RESUMO
BACKGROUND: Although vegan-vegetarian diets are increasingly popular, no recent systematic reviews on vegan-vegetarian diets in pregnancy exist. OBJECTIVES: To review the literature on vegan-vegetarian diets and pregnancy outcomes. SEARCH STRATEGY: PubMed, Embase, and the Cochrane library were searched from inception to September 2013 for pregnancy and vegan or vegetarian Medical Subject Headings (MeSH) and free-text terms. SELECTION CRITERIA: Vegan or vegetarian diets in healthy pregnant women. We excluded case reports and papers analysing vegan-vegetarian diets in poverty and malnutrition. Searching, paper selection, and data extraction were performed in duplicate. DATA COLLECTION AND ANALYSIS: The high heterogeneity of the studies led to a narrative review. MAIN RESULTS: We obtained 262 full texts from 2329 references; 22 selected papers reporting maternal-fetal outcomes (13) and dietary deficiencies (nine) met the inclusion criteria. None of the studies reported an increase in severe adverse outcomes or in major malformations, except one report of increased hypospadias in infants of vegetarian mothers. Five studies reported vegetarian mothers had lower birthweight babies, yet two studies reported higher birthweights. The duration of pregnancy was available in six studies and was similar between vegan-vegetarians and omnivores. The nine heterogeneous studies on microelements and vitamins suggest vegan-vegetarian women may be at risk of vitamin B12 and iron deficiencies. AUTHOR'S CONCLUSIONS: The evidence on vegan-vegetarian diets in pregnancy is heterogeneous and scant. The lack of randomised studies prevents us from distinguishing the effects of diet from confounding factors. Within these limits, vegan-vegetarian diets may be considered safe in pregnancy, provided that attention is paid to vitamin and trace element requirements.
Assuntos
Dieta Vegetariana , Proteínas Alimentares/administração & dosagem , Comportamento Alimentar , Resultado da Gravidez , Fatores de Confusão Epidemiológicos , Dieta Vegetariana/efeitos adversos , Dieta Vegetariana/estatística & dados numéricos , Feminino , Humanos , Fenômenos Fisiológicos da Nutrição Materna , Política Nutricional , Necessidades Nutricionais , Gravidez , Fatores de Risco , Vitaminas/administração & dosagemRESUMO
During endomitosis, megakaryocytes undergo several rounds of DNA synthesis without division leading to polyploidization. In primary megakaryocytes and in the megakaryocytic cell line CHRF, loss or knock-down of p53 enhances cell cycling and inhibits apoptosis, leading to increased polyploidization. To support the hypothesis that p53 suppresses megakaryocytic polyploidization, we show that stable expression of wild-type p53 in K562 cells (a p53-null cell line) attenuates the cells' ability to undergo polyploidization during megakaryocytic differentiation due to diminished DNA synthesis and greater apoptosis. This suggested that p53's effects during megakaryopoiesis are mediated through cell cycle- and apoptosis-related target genes, possibly by arresting DNA synthesis and promoting apoptosis. To identify candidate genes through which p53 mediates these effects, gene expression was compared between p53 knock-down (p53-KD) and control CHRF cells induced to undergo terminal megakaryocytic differentiation using microarray analysis. Among substantially downregulated p53 targets in p53-KD megakaryocytes were cell cycle regulators CDKN1A (p21) and PLK2, proapoptotic FAS, TNFRSF10B, CASP8, NOTCH1, TP53INP1, TP53I3, DRAM1, ZMAT3 and PHLDA3, DNA-damage-related RRM2B and SESN1, and actin component ACTA2, while antiapoptotic CKS1B, BCL2, GTSE1, and p53 family member TP63 were upregulated in p53-KD cells. Additionally, a number of cell cycle-related, proapoptotic, and cytoskeleton-related genes with known functions in megakaryocytes but not known to carry p53-responsive elements were differentially expressed between p53-KD and control CHRF cells. Our data support a model whereby p53 expression during megakaryopoiesis serves to control polyploidization and the transition from endomitosis to apoptosis by impeding cell cycling and promoting apoptosis. Furthermore, we identify a putative p53 regulon that is proposed to orchestrate these effects.
