Novel combination therapy for respiratory diseases of small ruminants: Field studies of over 10 years.

Objective: This study aimed to evaluate a new drug combination for small ruminant respiratory diseases to find a better treatment protocol for the potential replacement of older methods. Materials and Methods: A total of 6,886 animals received common respiratory disease therapies out of 15,845 animals that had respiratory disorders. The new combination therapy technique treated the remaining animals (8,968). The animals were given an oral suspension of triclabendazole or levamisole at an initial dosage of 0.2 ml/kg body weight (BW). The following day, 0.2 mg/kg of 1% ivermectin was subcutaneously administered. Then, on the third and fifth days of treatment, a subcutaneous injection of 30 mg/kg BW of florfenicol (30%) was administered. The survival and recovery rates for both groups were tracked throughout a 6-month period of observation. Postmortem and histopathological signs were also assessed. Results: In the group of the novel combination therapy, group A, clinical, postmortem, and histopathological signs were significantly reduced compared to group B. Clinical signs and mortality in group A were 90% and 93% lower than in group B, respectively. Animals that received the new combination therapy were healed of their disease and stayed immune for 6 months. Conclusion: This novel therapy demonstrated significant efficacy against respiratory diseases in a 10-year field study. The paper proved that the protocol introduced could be a new therapeutic approach.

Antitumor effects of erlotinib in combination with berberine in A431 cells.

BACKGROUND: First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, have been shown to target tumors with L858R (exon 21) and exon 19 deletions, resulting in significant clinical benefits. However, acquired resistance often occurs due to EGFR mutations. Therefore, novel therapeutic strategies for treatment of patients with EGFR-positive tumors are needed. Berberine (BBR) is an active alkaloid extracted from pharmaceutical plants such as Coptis chinensis. Berberine has been shown to significantly inhibit EGFR activity and mediate anticancer effects in multiple preclinical studies. We investigated whether combining BBR with erlotinib could augment erlotinib-induced cell growth inhibition of EGFR-positive cells in a mouse xenograft model. METHODS: We examined the antitumor activities and potential mechanisms of erlotinib in combination with berberine in vitro and in vivo using the MTT assay, immunoblotting, flow cytometry, and tumor xenograft models. RESULTS: In vitro studies with A431 cells showed that synergistic cell growth inhibition by the combination of BBR and erlotinib was associated with significantly greater inhibition of pEGFR and pAKT, and inhibition of cyclin D and Bcl-2 expression compared to that observed in response to BBR or erlotinib alone. The efficacy of the combination treatment was also investigated in nude mice. Consistent with the in vitro results, BBR plus erlotinib significantly reduced tumor growth. CONCLUSION: Our data supported use of BBR in combination with erlotinib as a novel strategy for treatment of patients with EGFR positive tumors.

Overexpression of Krüppel-Like Factor 9 Enhances the Antitumor Properties of Paclitaxel in Malignant Melanoma-Derived Cell Lines.

Over the past decade, the treatment of metastatic melanoma has improved significantly due to the development of innovative therapies, such as drugs that target the BRAF/MAPK kinase pathway and the PD-1 pathway. However, these therapies do not work for all patients, highlighting the need for additional research on the pathophysiology of melanoma. Paclitaxel is a chemotherapeutic agent used when first-line treatments are unsuccessful; however, its efficacy is limited. Since Krüppel-like factor 9 (KLF9) (antioxidant repressor) is downregulated in melanoma, we propose that restoring KLF9 levels may sensitize malignant melanoma to chemotherapeutic agents, such as paclitaxel. We used adenovirus overexpression and siRNA technologies to assess the role of KLF9 in mediating the response of malignant melanoma-derived cell lines RPMI-7951 and A375 to paclitaxel treatment. We found that increasing KLF9 levels potentiates the effectiveness of paclitaxel, as shown by apoptotic parameters such as decreased cell viability, pro-caspase-3 activation, increased number of annexin V-positive cells, and reduction in nuclear proliferation marker (KI67). These results suggest that KLF9 may be a potential target for improving chemotherapeutic response in melanoma.

