ABSTRACT
Despite the knowledge that HPV is responsible for high-grade CIN and cervical cancer, little is known about the use of therapeutic vaccines as a treatment. We aimed to synthesize and critically evaluate the evidence from clinical trials on the safety, efficacy, and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade CIN associated with HPV. A systematic review of clinical trials adhering to the PRISMA 2020 statement in MEDLINE/PubMed, Embase, CENTRAL Cochrane, Web of Science, Scopus, and LILACS was undertaken, with no data or language restrictions. Primary endpoints related to the safety, efficacy, and immunogenicity of these vaccines were assessed by reviewing the adverse/toxic effects associated with the therapeutic vaccine administration via histopathological regression of the lesion and/or regression of the lesion size and via viral clearance and through the immunological response of individuals who received treatment compared to those who did not or before and after receiving the vaccine, respectively. A total of 1184 studies were identified, and 16 met all the criteria. Overall, the therapeutic vaccines were heterogeneous regarding their formulation, dose, intervention protocol, and routes of administration, making a meta-analysis unfeasible. In most studies (n = 15), the vaccines were safe and well tolerated, with clinical efficacy regarding the lesions and histopathological regression or viral clearance. In addition, eleven studies showed favorable immunological responses against HPV, and seven studies showed a positive correlation between immunogenicity and the clinical response, indicating promising results that should be further investigated. In summary, therapeutic vaccines, although urgently needed to avoid progression of CIN 2/3 patients, still present sparse data, requiring greater investments in a well-designed phase III RCT.
ABSTRACT
Chemotherapy for cancer treatment may result in a temporary or long-term gonadal damage resulting in subfertility or infertility. Cyclophosphamide (CY) is a cytotoxic alkylating agent that has been widely used in the treatment of cancer. Recent studies have shown that synthetic resorcinol lipid AMS35AA (3-Heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one) may be an important adjuvant chemotherapy that potentiates mutagenic damage and increases apoptosis caused by CY. The present study investigates the action of AMS35AA alone or/in association with CY on testicular function. Animals were divided into four groups: (a) control group: received only water; (b) CY group: received 150 µg/g of CY b.w., i.p.; (c) AMS35AA group: received 10 µg/g of AMS35AA b.w., i.p; and (d) associated group: received 10 µg/g of AMS35AA + 150 µg/g of CY b.w., i.p. Four weeks after the treatment, the results showed that testes weight of CY and associated groups decreased. However, the number of Sertoli cell and Leydig cell per testis was similar in control and treated groups. Our findings provide strong evidence that the AMS35AA alone or in CY association is not toxic to spermatogenesis. The absence of toxicity of AMS35AA supports the view that the resorcinolic lipid could be used associated with CY chemotherapy without causing adverse effects to testes function.
Subject(s)
Benzofurans , Animals , Benzofurans/toxicity , Cyclophosphamide/toxicity , Male , Spermatogenesis , TestisABSTRACT
INTRODUCTION: Eighty per cent of the sexually active population will get human papillomavirus (HPV) infection, which is the most prevalent sexually transmitted disease worldwide. Persistence of high-grade HPV infection may evolve to a cervical intraepithelial neoplasia (CIN), and these lesions may be precursors of cervical cancer. However, this progression can be prevented by the administration of therapeutic vaccines which use the main oncoproteins responsible for cancer development in an attempt to trigger a more specific and effective immunological response against this disorder. We aim to evaluate the safety, efficacy and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade CIN 2/3 associated with HPV. METHODS AND ANALYSIS: A systematic review of clinical trials will be undertaken. Medline, Excerpta Medica Database, Cochrane Central Register of Controlled Trials, Web of Science, Latin American and Caribbean Health Sciences Literature, Scientific Electronic Library Online and Scopus will be searched, with no restriction regarding publication date. Primary outcomes will include measures related to safety, efficacy and the immunogenicity of the therapeutic vaccines used in these patients. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Methodological appraisal of the studies will be assessed by the Cochrane Risk-of-Bias Tool for randomised controlled trials, and the quality evidence of the risk of bias in single studies will be evaluated by Grading of Recommendations Assessment, Development and Evaluation. A narrative synthesis will be done for all included studies. Outcomes will be analysed according to the subgroups of HPV type, CIN grade, route of vaccine administration and vaccine type. Also, if sufficient data are available, a meta-analysis will be conducted. The effect sizes will be generated using Hedges' g score for both fixed and random effect models. I 2 statistics will be used to assess heterogeneity and identify their potential sources. ETHICS AND DISSEMINATION: Ethical approval is not required as primary data will not be collected. Findings will be disseminated widely via peer-reviewed publication and in different media, for example, conferences, congresses or symposia. PROSPERO REGISTRATION NUMBER: CRD42017077428.