Assuntos
Apoptose/fisiologia , Ciclo Celular/fisiologia , Diferenciação Celular/genética , Genes p53 , Megacariócitos/citologia , Sequência de Bases , Linhagem Celular , Primers do DNA , HumanosRESUMO
PURPOSE: Ablation index (AI) is a radiofrequency lesion quality marker. The AI value that allows effective and safe pulmonary vein isolation (PVI) is still debated. We evaluated the incidence of acute and late PV reconnection (PVR) with different AI settings and its predictors. METHODS: The Ablation Index Registry is a multicenter study that included patients with paroxysmal/persistent atrial fibrillation (AF) who underwent first-time ablation. Each operator performed the ablation using his preferred ablation catheter (ThermoCool® SmartTouch or Surround Flow) and AI setting (380 posterior-500 anterior and 330 posterior-450 anterior). We divided the study population into two groups according to the AI setting used: group 1 (330-450) and group 2 (380-500). Incidence of acute PVR was validated within 30 min after PVI, whereas the incidence of late PVR was evaluated at repeat procedure. RESULTS: Overall, 490 patients were divided into groups 1 (258) and 2 (232). There was no significant difference in the procedural time, fluoroscopy time, and rate of the first-pass PVI between the two study groups. Acute PVR was observed in 5.6% PVs. The rate of acute PVR was slightly higher in group 2 (64/943, 6.8%, PVs) than in group 1 (48/1045, 4.6% PVs, p = 0.04). Thirty patients (6%) underwent a repeat procedure and late PVR was observed in 57/116 (49%) PVs (number of reconnected PV per patient of 1.9 ± 1.6). A similar rate of late PVR was found in the two study groups. No predictors of acute and late PVR were found. CONCLUSION: Ablation with a lower range of AI is highly effective and is not associated with a higher rate of acute and late PVR. No predictors of PV reconnection were found.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Humanos , Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/cirurgia , Recidiva , Resultado do TratamentoRESUMO
The RAS oncogene is among the most commonly mutated in cancer. RAS mutations are identified in about half of patients diagnosed with metastatic colorectal cancer (mCRC), conferring poor prognosis and lack of response to anti-epidermal growth factor receptor (EGFR) antibodies. In the last decades, several investigational attempts failed in directly targeting RAS mutations, thus RAS was historically regarded as 'undruggable'. Recently, novel specific KRASG12C inhibitors showed promising results in different solid tumors, including mCRC, renewing interest in this biomarker as a target. In this review, we discuss different strategies of RAS targeting in mCRC, according to literature data in both clinical and preclinical settings. We recognized five main strategies focusing on those more promising: direct RAS targeting, targeting the mitogen-activated protein kinase (MAPK) pathway, harnessing RAS through immunotherapy combinations, RAS targeting through metabolic pathways, and finally other miscellaneous approaches. Direct KRASG12C inhibition is emerging as the most promising strategy in mCRC as well as in other solid malignancies. However, despite good disease control rates, tumor response and duration of response are still limited in mCRC. At this regard, combinational approaches with anti-epidermal growth factor receptor drugs or checkpoint inhibitors have been proposed to enhance treatment efficacy, based on encouraging results achieved in preclinical studies. Besides, concomitant therapies increasing metabolic stress are currently under evaluation and expected to also provide remarkable results in RAS codon mutations apart from KRASG12C. In conclusion, based on hereby reported efforts of translational research, RAS mutations should no longer be regarded as 'undruggable' and future avenues are now opening for translation in the clinic in mCRC.
Assuntos
Neoplasias do Colo , Genes ras , Humanos , MutaçãoRESUMO
OBJECTIVE: This study aimed to improve the post-marketing surveillance on mRNA anti-SARS-CoV-2 vaccines, characterizing the adverse events (AEs) after the first dose of mRNA BNT162b vaccine. The associations between the AEs and individuals' characteristics were explored. PATIENTS AND METHODS: All adult healthcare workers at Niguarda Hospital (Milan, Italy) who were referred for the first dose of vaccine were offered to participate in a cross-sectional survey during the second-dose administration, between 18 January and 7 February 2021. All participants completed a questionnaire about age, gender, weight, height, medical history, concurrent therapies, employment status, previous diagnosis/testing for SARS-CoV-2 infection, and a list of 24 AEs (solicited AEs). The development of at least one solicited AEs was the main outcome. AEs were stratified by the presence of injection-site symptoms, systemic symptoms or both, and the differences between strata were assessed as a secondary outcome. Biometric data and reports of a previous diagnosis of SARS-CoV-2 infection were also explored, as predictors of the main outcome. RESULTS: 7,014 healthcare workers were included. An incidence of 3 per 10.000 persons for serious AEs following the first administration of the mRNA BNT162b vaccine was found. An association between the development of non-serious AEs with young age, female gender, low body mass index, and previous history of SARS-CoV-2 was described. CONCLUSIONS: This real-life study supported data on the safety profile of the BNT162b2 mRNA vaccine. Our findings on the associations between the development of non-serious AEs with some individual characteristics may help physicians and patients make educated and informed medical decisions towards anti-COVID-19 vaccination.
