RESUMO
Chromium (Cr) and its compounds are closely associated with individuals' lives and extensively used in industry. Excessive exposure to hexavalent chromium (Cr(VI)) induces oxidative damage of various organs including the testes, posing a serious threat to male reproductive fitness. As an endogenous antioxidant, melatonin holds potent antioxidative and anti-inflammatory properties, becoming a potential candidate for treatment of a variety of diseases, including reproductive disorders. Here, by using a mouse model, we systematically assessed Cr(VI)-induced damage to male fertility as well as the preventive role of melatonin. We analyzed the histology and pathology of the testis and epididymis, the density, viability, and malformation of caudal epididymal sperm, the proliferative activity and apoptosis of various spermatogenic subtypes and Sertoli cells, as well as the fertility of mice at five timepoints within one cycle of spermatogenesis (Days 0, 14, 21, 28, and 35) post 14 days of Cr(VI) and/or melatonin intraperitoneal injection. We identified that the testicular damage caused by Cr(VI) persisted to Day 21 after administration and then started to be alleviated, with clear alleviation on Day 35. Pretreatment with melatonin evidently reduced Cr(VI)-induced testicular damage and accelerated spermatogenic restoration, generating an almost normal phenotype on Day 35. Melatonin pretreatment also retained the sperm quality at all time points investigated. Moreover, melatonin to some extent preserved the fertility of Cr(VI)-treated mice without apparent side effects. The findings shed light on the future clinical application of melatonin as a therapeutic agent for environmental heavy metal toxicant-induced male subfertility or infertility.
Assuntos
Melatonina , Masculino , Animais , Melatonina/farmacologia , Estudos Longitudinais , Sêmen , Antioxidantes/farmacologia , Cromo/toxicidade , FertilidadeRESUMO
BACKGROUND: Wendan decoction (WDD) has been used as a treatment for depression in China since the Tang Dynasty. However, high-quality evidence for this is lacking. This study proposed a novel synthetic external control method to evaluate its clinical efficacy. METHODS: We searched public databases for clinical trials of WDD for major depression. The rate of change of the Hamilton Depression Scale score from baseline was used as an efficacy indicator, and a model-based meta-analysis was performed to analyze the clinical efficacy of WDD. To establish a reference standard for efficacy, the antidepressant efficacy distributions of a placebo and 19 antidepressants were virtually synthesized based on the same conditions as the clinical trial characteristics of WDD. RESULTS: This study included 5 clinical trials with 177 participants. WDD showed a slow onset, with a time to reach the maximum effect of 9.71 weeks. At 8 weeks, the rate of change in the Hamilton Depression Scale score from baseline was 66.4% (95% CI = 62.3%-70.3%) in the WDD group. The pure effect value of WDD, after deducting the placebo effect, was 26.9% (95%CI = 23.0%-30.9%), which was comparable with 5 types of antidepressants and significantly higher than the others. CONCLUSION: The proposed external synthetic control method provides a solution to the bottleneck problem of clinical efficacy evaluation in real-world research on traditional Chinese medicine. WDD has high clinical development value for the treatment of depression, and large-scale randomized controlled trials are recommended to confirm its antidepressant effect.
Assuntos
Transtorno Depressivo Maior , Medicamentos de Ervas Chinesas , Humanos , Antidepressivos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Resultado do Tratamento , Transtorno Depressivo Maior/tratamento farmacológicoRESUMO
OBJECTIVES: This study aimed to quantitatively compare the efficacy and safety of long-acting ß2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) and LABA/inhaled corticosteroid (ICS) fixed-dose combinations (FDCs) in preventing moderate or severe chronic obstructive pulmonary disease (COPD) exacerbations. METHODS: A literature search was performed using public databases. The time course characteristics of the probability of a moderate or severe exacerbation in stable COPD patients treated with LABA/LAMA and LABA/ICS FDCs were described by the parametric survival function. A random-effects model in a single-arm meta-analysis was used to analyze the incidence of serious adverse events (SAEs) and pneumonia. RESULTS: Twenty studies including 23,955 participants were included. The proportion of participants with a history of COPD exacerbation (%) in the previous year and the postbronchodilator forced expiratory volume in the first second (FEV1) (%predicted) were important factors affecting drug efficacy. After adjusting the above factors to median levels of 100% and 45.5%, respectively, the moderate or severe exacerbation rates at 52 weeks for olodaterol/tiotropium, formoterol/budesonide, indacaterol/glycopyrronium, formoterol/glycopyrronium, vilanterol/fluticasone, salmeterol/fluticasone, and vilanterol/umeclidinium were 38.3%, 41.0%, 42.6%, 47.0%, 47.5%, 47.9%, and 53.0%, respectively. In terms of safety, significant differences were observed among drugs containing different LABA/LAMA FDCs. CONCLUSIONS: This study showed that not all LABA/LAMA FDCs were superior to LABA/ICS FDCs in safety and in preventing moderate or severe exacerbations in patients with stable COPD, providing important quantitative information for COPD-related guidelines.