Subject(s)
Immunogenicity, Vaccine/immunology , Papillomaviridae/immunology , Papillomavirus Infections/therapy , Papillomavirus Vaccines/administration & dosage , Uterine Cervical Dysplasia/therapy , Uterine Cervical Neoplasms/therapy , Female , Humans , Treatment Outcome , Systematic Reviews as TopicABSTRACT
Estima-se que 80% da população sexualmente ativa será acometida por pelo menos um subtipo de papilomavírus humano (HPV) em algum momento da vida, o que representa uma alta prevalência e incidência dessa infecção sexualmente transmissível (IST), principalmente em países subdesenvolvidos. O HPV é responsável pelas Neoplasias Intraepiteliais Cervicais (NIC) de alto grau e do câncer cervical, que constituem um problema relevante para a saúde pública global, cursando com elevado ônus psicossocial e econômico aos pacientes, familiares e aos sistemas de saúde. Entretanto, a progressão ao câncer cervical pode ser evitada pela administração de vacinas terapêuticas que utilizam as principais oncoproteínas responsáveis pelo seu desenvolvimento, na tentativa de desencadear uma resposta imunológica mais específica e eficaz contra essa patologia. Atualmente, os tratamentos disponíveis para as neoplasias estão associados a morbidades para a paciente, relacionadas principalmente com o perfil reprodutivo e a recorrência da lesão, demonstrando a necessidade de terapias seguras e efetivas. O objetivo desse estudo foi sintetizar e avaliar criticamente as evidências científicas oriundas de estudos experimentais sobre a segurança, eficácia, e imunogenicidade de vacinas terapêuticas no tratamento de pacientes com NIC de alto grau associadas ao HPV. Realizou-se uma revisão sistemática de ensaios clínicos guiada pelas recomendac?o?es da Cochrane Collaboration. A estratégia de busca foi realizada nas bases de dados eletrônicas MEDLINE, Embase, CENTRAL Cochrane, Web of Science, LILACS e Scopus, sem restrição de data e de idioma. Obteve-se a aprovação/publicação do resgistro do protocolo desta revisão na International Prospective Register of Systematic Reviews-PROSPERO/NHS sob o número CRD42017077428. Os desfechos primários incluíram a segurança, eficácia e imunogenicidade das vacinas terapêuticas testadas em pacientes com NIC 2/3. Para a avaliação metodológica dos estudos, utilizamos a ferramenta de Risco-de-Viés da Cochrane para ensaios clínicos randomizados (ECR) e a ferramenta ROBINS-I (Risk-of-Bias In Non- Randomized Studies) para avaliação dos ensaios clínicos não randomizados. Foram identificados 1.184 estudos, sendo 15 selecionados e analisados. Verificou-se que, a confiabilidade dos resultados pode ser questionada, principalmente, pelo alto risco de vie?s observado em 80% dos estudos avaliados pela ferramenta da Cochrane e em 90,9% dos ensaios avaliados pela ROBINS-I, evidenciado principalmente pelos viéses de seleção e de performance presentes nos estudos. De modo geral, as vacinas terapêuticas mostraram-se heterogêneas quanto à sua formulação, dose, protocolo de intervenção e vias de administração. Na maioria dos estudos (93,3%) as vacinas apresentaramse seguras e bem toleradas, com eficácia clínica observada em 93,3% à partir da regressão das lesões, regressão histopatológica e/ou depuração viral. Adicionalmente, 73,3% dos estudos apresentaram respostas imunológicas favoráveis contra o HPV e 54,5% apresentaram correlação positiva entre imunogenicidade e resposta clínica, indicando resultados promissores que merecem maior investigação. Vacinas terapêuticas, apesar de urgentes, ainda apresentam barreiras a serem superadas antes de estarem disponíveis para a população, necessitando de maiores investimentos em ECR de fase III bem delineados de modo a beneficiar pacientes com NICs de alto grau, evitando assim sua progressão para o câncer cervical, de modo a melhorar os desfechos em saúde com impacto positivo nas taxas de sobrevida e na qualidade de vida dessas pacientes