Assuntos
Vacina BNT162/efeitos adversos , COVID-19/prevenção & controle , Vacinação/efeitos adversos , Adulto , Fatores Etários , Vacina BNT162/administração & dosagem , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Estudos Transversais , Feminino , Pessoal de Saúde/estatística & dados numéricos , Humanos , Masculino , Anamnese/estatística & dados numéricos , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados/estatística & dados numéricos , Fatores de Risco , SARS-CoV-2/imunologia , Fatores Sexuais , Vacinação/estatística & dados numéricosRESUMO
Differentiation of hematopoietic stem and progenitor cells is an intricate process controlled in large part at the level of transcription. While some key megakaryocytic transcription factors have been identified, the complete network of megakaryocytic transcriptional control is poorly understood. Using global gene expression microarray analysis, Gene Ontology-based functional annotations, and a novel interlineage comparison with parallel, isogenic granulocytic cultures as a negative control, we closely examined the mRNA level of transcriptional regulators in megakaryocytes derived from human mobilized peripheral blood CD34(+) hematopoietic cells. This approach identified 199 differentially expressed transcription factors or transcriptional regulators. We identified and detailed the transcriptional kinetics of most known megakaryocytic transcription factors including GATA1, FLI1, and MAFG. Furthermore, many genes with transcription factor activity or transcription factor binding activity were identified in megakaryocytes that had not previously been associated with that lineage, including BTEB1, NR4A2, FOXO1A, MEF2C, HDAC5, VDR, and several genes associated with the tumor suppressor p53 (HIPK2, FHL2, and TADA3L). Protein expression and nuclear localization were confirmed in megakaryocytic cells for four of the novel candidate megakaryocytic transcription factors: FHL2, MXD1, E2F3, and RFX5. In light of the hypothesis that transcription factors expressed in a particular differentiation program are important contributors to such a program, these data substantially expand our understanding of transcriptional regulation in megakaryocytic differentiation of stem and progenitor cells.
Assuntos
Antígenos CD34/metabolismo , Regulação da Expressão Gênica , Megacariócitos/citologia , Megacariócitos/metabolismo , Trombopoese , Transcrição Gênica , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Células Cultivadas , Análise por Conglomerados , Citometria de Fluxo , Imunofluorescência , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Granulócitos/citologia , Granulócitos/efeitos dos fármacos , Humanos , Megacariócitos/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Trombopoese/efeitos dos fármacos , Trombopoetina/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica/efeitos dos fármacosRESUMO
Until recently, the development of heart failure was related exclusively to the acute or chronic impairment in systolic function. Currently, the concept of heart failure not sustained primarily by a significant reduction in contractility has been clearly defined by several epidemiological and pathophysiological observations. This condition, defined as 'diastolic heart failure' or 'heart failure with preserved systolic function' can be related to different cardiac diseases with a higher prevalence in the elderly. Afterload mismatch situations, such as hypertension or aortic stenosis, as well as hypertrophic cardiomyopathy or pericardial diseases, determine this common clinical syndrome more frequently. Currently, the treatment of diastolic heart failure is still empirical, as there are few and inconclusive data coming from evidence-based medicine.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Diástole , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , PrognósticoRESUMO
A positive correlation between cholesterol esterification and growth rate potential was previously found in our laboratory during the growth of CEM and MOLT4 lymphoblastic cells. In the current study, we investigated whether the rates of cholesterol esters synthesis correlate with changes of acyl-CoAcholesterol acyltransferase (ACAT) mRNA levels and of other genes implied in cholesterol biosynthesis and uptake, such as 3-hydroxy-3-methylglutaryl-CoA (HMGCoA) reductase and low density lipoprotein (LDL) receptor. The results showed that the more rapid growing CEM cells had lower levels of expression of HMGCoA-reductase and LDL receptors compared to MOLT4. By contrast, ACAT mRNA levels were higher in CEM cells, further supporting the concept of a possible involvement of cholesterol esters in the regulation of cell growth and division. In this study, high levels of cholesterol esterification and of expression of ACAT gene were also associated with a markedly increased expression of multidrug resistance (MDR1) gene, suggesting that MDR1 activity might contribute to regulate the rate of cell growth and division by modulating intracellular cholesterol ester levels.