Assuntos
Antagonistas Muscarínicos , Doença Pulmonar Obstrutiva Crônica , Humanos , Administração por Inalação , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Broncodilatadores/uso terapêutico , Combinação de Medicamentos , Fluticasona/uso terapêutico , Fumarato de Formoterol/uso terapêutico , Glicopirrolato/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológicoRESUMO
tRNA-derived small RNAs (tsRNAs) from spermatozoa could act as acquired epigenetic factors and contribute to offspring phenotypes. However, the roles of specific tsRNAs in early embryo development remain to be elucidated. Here, using pigs as a research model, we probed the tsRNA dynamics during spermatogenesis and sperm maturation and demonstrated the delivery of tsRNAs from semen-derived exosomes to spermatozoa. By microinjection of antisense sequences into in vitro fertilized oocytes and subsequent single-cell RNA-seq of embryos, we identified a specific functional tsRNA group (termed here Gln-TTGs) that participate in the early cleavage of porcine preimplantation embryos, probably by regulating cell cycle-associated genes and retrotransposons. We conclude that specific tsRNAs present in mature spermatozoa play significant roles in preimplantation embryo development.
Assuntos
Blastocisto , Divisão Celular , RNA de Transferência de Glutamina/fisiologia , RNA/metabolismo , Espermatozoides/metabolismo , Animais , Desenvolvimento Embrionário , Feminino , Masculino , Microinjeções , Gravidez , Maturação do Esperma , Espermatogênese , SuínosRESUMO
PURPOSE: Paclitaxel-platinum chemotherapy is the first-line treatment for advanced non-small cell lung cancer (NSCLC) patients. This study quantitatively evaluated the factors influencing the efficacy and safety of the paclitaxel-platinum regimen to provide the necessary reference for the development of clinical practice and clinical trials. METHODS: A literature search was performed using public databases. The parametric survival function was used to analyze the overall survival (OS) time course of patients treated with the paclitaxel-platinum regimen. The random effects model in the single-arm meta-analysis was used to analyze the objective response rate (ORR) and the incidence of grade 3-4 adverse events (AEs) under the predefined subgroups according to race and the regimen. RESULTS: A total of 31 studies consisting of 3365 participants were included in the analysis. Race was the most important determinant of efficacy and safety in the paclitaxel-platinum regimen, with the median survival time and ORR in East Asians and non-East Asians being 12.2 months (95% CI: 10.5-14.4 months) and 37% (95% CI: 32-41%) and 8.4 months (95% CI: 6.5-11.0 months) and 28% (95% CI: 25-32%), respectively. The incidence of grade 3-4 AEs such as leukopenia and neutropenia was about three times higher in East Asians compared to non-East Asians. CONCLUSIONS: The efficacy and safety of the paclitaxel-platinum regimen can vary between East Asian and non-East Asian populations and between different treatment schedules. The results of this study can provide a reliable and precise external control for the future evaluation of new treatment options for advanced NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Povo Asiático , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Neoplasias Pulmonares/mortalidade , Método de Monte Carlo , Estadiamento de Neoplasias , Paclitaxel/uso terapêutico , Platina/uso terapêutico , Análise de SobrevidaRESUMO