It is estimated that 80% of the sexually active population will be affected by at least one human papillomavirus (HPV) subtype at some moment in their lives, representing a high prevalence and incidence of this sexually transmitted infection (STI), especially in underdeveloped countries. HPV is responsible for high-grade Cervical Intraepithelial Neoplasms (CIN) and cervical cancer, which are a relevant problem for global public health, with a high psychosocial and economic burden in patients, families and health systems. However, progression to cervical cancer can be avoided by the administration of therapeutic vaccines that use the major oncoproteins responsible for its development, in attempts to trigger a more specific and effective immune response against this disorder. Currently, the available treatments for neoplasias are associated with morbidities for the patient, which are mainly related to the reproductive profile and the recurrence of the lesion, demonstrating the need for safe and effective therapies. The purpose of this study was to synthesize and critically evaluate the scientific evidence from experimental studies on the safety, efficacy, and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade CIN associated with HPV. A systematic review of clinical trials guided by Cochrane Collaboration recommendations was carried out. The search strategy was performed in the electronic databases MEDLINE, Embase, Cochrane CENTRAL, Web of Science, LILACS and Scopus, with neither date nor language restriction. Approval for this review protocol was obtained from the International Prospective Register of Systematic Reviews-PROSPERO/NHS under the number CRD42017077428. Primary outcomes such as safety, efficacy, and immunogenicity of therapeutic vaccines tested in patients with CIN 2/3 were included. For the critical appraisal of the studies, we have used the Cochrane Risk-of-Bias tool for randomized clinical trials (RCTs) and the Risk-of-Bias In Non-Randomized Studies tool for assessment of non-randomized clinical trials. A total of 1,184 studies were identified, 15 of which were selected and analyzed. It was verified that the reliability of the results can be questioned mainly by the high risk-of-bias observed in 80% of the studies evaluated by the Cochrane tool, and in 90.9% of the trials assessed by ROBINS-I, as evidenced mainly by the selection bias as well as performance bias present within the studies. Overall, the therapeutic vaccines were heterogeneous with regards to their formulation, dose, intervention protocol and routes of administration. In most of studies (93.3%), the vaccines were safe and well tolerated, with clinical efficacy observed in 93.3% with regards to lesion regression, histopathological regression, and or viral clearance. In addition, 73.3% of the studies showed favorable immunological responses against HPV and 54.5% showed a positive correlation between immunogenicity and clinical response, indicating promising results that might be further investigated. Therapeutic vaccines, although urgent, still present barriers to be overcome before they are available to the population, requiring greater investments in welldesigned phase III RCTs to benefit patients with high-grade CIN, preventing their progression to cervical cancer disease in order to improve health outcomes with a positive impact on patients' survival rates and quality of life
Subject(s)
Humans , Vaccines , Immunogenicity, Vaccine , Papillomaviridae , NeoplasmsABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Gochnatia polymorpha ssp. floccosa (Asteraceae) also known as ''Cambará'' is used as medicinal plant in Brazil to treat infections and inflammation. Previous studies showed that its ethanolic extract could be bioprospecting of a new anti-inflammatory phytotherapy for use during pregnancy. This work aimed to evaluate dichloromethane (DCM) and butanolic (BT) fractions from G. polymorpha on embryo-fetal development and DNA integrity in mice. MATERIALS AND METHODS: Female mice were treated with 50 and 20mg/kg of the DCM and BT fractions, respectively, during organogenesis and gestational period. RESULTS AND CONCLUSION: The present study shows that DCM and BT fractions from G. polymorpha possess mutagenic activity but are not teratogenic. Based on the fact that the reproductive indices are similar in control and treated animals, we may infer that the mutagenic effect was in somatic cell, at least in part, because the reabsorption number and reabsorption rates did not change in DCM and BT exposed groups.