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Ésteres do Colesterol/metabolismo , Leucemia de Células T , Animais , Divisão Celular/fisiologia , Colesterol/biossíntese , Primers do DNA , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Camundongos , RNA Mensageiro/análise , Receptores de LDL/genética , Receptores de LDL/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esterol O-Aciltransferase/genética , Esterol O-Aciltransferase/metabolismo , Células Tumorais Cultivadas/química , Células Tumorais Cultivadas/citologia , Células Tumorais Cultivadas/enzimologiaRESUMO
Chemotherapy of HIV-1 infection/AIDS currently employs inhibitors of two products of the viral pol gene, the reverse transcriptase and protease enzymes. However, a third product of the pol gene is essential for retroviral multiplication, the integrase. As no cellular homologue of HIV integrase has been described, potential inhibitors could be relatively nontoxic. Development of HIV-1 integrase inhibitors could have favorable implication for combination therapy, including potential synergy with currently available inhibitors, as well as prevention of the chronic carrier state and the emergence of resistant mutants. Although several classes of putative integrase inhibitors that been described, still no clinically useful anti-integration drugs are available. It is the structural and functional complexity of the integration process together with the limitations of the available in vitro assays that has made it problematic to develop inhibitors of the HIV integrase. In this review we summarize current knowledge concerning the biology of this enzyme and of the integration process, and discuss major classes representatives of integrase inhibitors considering the obstacles to the development of true anti-integrase drugs.
Assuntos
Desenho de Fármacos , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , Animais , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/ultraestrutura , HumanosRESUMO
A number of aroylpyrroleacrylic acid derivatives were synthesized by standard procedures and evaluated for cytotoxicity in Vero cells and for capacity to inhibit the multiplication of viruses, bacteria, and fungi. While none of the test compounds showed any activity against bacteria and fungi, most of them inhibited the replication of some DNA viruses at concentrations allowing the exponential growth of uninfected cells. In particular three compounds (8, 9c, and 10h) showed an antiviral activity at doses that were from 4- to greater than 8-fold lower than the maximum nontoxic doses.
Assuntos
Antibacterianos/síntese química , Antifúngicos/síntese química , Antivirais/síntese química , Animais , Antibacterianos/química , Antifúngicos/química , Antivirais/química , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Relação Dose-Resposta a Droga , Ácidos Hidroxâmicos/antagonistas & inibidores , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Pirróis , Análise de Regressão , Relação Estrutura-Atividade , Células VeroRESUMO
Several pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one ribonucleosides were prepared and tested for antiviral/antitumor activities. Appropriate heterocyclic bases were prepared by standard methodologies. Glycosylation of pyrazoles 6a-e,g,i and of pyrazolo[4,3-d]-1,2,3-triazin-4-ones 12f-1 mediated by silylation with hexamethyldisilazane, with 1-beta-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose, gave in good yields the corresponding glycosides 7a-e,g, 8g,i, 13f,h,k, and 14f, but could not be applied to compounds 12g,i,j,l. To overcome this occurrence, a different strategy involving the preparation, diazotization, and in situ cyclization of opportune pyrazole glycosides 9 and 10 was required. Moreover derivatives having the general formula 5 were considered not only as synthetic intermediates in the synthesis of 3 but also as carbon bioisosteres of ribavirin 4. All compounds were evaluated in vitro for cytostatic and antiviral activity. The pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides that resulted were substantially devoid of any activity; only 15h,k showed a moderate cytostatic activity against T-cells. However, pyrazole nucleosides 9b,c,e were potent and selective cytotoxic agents against T-lymphocytes, whereas 9e showed a selective, although not very potent, activity against coxsackie B1.