Spermatogenesis, an intricate process occurring in the testis, is responsible for ongoing production of spermatozoa and thus the cornerstone of lifelong male fertility. In the testis, spermatogenesis occurs optimally at a temperature 2-4°C lower than that of the core body. Increased scrotal temperature generates testicular heat stress and later causes testicular atrophy and spermatogenic arrest, resulting in a lower sperm yield and therefore impaired male fertility. Melatonin (N-acetyl-5-methoxytryptamine), a small neuro-hormone synthesized and secreted by the pineal gland and the testis, is widely known as a potent free-radical scavenger; it has been reported that melatonin protects the testis against inflammation and reactive oxygen species generation thereby playing anti-inflammatory, -oxidative and -apoptotic roles in the testis. Nevertheless, the role of melatonin in the testicular response to heat stress has not been studied. Here, by employing a mouse model of testicular hyperthermia, we systematically investigated the testicular response to heat stress as well as the occurrence of autophagy, apoptosis and oxidative stress in the testis. Importantly, we found that pre-treatment with melatonin attenuated heat-induced apoptosis and oxidative stress in the testis. Also, post-treatment with melatonin promoted recovery of the testes from heat-induced damage, probably by maintaining the integrity of the Sertoli cell tight-junction. Thus, we for the first time provide the proof of concept that melatonin can protect the testis against heat-induced damage, supporting the potential future use of melatonin as a therapeutic drug in men for sub/infertility incurred by various testicular hyperthermia factors.
Assuntos
Temperatura Alta/efeitos adversos , Melatonina/uso terapêutico , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Masculino , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/ultraestrutura , Testículo/lesões , Testículo/patologia , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/ultraestruturaRESUMO
OBJECTIVE: This study aimed to quantitatively evaluate drug efficacy and identify relevant factors that affect the relief of hot flashes in patients with breast cancer. METHODS: A comprehensive literature search was performed using public databases. Randomized clinical studies on drug therapy for the treatment of hot flashes in patients with breast cancer were identified. A time-effect model was established, and crucial pharmacodynamic parameters, such as maximal efficacy (Emax) and onset time (ET50), were used to reflect the differences in efficacy among the drugs. RESULTS: Eighteen studies involving 5178 subjects were included. It was found that the baseline of hot flashes was an important factor for the Emax value of drugs. After correcting the baseline to the level of eight times per day, the Emax values of progesterone, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs), neuroleptic agents, tibolone, phytoestrogen, other types of drugs, and placebo were 8.3(95%CI 6.8, 9.9),5.1(95%CI 4.4, 5.7), 4.4(95%CI 3.6, 5.3), 4.0(95%CI 3.6, 4.3), 3.4(95%CI 2.4, 4.3), 2.5(95%CI 0.8, 4.2), and 2.7(95%CI 2.1, 3.3), respectively. The ET50 of all the drugs were approximately 2-2.5 weeks, which was obviously longer than that of the placebo (1.2 weeks). When compared with the previously reported efficacy characteristics in natural menopausal women, no significant difference was found between the two populations. CONCLUSIONS: Progesterone showed the highest efficacy, followed by SSRIs/SNRIs, neuroleptic agents, and tibolone, while phytoestrogen and other types of drugs showed no efficacy advantages. There is a significant association between the baseline of hot flashes and drug efficacy, while there was no significant difference between breast cancer patients and natural menopausal women.