Engineered extracellular vesicles: A novel platform for cancer combination therapy and cancer immunotherapy.

Extracellular vesicles (EVs), phospholipid membrane-bound vesicles, produced by most cells, contribute to cell-cell communication. They transfer several proteins, lipids, and nucleic acids between cells both locally and systemically. Owing to the biocompatibility and immune activity of EVs, therapeutic approaches using these vesicles as drug delivery systems are being developed. Different methods are used to design more effective engineered EVs, which can serve as smart tools in cancer therapy and immunotherapy. Recent progress in the field of targeted-cancer therapy has led to the gradual use of engineered EVs in combinational therapy to combat heterogeneous tumor cells and multifaceted tumor microenvironments. The high plasticity, loading ability, and genetic manipulation capability of engineered EVs have made them the ideal platforms to realize numerous combinations of cancer therapy approaches. From the combination therapy view, engineered EVs can co-deliver chemotherapy with various therapeutic agents to target tumor cells effectively, further taking part in immunotherapy-related cancer combination therapy. However, a greater number of studies were done in pre-clinical platforms and the clinical translation of these studies needs further scrutiny because some challenges are associated with the application of engineered EVs. Given the many therapeutic potentials of engineered EVs, this review discusses their function in various cancer combination therapy and immunotherapy-related cancer combination therapy. In addition, this review describes the opportunities and challenges associated with the clinical application of engineered EVs.

Cyclopentadienyl ruthenium(II) carbosilane metallodendrimers as a promising treatment against advanced prostate cancer.

In searching for efficient and selective antitumour drugs, a new family of carbosilane metallodendrimers functionalized with [Ru(η5-C5H5)(PTA)Cl] (PTA = 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1] decane) is reported. Experiments of the biophysical characterization showed an ability to interact with biological membranes, as well as with proteins (e.g. human serum albumin) without affecting their usual biological activity. These metallodendrimers possessed potent and selective anticancer activity in vitro in a panel of tumour cell lines. Importantly, the first generation metallodendrimer, bearing 4 Ru(II) complexes, was remarkably active towards resistant prostate cancer cells, inhibiting both cell proliferation and metastasis to bone tissues. Such promising antitumour activity can be further improved when given with docetaxel, with in vitro cytotoxicity being in the nanomolar range. Furthermore, its intravenous administration to an advanced prostate cancer mice model inhibited tumour growth up to 25% and 45% when given 10 mg/kg/week and 7.5 mg/kg/4-5 days, respectively.

Granulin A synergizes with cisplatin to inhibit the growth of human hepatocellular carcinoma / 中国药理学与毒理学杂志

OBJECTIVE Granulin A (GRN A), a cytokinesis protein, is derived from proteolysis of progranulin. The previous study in our laboratory has shown that GRN A is able to inhibit cancer cell growth significantly. This study aimed to investigate the effect of combination of GRN A and cisplatin on in vitro and in vivo on the growth of hepatocellular carcinoma. METHODS The in vitro and in vivo antitumor effects of combination of GRN A and Cisplatin were evaluated with MTS assay and subcuta-neous transplantation tumor model.Chou-Talalay method was used to calculate the combination index (CI). Colony formation assay and flow cytometry were used to detect the effects of GRN A on apoptosis. The expression of apoptosis-related proteins were detected by Western blot. RESULTS MTS assay showed that GRN A significantly inhibit hepatocellular carcinoma cells growth with the IC50of 5.6 μmol·L-1, and GRN A combined with cisplatin synergistically inhibit hepatocellular carcinoma proliferation, with the CI<1.The colony-formation assay showed that GRN A significantly enhanced the inhibitory effects of cisplatin on cellular anchorage-independent growth. Flow cytometry showed that GRN A combined with cisplatin synergistically induced apoptosis,with the apoptotic rates of 5.87%,32.74%,35.67% and 67.15% in control, GRN A, Cisplatin, and combination of GRN A and Cisplatin groups, respectively. Western blot confirmed that the two drugs synergistically changed the expressions of proteins related to apoptosis.In vivo experiment indicated that combination of GRN A and cisplatin significantly suppressed tumor growth compared with single drug treatment groups.CONCLUSION The combination of GRN A and cisplatin resulted in synergistic antitumor effects against hepatocellular carcinoma both in vitro and in vivo.