Assuntos
Antineoplásicos/síntese química , Antivirais/síntese química , Nucleosídeos/síntese química , Compostos de Organossilício , Pirazóis/síntese química , Animais , Antineoplásicos/farmacologia , Antivirais/farmacologia , Linfócitos B/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Ciclização , Enterovirus/efeitos dos fármacos , Glicosilação , HIV-1/efeitos dos fármacos , Humanos , Leucemia L1210/patologia , Camundongos , Estrutura Molecular , Nucleosídeos/farmacologia , Pirazóis/farmacologia , Silício , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Células Tumorais Cultivadas , Células VeroRESUMO
Derivatives of the new ring system indolo[1,2-c]benzo[1,2,3]triazine 5 were synthesized by diazotization of substituted 2-(2-aminophenyl)indoles followed by an intramolecular coupling reaction of the diazonium group with the indole nitrogen. To obtain the indolobenzotriazine system it was necessary to protect the 3 position of the indole nucleus to avoid cyclization into the indolo[3,2-c]cinnoline system 4. Indolobenzotriazines 5a-g were evaluated in vitro for antitumor activity against a panel of leukemia-, lymphoma-, carcinoma-, and neuroblastoma-derived cell lines. Some compounds inhibited the proliferation of T and B cell lines at submicromolar concentrations, whereas their activity against solid tumor cell lines was in the micromolar range. When evaluated for their antifungal potential 5a,d inhibited some of the fungi tested, although at concentrations very close to those inhibiting the proliferation of human cells. On the contrary, all indolobenzotriazines proved fairly potent and selective inhibitors of Streptococcus and Staphylococcus. In particular 5b,c,g were up to 80 times more potent than the reference drug streptomycin and inhibited the growth of the above Gram-positive bacteria at concentrations far lower than those cytotoxic for animal cells.
Assuntos
Anti-Infecciosos/síntese química , Antineoplásicos/síntese química , Triazinas/síntese química , Antibacterianos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Avaliação Pré-Clínica de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , HIV-1 , Humanos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacologia , Células Tumorais CultivadasRESUMO
A new set of phthalein derivatives stemming from the lead compound, phenolphthalein, were designed to specifically complement structural features of a bacterial form of thymidylate synthase (Lactobacillus casei, LcTS) versus the human TS (hTS) enzyme. The new compounds were screened for their activity and their specificity against TS enzymes from different species, namely, L. casei (LcTS), Pneumocystis carinii (PcTS), Cryptococcus neoformans (CnTS), and human thymidylate synthase (hTS). Apparent inhibition constants (Ki) for all the compounds against LcTS were determined, and inhibition factors (IF, ratio between the initial rates of the enzymatic reaction in the presence and absence of each inhibitor) against each of the four TS species were measured. A strong correlation was found between the two activity parameters, IF and Ki, and therefore the simpler IF was used as a screening factor in order to accelerate biological evaluation. Compounds 5b, 5c, 5ba, and 6bc showed substantial inhibition of LcTS while remaining largely inactive against hTS, illustrating for the first time remarkable species specificity among TSs. Due to sequence homology between the enzymes, several compounds also showed high activity and specificity for CnTS. In particular, 3-hydroxy-3-(3-chloro-4-hydroxyphenyl)-6-nitro-1H, 3H-naphtho[1,8-c,d]pyran-1-one (6bc) showed an IF < 0.04 for CnTS (Ki = 0.45 microM) while remaining inactive in the hTS assay at the maximum solubility concentration of the compound (200 microM). In cell culture assays most of the compounds were found to be noncytotoxic to human cell lines but were cytotoxic against several species of Gram-positive bacteria. These results are consistent with the enzymatic assays. Intriguingly, several compounds also had selective activity against Cr. neoformans in cell culture assay. In general, the most active and selective compounds against the Gram-positive bacteria were those designed and found in the enzyme assay to be specific for LcTS versus hTS. The original lead compound was least selective against most of the cell lines tested. To our knowledge these compounds are the first TS inhibitors selective for bacterial TS with respect to hTS.