Assuntos
Neoplasias da Mama/complicações , Fogachos/tratamento farmacológico , Fogachos/etiologia , Algoritmos , Neoplasias da Mama/tratamento farmacológico , Interpretação Estatística de Dados , Feminino , Humanos , Menopausa , Modelos Estatísticos , Progesterona/administração & dosagem , Progesterona/efeitos adversos , Progesterona/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Software , Resultado do TratamentoRESUMO
OBJECTIVES: This study aimed to establish a pharmacodynamic model to quantitatively compare the efficacy characteristics of seven kinds of triptans and their different dosage forms in the treatment of acute migraines. METHODS: Clinical studies of triptans in the treatment of acute migraines were comprehensively searched in the public databases. Pharmacodynamic models were established to describe the dose-effect and time-course of each kind of triptan for the proportion of patients who became pain free or had pain relief. RESULTS: A total of 92 articles involving 47,376 subjects were included in the analysis. After eliminating the placebo effect, oral eletriptan (40 mg) had the highest efficacy among all oral drugs at the maximum approved dose, and the proportion of patients who became pain free and had pain relief were 30.9% and 37.9% at 2 h, respectively. However, oral naratriptan (2.5 mg) had the lowest efficacy, and the proportion of patients who became pain free and had pain relief was 10.3% and 21.6% at 2 h, respectively. The efficacy of subcutaneous administration was significantly higher than that of oral administration, and the efficacy of nasal spray administration was comparable to that of oral administration. Regarding the dose-effect, the efficacy of the sumatriptan nasal spray significantly increased within the FDA (Food and Drug Administration)-approved dose range. When the dose was increased from 5 to 20 mg of sumatriptan nasal spray, the proportion of patients who became pain free and had pain relief increased by 16.8% and 18.3% at 2 h, respectively. Regarding the time-course, the time of onset of subcutaneous sumatriptan (6 mg) was the fastest, and the fraction of patients who were pain free at 2 h accounted for 90.6% of that at 4 h. CONCLUSIONS: This study evaluated the efficacy characteristics of seven kinds of triptans and their different dosage forms. The present findings provide necessary quantitative information for migraine medication guidelines.
Assuntos
Transtornos de Enxaqueca/tratamento farmacológico , Modelos Biológicos , Dor/tratamento farmacológico , Agonistas do Receptor de Serotonina/administração & dosagem , Triptaminas/administração & dosagem , Vasoconstritores/administração & dosagem , Doença Aguda , Administração Oral , Relação Dose-Resposta a Droga , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
PURPOSE: This study aimed to establish a non-linear mixed effects model to quantitatively analyze the placebo responses of neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD). METHODS: A comprehensive literature search was conducted in public databases. Placebo-controlled randomized AD clinical trials using the neuropsychiatric inventory (NPI) score as the primary or secondary outcome were included. Non-linear mixed effects model was used to describe the time course of the placebo responses of NPS in AD clinical trials. Potential affecting factors were tested as covariates. RESULTS: A total of 32 clinical studies (involving 3942 subjects) were included in model-based analysis. We found that the maximal placebo responses of NPS were reached at week 4 approximately, after which rebound effects appeared. The baseline NPI score had a significant impact on the placebo responses. Higher baseline NPI score tended to cause greater reductions in NPI score at week 8 and a smaller degree of rebound. For AD patients whose normalized baseline NPI score was 10 points and 30 points, the reduction in normalized NPI score at week 8 was estimated to be 0.83 and 7.43 points, respectively; and the rebound rate after week 8 was estimated to be 0.1 points/week and 0.08 points/week, respectively. CONCLUSIONS: The duration of 4 weeks is sufficient to determine the drug efficacy for assessing NPS in AD clinical trials. The baseline NPI score was a key factor associated with placebo responses of NPS, which should be considered when designing future clinical trials and conducting comparisons across trials.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Dinâmica não Linear , Efeito Placebo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Inibidores da Colinesterase/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Nootrópicos/uso terapêutico , Escalas de Graduação Psiquiátrica , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Mammalian spermatozoa are highly susceptible to reactive oxygen species (ROS) stress. The aim of the present study was to investigate whether and how melatonin protects rabbit spermatozoa against ROS stress during cryopreservation. Semen was diluted with Tris-citrate-glucose extender in presence of different concentrations of melatonin. It was observed that addition of 0.1â¯mM melatonin significantly improved spermatozoa motility, membrane integrity, acrosome integrity, mitochondrial membrane potential as well as AMP-activated protein kinase (AMPK) phosphorylation. Meanwhile, the lipid peroxidation (LPO), ROS levels and apoptosis of post-thaw spermatozoa were reduced in presence of melatonin. Interestingly, when fresh spermatozoa were incubated with 100⯵Mâ¯H2O2, addition of 0.1â¯mM melatonin significantly decreased the oxidative damage compared to the H2O2 treatment, whereas addition of luzindole, an MT1 receptor inhibitor, decrease the effect of melatonin in spermatozoa. It was observed that the glutathione (GSH) content and activities of glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) were significantly increased with addition of melatonin during cryopreservation. In conclusion, addition of melatonin to the freezing extender protects rabbit spermatozoa against ROS attack by enhancing AMPK phosphorylation for increasing the antioxidative defense.
