study the alkaloid constituents of Huperzia serrata (Thunb.) Trev..</p><p><b>METHODS</b>Chromatographic methods were used for the isolation and purification. Structure was elucidated on the basis of chemical analysis and spectroscopic data.</p><p><b>RESULTS</b>An alkaloid constituent was isolated from H. serrata (Thumb.) Trev..</p><p><b>CONCLUSION</b>The compound was found to be a novel phlegmariurine type alkaloid, named 8 beta-hydroxy phlegmariurine B.</p>

A new monoterpene glycoside from Paeonia lactiflora Pall / 药学学报

<p><b>AIM</b>To study the chemical constituents of Paeonia lactiflora.</p><p><b>METHODS</b>The constituents of P. lactiflora were separated by using various kinds of modern chromatography and was identified its structure on the basis of spectral analysis.</p><p><b>RESULTS</b>A monoterpene glucoside named albiflorin R1 was isolated from the roots of Paeonia lactiflora Pall. In the structure of albiflorin R1, the aglycone connected with a glucose at its 2-OH while the hemiacetal hydroxyl in glucose moiety was free.</p><p><b>CONCLUSION</b>Albiflorin R1 is a new monoterpene glycoside.</p>

Synthesis of 4-substituted pyrimido [5,4-C] cinnoline derivatives

Reaction of 4-aminocinnoline-3-carboxamide or its 8-methyl derivative 1a, b with triethyl orthoformate and acetic anhydride gave rise to the corresponding pyrimido[5,4-c]cinnolin-3H-4-ones 2a-d. 2-Methylpyrimido derivatives 2c,d could also be obtained via ammonolysis of 2-methyl-1,3-oxazino[5,4-c] cinnolin-4-ones 4a,b. On the other hand, reaction of 1a,b with araldehydes afforded 2-arylpyrimidocinnolines 5a-e. Reacting compounds 2a-d with hydrazine and different amines produced the corresponding 4-substituted amino or hydrazino derivatives 7-9. This revealed the reactivity of the 4-position of 2 towards nucleophilic substitution. Attempts to cyclize 7a-d to triazolopyrimidocinnolines are discussed