Assuntos
Anti-Infecciosos/síntese química , Clorofenóis/síntese química , Cromonas/síntese química , Inibidores Enzimáticos/síntese química , Timidilato Sintase/antagonistas & inibidores , Antibacterianos , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Linhagem Celular , Clorofenóis/química , Clorofenóis/farmacologia , Cromonas/química , Cromonas/farmacologia , Cryptococcus neoformans/enzimologia , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Lacticaseibacillus casei/enzimologia , Modelos Moleculares , Fenolftaleína/química , Pneumocystis/enzimologia , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
Eighty nephrotic adults with focal segmental glomerulosclerosis (FSGS) and plasma creatinine lower than 3 mg/dL were given corticosteroids (53 patients) or immunosuppressive agents (27 patients) for a median of 16 and 75 weeks, respectively. Forty-two patients responded with complete remission (29 patients, 36%) or partial remission (13 patients, 16%). Twenty-six patients who did not respond were treated again. Two patients obtained complete remission and 13 partial remission. The probability of remission was associated with treatment with corticosteroids (P = 0.0001; RR, 3. 93; 95% CI, 2.00 to 7.72), absence of arterial hypertension (P = 0. 0023; RR, 2.59; 95% CI, 1.41 to 4.79), and a percentage of hyaline glomeruli lower than 5% (P = 0.0152; RR, 2.04; 95% CI, 1.15 to 3.64). The probability of being alive at 110 months without doubling of plasma creatinine was 69%. The risk of renal insufficiency was correlated with mesangial proliferation (P = 0.0025; RR, 5.50; 95% CI, 1.82 to 16.60) and with interstitial fibrosis (P = 0.0231; RR, 4. 44; 95% CI, 1.23 to 16.08) at initial biopsy. Considering partial or complete remission as a time-dependent variable, only the lack of remission (P = 0.0027; RR, 7.23; 95% CI, 1.98 to 26.33) and mesangial proliferation (P = 0.0069; RR, 4.59; 95% CI, 1.52 to 13. 88) were correlated with renal failure. Major side effects were observed in 11 patients (5 infections, 1 peptic ulcer, 2 diabetes, 3 neoplasias). This study shows that 70% of nephrotic adults with FSGS may obtain complete or partial remission and maintain stable renal function for about 10 years when given a prolonged therapy with corticosteroids or immunosuppressive drugs.
Assuntos
Corticosteroides/administração & dosagem , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Imunossupressores/administração & dosagem , Síndrome Nefrótica/tratamento farmacológico , Corticosteroides/efeitos adversos , Adulto , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Glomerulosclerose Segmentar e Focal/mortalidade , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Imunossupressores/efeitos adversos , Testes de Função Renal , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/patologia , Assistência de Longa Duração , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Síndrome Nefrótica/mortalidade , Síndrome Nefrótica/patologia , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Despite the unprecedented successes in the therapy of HIV infection, AIDS remains a major world health problem being the first cause of death in Africa and the fourth leading cause of death worldwide. Rapid emergence of drug-resistant HIV variants and severe side effects limit the efficacy of existing therapies. The intrinsic high variability of HIV calls for combining different drugs with distinct mode of action to achieve synergistic antiviral activity. Efforts are being made to develop agents addressing new steps in HIV replication and to optimize both antiviral activity and pharmacokinetic of the current drugs targeting reverse transcriptase and protease. The class of viral entry inhibitors is undergoing evaluation for both systemic and topical administration, and compounds targeting the fusion step may be the first to reach the market. Identification of compounds unambiguously affecting HIV replication by targeting integrase supports the potential of this crucial viral enzyme as a drug target. Targeting HIV gene regulation, which could also lead to cellular toxicity, may also become an important discovery strategy, provided that inhibitors with sufficient specificity are identified. In this review we will summarize the current understanding of the key steps in HIV life cycle in the context of representative inhibitors based on their modes of action. We then present a summary of compounds under clinical development, with the aim of providing a picture of the current potential for targeting HIV.
Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV/efeitos dos fármacos , Terapia Antirretroviral de Alta Atividade , Proteínas do Capsídeo/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/virologia , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Humanos , Receptores Virais/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêuticoRESUMO
N-acetyl-L-cysteine (NAC) is known to antagonize the PMA- or cytokine-stimulated HIV-1 replication in latently and acutely infected monocytic and lymphocytic cell lines, and to reduce the virus multiplication in acutely infected, PHA-stimulated PBMC. We here report on the modulatory effects of NAC on the HIV-1 multiplication in both chronically and acutely infected lymphocytes that produce high virus levels independently from cytokine activation. In both cases, NAC doses of 0.12 and 0.25 mM decreased, whereas doses of 0.5-2 mM increased the infectious HIV-1 yield. At these concentrations, the modulatory effect of NAC on the HIV-1 multiplication paralleled that on cell proliferation, suggesting a close correlation between the two phenomena; in fact, under conditions where NAC could not modulate the cell growth, the drug also failed to modulate the HIV-1 multiplication. High NAC concentrations (4-16 mM), which were able to increase the proliferative rate of both chronically infected H9/IIIB and normal T lymphocytes, increased up to 6-fold the virus multiplication in H9/IIIB cells but were inhibitory to HIV-1 in acutely infected cells. This inhibition was due to the fact that, like dextran sulfate, NAC interfered with an early event in the virus growth cycle. The finding that high NAC doses were also capable of preventing syncytium formation in H9/IIIB and C8166 (or MT-4) cocultures further indicated an interference of the drug with receptor-binding-related events.
Assuntos
Acetilcisteína/farmacologia , Antivirais/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Linfócitos T/microbiologia , Replicação Viral/efeitos dos fármacos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Divisão Celular/efeitos dos fármacos , Fusão Celular/fisiologia , Linhagem Celular , Sulfato de Dextrana/farmacologia , HIV-1/crescimento & desenvolvimento , Humanos , Tecido Linfoide/citologia , Tecido Linfoide/microbiologia , Linfócitos T/efeitos dos fármacos , Zidovudina/farmacologiaRESUMO
The biosynthesis of catecholamines and indoleamines was investigated in the sea pansy Renilla koellikeri by radiochemical screening of tissue samples exposed in vivo to labelled amino acid precursors and analysed by high-performance liquid chromatography coupled with electrochemical detection. Incubation of sea pansy tissues in [3H]tyrosine resulted in substantial accumulation of radioactivity recovered in chromatograms coeluting with tyrosine and 4-hydroxy-3-methoxy mandelic acid and, to a lesser extent, with 3,4-dihydroxy-phenylalanine, dopamine, norepinephrine, epinephrine, normetanephrine and 3,4-dihydroxyphenyl acetic acid. The catecholamine synthesis inhibitor alpha-methyl-p-tyrosine effectively reduced several of these [3H]tyrosine by-products formed as well as endogenous stores of these amines. Incubations in [3H]tryptophan resulted in large amounts of radioactivity associated with liquid chromatographic peaks coeluting with tryptophan and 5-hydroxytryptophan and lesser amounts with 5-hydroxytryptamine, N-acetyl-5-hydroxytryptamine and 5-hydroxy-3-indole acetic acid. The indoleamine synthesis inhibitor p-chlorophenylalanine reduced the amounts of products formed and depleted stores of the endogenous indoleamines. Enzyme activities which appear to involve tyrosine hydroxylase (EC 1. 12. 16. 2), tryptophan hydroxylase (EC 1. 14. 16. 4) and phenylethanolamine N-methyltransferase (EC 2. 1. 1. 28) were also detected in rachidial tissues by HPLC analysis of reaction products (hydroxylases) and by a radioenzymatic assay (methyltransferase). The sea pansy being a representative of the earliest invertebrates possessing a nervous system, these results support the hypothesis that vertebrate-like enzymatic pathways for the biosynthesis and degradation of monoamine neurotransmitters were conserved throughout evolution.