Assuntos
Antioxidantes/farmacologia , Crioprotetores/farmacologia , Melatonina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Preservação do Sêmen/métodos , Espermatozoides/efeitos dos fármacos , Acrossomo/efeitos dos fármacos , Animais , Catalase/metabolismo , Criopreservação/métodos , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Coelhos , Espécies Reativas de Oxigênio/metabolismo , Receptor MT1 de Melatonina/antagonistas & inibidores , Sêmen/metabolismo , Análise do Sêmen , Motilidade dos Espermatozoides/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Triptaminas/farmacologiaRESUMO
BACKGROUND/AIMS: ATP is essential for mammalian sperm to survive and maintain fertilizing capacity. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. The aims of the present study were to explore the localization of AMPK in goat sperm and to investigate whether and how AMPK regulates sperm functions in vitro. METHODS: Sperm were treated with AMPK modulators (AICAR, metformin and Compound C) during incubation. Sperm motility was assessed with a computer-assisted spermatozoa analysis system (CASA). Membrane integrity, acrosome reaction and mitochondrial membrane potentials were detected by SYBR-14/PI, FITC-PNA and JC-1 staining, respectively. And the lactate content, ATP content, AMPK activity, activity of pyruvate kinase (PK) and lactate dehydrogenase (LDH) were also measured with the commercial assay kits. Immunofluorescence staining was used to analyze the distribution of PK, LDH, AMPK and phospho-Thr172-AMPK in sperm. The role of AMPK was further studied during induction of capacitation and acrosome reaction. RESULTS: We found that AMPKα was localized in the entire acrosomal region, the midpiece and the flagellum, while the phospho-Thr172-AMPK was distributed in the head, the midpiece and flagellum. Activation of AMPK by AICAR and metformin significantly improved sperm motility, membrane integrity and acrosome reaction, largely maintained sperm mitochondrial membrane potentials, lactate content and ATP content, and enhanced the activity of AMPK, PK and LDH, whereas inhibition by Compound C triggered the converse effects. Moreover, PK was localized in the acrosomal area and the midpiece, while LDH was distributed in the tail. Induction of capacitation and acrosome reaction led to AMPK phosphorylation. AMPK phosphorylation regulated the activity of energetic enzymes. CONCLUSION: This study for the first time provides evidence that AMPK governs goat sperm functions through energy metabolism in vitro. This finding will help to improve assisted reproductive techniques in goats and the other species.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Reação Acrossômica/fisiologia , Metabolismo Energético/fisiologia , Espermatozoides/enzimologia , Animais , Cabras , Masculino , Fosforilação/fisiologia , Espermatozoides/citologiaRESUMO
Given the potential biological functions of spermatogonial stem cells (SSCs) in spermatogenesis and in delivering parental genetic information to the next generation, how these cells respond to environmental toxins and carcinogens should be investigated. We examined the toxic effect of hexavalent chromium (Cr(VI)) on global histone modifications and apoptotic signaling pathways in SSCs. We determined the effect of melatonin, one of the most powerful endogenous free radical scavengers and wide-spectrum antioxidants, in protecting SSCs from Cr(VI)-induced apoptosis and global histone modification by Western blot analysis. In addition, we examined the in vivo effect of melatonin on Cr(VI)-induced histological changes of seminiferous tubules in mouse testes. We also evaluated the fertility of male mice by monitoring litter size following intraperitoneal injection of these chemicals. Our study demonstrated the Cr(VI)-induced global increases in H3K9me3 and H3K27me3 and activated the apoptotic signaling pathway. Pretreatment of SSCs with melatonin alleviated Cr(VI)-induced apoptosis and the global increase of H3K9me3. Exposure to melatonin also attenuated the Cr(VI)-induced increase of the abundance of histone methyltransferase ESET. Furthermore, exogenous administration of melatonin protected mice against Cr(VI)-induced changes in testicular histology and germ cell apoptosis, which helped maintain normal spermatogenesis and male fertility. Our study revealed a potential new therapeutic approach for male reproductive injury caused by Cr(VI).