Subject(s)
1-Butanol/pharmacology , Asteraceae , Fetal Development/drug effects , Methylene Chloride/pharmacology , Plant Extracts/pharmacology , Reproduction/drug effects , Animals , DNA/physiology , Female , Fetal Development/physiology , Maternal Health , Mice , Plant Bark , Plant Extracts/isolation & purification , Pregnancy , Random Allocation , Reproduction/physiology , Treatment OutcomeABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Gochnatia polymorpha ssp. floccosa is used in folk medicine to treat inflammation and infections. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly consumed medications during pregnancy in women with inflammatory diseases. However, the relationship between the use of NSAIDs and the risk of miscarriage and birth defects and/or benefits is not fully understood. Thus, an investigation regarding the use of Gochnatia polymorpha during gestation is of relevance for developing safe anti-inflammatory drugs for use during pregnancy. MATERIALS AND METHODS: The pregnant females were randomly divided into 5 groups. Control group received a hydroalcoholic solution (1.2%), via gavage, for at least 15 days prior to mating and throughout the gestational period. The pre-treatment group received Gochnatia polymorpha ethanol extract (GPEE), via gavage, at a dose of 100mg/kg body weight (b.w.) for at least 15 days prior to mating and up to the appearance of the vaginal plug. The organogenesis group received GPEE at a dose of 100mg/kg (b.w.), via gavage, on the 5-15th gestacional day. The pregnancy group received GPEE at a dose of 100mg/kg (b.w.), via gavage, throughout the gestational period (from the 1st to the 18th day of pregnancy). The pre+pregnancy group received GPEE at a dose of 100mg/kg (b.w.), via gavage, for at least 15 days prior to mating and throughout the entire gestational period. The clinical signals of maternal toxicity and teratogenesis were evaluated. Additional assays to evaluate chronic inflammation, antigenotoxicity and immunomodolatory activity were performed. RESULTS AND CONCLUSIONS: The results indicated that GPEE does not interfere with reproductive performance or embryo-fetal development but does correlate with reduced weight and fetal length. The extract was not teratogenic or mutagenic or an immunomodulator. However, GPEE did exhibit effective anti-inflammatory activity. Based on this study, it can be inferred that GPEE is an important, safe anti-inflammatory agent for use during pregnancy according to the experimental design we utilized, which opens up possibilities for the bioprospecting of a new anti-inflammatory phytotherapy for use during pregnancy.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/toxicity , Asteraceae/chemistry , Embryonic Development/drug effects , Fetal Development/drug effects , Organogenesis/drug effects , Plant Extracts/toxicity , Animals , Anti-Inflammatory Agents, Non-Steroidal/isolation & purification , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Blood Cell Count , Edema/drug therapy , Ethnopharmacology , Female , Male , Maternal Exposure , Mice , Micronucleus Tests , Organ Size/drug effects , Phagocytosis/drug effects , Plant Extracts/isolation & purification , Plant Extracts/therapeutic use , Pregnancy , Spleen/cytologyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Byrsonima verbascifolia is used in folk medicine to treat diarrhea, intestinal infections, chronic wounds, Chagas disease, inflammation and as a diuretic. However there is no investigation regarding the Byrsonima verbascifolia hydrometanolic extract (BVHME) used during gestation. MATERIALS AND METHODS: The pregnant females were randomly divided into 5 groups. Control group received saline plus DMSO (1%) in a volume of 0.1 mL/10 g (b.w.), via gavage, for at least 15 days prior to mating and throughout the gestational period. The Pre-treatment group received the BVHME, via gavage, at a dose of 50 mg/kg (b.w.) for at least 15 days prior to mating and up to the appearance of the vaginal plug. The Organogenesis group received the BVHME at a dose of 50 mg/kg (b.w.), via gavage, on the 5-15th gestational day. The Gestational group received the BVHME at a dose of 50 mg/kg (b.w.), via gavage, throughout the gestational period (from the 1st to the 18th day of pregnancy). The Pre+Gestational group received the BVHME at a dose of 50mg/kg (b.w.), via gavage, for at least 15 days prior to mating and up to throughout the gestational period. The clinical signals of maternal and fetuses toxicity were evaluated, as the mutagenicity and immunomodulation tests were performed. RESULTS AND CONCLUSIONS: The present investigation shows, for the first time, that the use of Byrsonima verbascifolia extract in pregnant Swiss mice, did not alter the female reproductive function, mutagenicity or immunostimulation as well as not interfere with embryofetal development at least in our experimental conditions.