Assuntos
Catecolaminas/metabolismo , Cnidários/metabolismo , Indóis/metabolismo , Animais , Evolução Biológica , Feniletanolamina N-Metiltransferase/análise , Triptofano Hidroxilase/análise , Tirosina 3-Mono-Oxigenase/análiseRESUMO
Worldwide, the heterosexual route is the prevalent mode of transmission of AIDS; therefore, demands have been raised for measures that block sexual spreading of the HIV infection. Development of microbicides for topical use may represent an efficacious alternative to condoms. Several approaches are being investigated. Besides surfactants, which directly act on the virus particle, and measures that enhance natural defence mechanisms, promising new candidates appear to be drugs that block the early steps of HIV multiplication. We describe herein a long-term assay which enables the establishment of whether the above drugs reversibly (virustatic action) or irreversibly (virucidal action) inhibit HIV-1 multiplication, thus allowing screening for effective and potent microbicides. We validated our assay with nucleoside (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Following a chronic treatment, the NRTIs tested (didanosine, zalcitabine, stavudine and lamivudine) simply delayed the viral breakthrough with respect to infected, untreated controls. Under the same experimental conditions, non-nucleoside reveres transcriptase inhibitors (NNRTIs), such as MKC-442, alphaAPA, nevirapine, efavirenz and 3,4-dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs) MC 1047 and MC 1220 suppressed HIV-1 replication for the entire experimental period (40 days). When cell culture samples were evaluated for the presence of infectious virus, p24 antigen and viral DNA sequences, none of them was detected up to day 40 post-infection (p.i.). Identical results were obtained after a treatment with the above NNRTIs limited to the first 4 days p.i. Under more selective experimental conditions, that is drug treatments limited to the first 4 h p.i., nevirapine and efavirenz proved to be virustatic; in fact, viral breakthrough ensued shortly after their removal from the culture medium. Conversely, DABO MC 1220 was endowed with potent virucidal activity; in fact, at 3.5 microM it was able to suppress HIV-1 multiplication in cultures acutely infected with a very high multiplicity of infection (5 CCID50/cell), thus allowing exponential cell multiplication as in uninfected cultures for the next 40 days.
Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/prevenção & controle , Mucosa/virologia , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Linhagem Celular , DNA Viral/análise , Infecções por HIV/transmissão , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/fisiologia , Humanos , Técnicas In Vitro , Replicação Viral/efeitos dos fármacosRESUMO
Several 5-alkyl, 5-alkenyl, 5-iso-alkyl, 5-halo, 5-aminomethyl and 5-carboxy derivatives of S-DABOs (dihydro-alkyl (or cyclo-alkyl)thio-benzyloxopyrimidines), DATNOs (dihydro-alkylthionaphthylmethyl-oxopyrimidines) and F2-S-DABOs (dihydro-alkyl (or cyclo-alkyl)thio-2,6-difluorobenzyl-oxopyrimidines) have been prepared and tested as anti-HIV-1 agents. S-DABO derivatives bearing at C-6 position monosubstituted phenylmethyl or heteroarylmethyl units have also been synthesized. 2-Alkylthio-3,4-dihydropyrimidin-4(3H)-one derivatives of F2-S-DABO series bearing small alkyl groups at C-5 proved to be potent inhibitors of HIV-1 replication in vitro with selectivity indexes ranging from 250 to >2,500.
Assuntos
Fármacos Anti-HIV/química , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Pirimidinonas/química , Inibidores da Transcriptase Reversa/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/toxicidade , Linhagem Celular , Fenômenos Químicos , Físico-Química , Desenho de Fármacos , HIV-1/fisiologia , HIV-2/fisiologia , Humanos , Estrutura Molecular , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Pirimidinonas/toxicidade , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/toxicidade , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
In the presence of sodium hydride, reaction of aryl-disulphides with ethyl esters of indole-2-carboxylic acids furnished ethyl 3-arylthioindole-2-carboxylates, which were cyclized intramolecularly to afford 5H-indolo[3,2-b][1,5]benzothiazepin-6(7H)-ones or hydrolysed in alkaline medium to give 3-arylthioindole-2-carboxylic acids. These acids, also obtained by the action of aryldisulphides on indole-2-carboxylic acids, afforded tetracyclic 5H-indolo [3,2-b][1,5]benzothiazepin-6(7H)-ones upon treatment with EDCI-DMAP. Transformation of cyclic sulphides into the required sulphones was achieved by treatment with hydrogen peroxide or with m-chloroperbenzoic acid. The title derivatives are conformationally constrained analogues of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor 3-benzene-sulphonyl-5-chloroindole-2-carboxamide (L-737, 126). Although the indolobenzothiazepine derivatives, as well as the indolyl aryl sulphones used for their synthesis, were endowed with anti-HIV-1 activities in the submicromolar and micromolar range, none of them proved more potent than L-737,126.