Assuntos
Células-Tronco Germinativas Adultas/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Cromo/toxicidade , Epigênese Genética/efeitos dos fármacos , Histonas/biossíntese , Melatonina/farmacologia , Células-Tronco Germinativas Adultas/metabolismo , Células-Tronco Germinativas Adultas/patologia , Animais , Antioxidantes/farmacologia , Apoptose/fisiologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Epigênese Genética/fisiologia , Histonas/genética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Distribuição AleatóriaRESUMO
Palladium (Pd) is widely used in chemistry, biology, environmental science etc., and Pd2+ is the most plenitudinous oxidation state of the Pd that can exist under physiological conditions or in living cells, which could have adverse effects on both our health and environment. Thus, it is of great significance to monitor the changes of Pd2+. Hence, a novel near-infrared fluorescent probe M-PD has been developed for selective detection of Pd2+ based on naphthofluorescein in this work. The result demonstrated that M-PD exhibited favorable properties for sensing Pd2+ such as excellent water solubility, high selectivity and sensitivity. And the limit of detection was estimated as 10.8â¯nM, much lower than the threshold in drugs (5-10â¯ppm) specified by European Directorate for the Quality Control of Medicines. More importantly, detection and recovery experiments of Pd2+ in aspirin aqoeous solution and soil are satisfactory. In addition, M-PD has also been successfully used for near-infrared fluorescence imaging of Pd2+ in living cells, indicating that the probe has better feasibility and application potential in the determination of Pd2+.
Assuntos
Corantes Fluorescentes/química , Paládio/análise , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Íons/química , Limite de Detecção , Microscopia Confocal , Espectroscopia de Luz Próxima ao Infravermelho , Água/químicaRESUMO
Mammalian spermatozoa are extremely susceptible to high doses of reactive oxygen species (ROS). The aim of the present study was to investigate the potential role of glutamine in protecting rabbit spermatozoa against ROS stress during cryopreservation and post-thaw incubation. Freshly ejaculated semen was diluted with Tris-citrate-glucose extender supplemented with glutamine. The addition of 20mM glutamine significantly improved sperm motility, acrosome integrity, membrane integrity and mitochondrial activity. Meanwhile, 20mM glutamine addition decreased lipid peroxidation and DNA damage in frozen-thawed spermatozoa. Interestingly, supplementation with 20mM glutamine led to increases in glutathione content and γ-glutamyl cysteine synthetase and glutathione peroxidase activity, with concomitant decreases in ROS levels during cryopreservation and post-thaw incubation. In conclusion, the addition of glutamine to extender solutions protects rabbit spermatozoa from ROS attack by enhancing glutathione synthesis.
Assuntos
Antioxidantes/farmacologia , Glutamina/farmacologia , Glutationa/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Acrossomo/efeitos dos fármacos , Animais , Criopreservação , Dano ao DNA/efeitos dos fármacos , Masculino , Coelhos , Espécies Reativas de Oxigênio/metabolismo , Preservação do Sêmen , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismoRESUMO
OBJECTIVE: This study was aimed at exploring the accuracy of population pharmacokinetic method in evaluating the bioequivalence of pidotimod with sparse data profiles and whether this method is suitable for bioequivalence evaluation in special populations such as children with fewer samplings. Methods In this single-dose, two-period crossover study, 20 healthy male Chinese volunteers were randomized 1 : 1 to receive either the test or reference formulation, with a 1-week washout before receiving the alternative formulation. Noncompartmental and population compartmental pharmacokinetic analyses were conducted. Simulated data were analyzed to graphically evaluate the model and the pharmacokinetic characteristics of the two pidotimod formulations. Various sparse sampling scenarios were generated from the real bioequivalence clinical trial data and evaluated by population pharmacokinetic method. RESULTS: The 90% confidence intervals (CIs) for AUC0-12h, AUC0-∞, and Cmax were 97.3 - 118.7%, 96.9 - 118.7%, and 95.1 - 109.8%, respectively, within the 80 - 125% range for bioequivalence using noncompartmental analysis. The population compartmental pharmacokinetics of pidotimod were described using a one-compartment model with first-order absorption and lag time. In the comparison of estimations in different dataset, the estimation of random three- and< fixed four-point sampling strategies can provide results similar to those obtained through rich sampling. The nonlinear mixed-effects model requires fewer data points. Moreover, compared with the noncompartmental analysis method, the pharmacokinetic parameters can be more accurately estimated using nonlinear mixed-effects model. CONCLUSIONS: The population pharmacokinetic modeling method was used to assess the bioequivalence of two pidotimod formulations with relatively few sampling points and further validated the bioequivalence of the two formulations. This method may provide useful information for regulating bioequivalence evaluation in special populations.
Assuntos
Fatores Imunológicos/farmacocinética , Modelos Biológicos , Ácido Pirrolidonocarboxílico/análogos & derivados , Tiazolidinas/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Povo Asiático , Estudos Cross-Over , Humanos , Fatores Imunológicos/administração & dosagem , Masculino , Dinâmica não Linear , Ácido Pirrolidonocarboxílico/administração & dosagem , Ácido Pirrolidonocarboxílico/farmacocinética , Equivalência Terapêutica , Tiazolidinas/administração & dosagem , Adulto JovemRESUMO
AIM: This study aimed to quantitate the efficacy of soy isoflavones in the treatment of menopausal hot flashes. METHODS: Model based meta-analysis (MBMA) was used to quantitate the efficacy of soy isoflavones. We conducted a systemic literature search to build a time-effect model for placebo and soy isoflavones in treating menopausal hot flashes. Studies were identified, subjected to inclusion and exclusion criteria, and reviewed. RESULTS: From 55 articles, 16 studies of soy isoflavones met the inclusion criteria, and contained 65 and 66 mean effect values in placebo and soy isoflavone groups, respectively, from about 1710 subjects. Interestingly, the developed model was found to describe adequately the time course of hot flashes reduction after administration of placebo and soy isoflavones. Using this model, we found that the maximal percentage change of hot flashes reduction by soy isoflavones was 25.2% after elimination of the placebo effect, accounting for 57% of the maximum effects of estradiol (Emax-estradiol = 44.9%). However, a time interval of 13.4 weeks was needed for soy isoflavones to achieve half of its maximal effects, much longer than estradiol, which only required 3.09 weeks. These results suggest that treatment intervals of 12 weeks are too short for soy isoflavones, which require at least 48 weeks to achieve 80% of their maximum effects. CONCLUSIONS: Soy isoflavones show slight and slow effects in attenuating menopausal hot flashes compared with estradiol.
Assuntos
Glycine max/química , Fogachos/tratamento farmacológico , Isoflavonas/uso terapêutico , Menopausa , Ensaios Clínicos como Assunto , Feminino , Humanos , Isoflavonas/administração & dosagem , Isoflavonas/isolamento & purificação , Modelos Estatísticos , Método de Monte Carlo , Resultado do TratamentoRESUMO
With the wide application of electronic data management (EDC), the data management is shifting to a new mode. In order to recognize the advantages of EDC, we choose 20 representative registered clinical trials, which involve 5 404 subjects and 321 sites. We found that EDC has many beneficial impacts on the course of clinical trial data management, including the process of data collection, data cleaning, data quality control and clinical trial decision-making. The result also provides a reference for the adoption of EDC in clinical trials.
Assuntos
Ensaios Clínicos como Assunto , Coleta de Dados/normas , Armazenamento e Recuperação da Informação/normas , Controle de QualidadeRESUMO
AIM: To develop a population pharmacokinetic model of adefovir dipivoxil in healthy volunteers and evaluate the effect of individual factors on the pharmacokinetics of adefovir dipivoxil. METHODS: Plasma concentration data collected from 32 healthy Chinese subjects in a Phase I clinical study was pooled. Subjects received a single oral dose of 10 mg, 20 mg, or 30 mg adefovir dipivoxil, or multiple doses of 10 mg once a day for 9 days. Plasma concentrations of adefovir dipivoxil were measured using a validated liquid chromatography-mass spectrometric method. A nonlinear mixed-effect model was used to analyze the plasma concentration data of adefovir dipivoxil in healthy volunteers and to calculate the relevant parameters as well as inter- and intra-individual variability. RESULTS: The time course of adefovir dipivoxil concentration is best described by a first-order absorption and first-order elimination two-compartment model with lag time. The final estimate of total body clearance (CL) is 56.9 L/h and 78.7 L/h for single and multiple dosing regimen, respectively; the volume distribution of the central compartment (V2) is 106 L; inter-compartmental clearance (Q) is 220 L/h; volume distribution of the peripheral compartment (V3) is 498 L and 800 L for single and multiple dosing regimen, respectively; absorption rate is 0.509 h-1; and lag time is 0.315 hours. The inter-individual variabilities of CL and V2 were 22.4% and 58.9%, respectively. The proportional error of residual variability is 14.1% and the additive error is 0.30 ng/L. The final pharmacokinetic model was evaluated using a bootstrap method. CONCLUSIONS: A nonlinear mixed effect model for oral adefovir dipivoxil formulations was developed in healthy Chinese subjects. A multiple dosing regimen may significantly increase the body clearance and volume distribution of the peripheral compartment compared to a single dosing regimen. *These authors contribute equally to this work.
Assuntos
Adenina/análogos & derivados , Antivirais/farmacocinética , Organofosfonatos/farmacocinética , Adenina/administração & dosagem , Adenina/farmacocinética , Adulto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Modelos Biológicos , Organofosfonatos/administração & dosagem , ComprimidosRESUMO
Mild magnetic hyperthermia therapy (MMHT) holds great potential in treating deep-seated tumors, but its efficacy is impaired by the upregulation of heat shock proteins (HSPs) during the treatment process. Herein, Lac-FcMOF, a lactose derivative (Lac-NH2 ) modified paramagnetic metal-organic framework (FcMOF) with magnetic hyperthermia property and thermal stability, has been developed to enhance MMHT therapeutic efficacy. In vitro studies showed that Lac-FcMOF aggravates two-way regulated redox dyshomeostasis (RDH) via magnetothermal-accelerated ferricenium ions-mediated consumption of glutathione and ferrocene-catalyzed generation of âOH to induce oxidative damage and inhibit heat shock protein 70 (HSP70) synthesis, thus significantly enhancing the anti-cancer efficacy of MMHT. Aggravated RDH promotes glutathione peroxidase 4 inactivation and lipid peroxidation to promote ferroptosis, which further synergizes with MMHT. H22-tumor-bearing mice treated with Lac-FcMOF under alternating magnetic field (AMF) demonstrated a 90.4% inhibition of tumor growth. This work therefore provides a new strategy for the simple construction of a magnetic hyperthermia agent that enables efficient MMHT by downregulating HSPs and promoting ferroptosis through the aggravation of two-way regulated RDH.
Assuntos
Ferroptose , Hipertermia Induzida , Estruturas Metalorgânicas , Neoplasias , Animais , Camundongos , Proteínas de Choque Térmico , Neoplasias/terapia , Campos Magnéticos , OxirreduçãoRESUMO
A biological nanoplatform (Gal-ANI@ZnAP NPs) was constructed based on a prodrug-skeletal metal-organic framework (MOF) using purine nucleobase analogue prodrug 6-allylthiopurine as a bioactive ligand, and functionalized with AIE fluorescent PARP inhibitor glycoconjugate for visualization therapy and synthetic lethal cancer therapy. This nanoplatform could actively target cancer cells, selectively release drugs in response to esterase/pH, and visualize drug uptake. In vitro studies revealed that Gal-ANI@ZnAP NPs increased the synthetic lethality in cancer cells by inducing DNA repair failure with the simultaneous targeting of PARP and nucleotide metabolism, thereby exhibiting a significant cancer-killing effect. The study presents a novel strategy to construct an AIE nanoplatform using pharmaceutical molecules for drug uptake visualization and boosting synthetic lethality in cancer.