Terapias alternativas e combinadas para o tratamento da Leishmaniose Cutânea Americana: uma abordagem experimental in vitro e in vivo

A leishmaniose é uma doença tropical causada por protozoários do gêneroLeishmania que afeta 12 milhões de pessoas em 98 países. Seu tratamentoconta com um restrito arsenal terapêutico e exige a administração defármacos tóxicos por longos períodos. Na busca por novas terapias, oreposicionamento de fármacos e a associação terapêutica têm sidoaplicados com sucesso para doenças negligenciadas. O presente estudoteve como objetivo a avaliação in vitro, ex vivo e in vivo do potencial antiLeishmania(Leishmania) amazonensis dos fármacos amitriptilina, econazol,sertralina e triclosan, bem como o estudo de associações terapêuticas invitro e/ou ex vivo e mecanismo de ação in vitro dos fármacos amitriptilina etriclosan. Os resultados demonstraram que todos os fármacos estudados apresentaram atividade contra formas promastigotas e amastigotasintracelulares de L. (L.) amazonensis, com valores de Concentração Efetiva50% que variam de 1,50 a 51,48 µM. Os resultados obtidos a partir das associações entre os fármacos estudados e fármacos padrões foram classificados como aditivos ou indiferentes. Por meio da investigação domecanismo de ação leishmanicida, foi possível concluir que a mitocôndria é uma organela alvo do fármaco amitriptilina, enquanto que o fármaco triclosaninduz danos à membrana plasmática parasitária. Quando tratados comeconazol por via oral (10 mg/kg/dia por 28 dias consecutivos) ou triclosanpor via tópica (creme 1% por 14 dias consecutivos), houve uma redução de75 a 89% da carga parasitária dos camundongos infectados com L. (L.) amazonensis. Os resultados obtidos contribuem para a investigação de novas alternativas para o tratamento da leishmaniose cutânea e sugerem que novos estudos utilizando associação ou coadministração dessesfármacos com fármacos padrões podem ser promissores em modelosanimais.

Leishmaniasis is a tropical disease caused by protozoa of the genusLeishmania that affects 12 million people in 98 countries. There is a limitedtherapeutic arsenal and the treatment requires the administration of toxicdrugs for long periods. In the search for new therapies, the drug repositioningand therapeutic association have been successfully applied to neglecteddiseases. The aim of the present study was to evaluate in vitro, ex vivo andin vivo anti-Leishmania (Leishmania) amazonensis potential of the drugsamitriptyline, econazole, sertraline and triclosan, as well as the study of invitro and / or ex vivo therapeutic associations and mechanism of action of thedrugs amitriptyline and triclosan. The results showed that all studied drugshave activity against L. (L.) amazonensis promastigotes and intracellularamastigotes, with 50% Effective Concentration values ranging from 1.50 to51.48 μM. The results obtained from the combination between the studieddrugs and standard drugs were classified as additives or indifferent. Throughthe investigation of the leishmanicial mechanism of action, it was possible toconclude that the mitochondria is a target organelle of the drug amitriptyline,whereas the drug triclosan induces damage to the parasitic plasmamembrane. When treated with oral econazole (10 mg/kg/day for 28consecutive days) or triclosan topically (1% cream for 14 consecutive days),there was a 75 - 89% reduction in the parasite load of the mice infected withL. (L.) amazonensis. The results obtained contribute to the investigation ofnew alternatives for the treatment of cutaneous leishmaniasis and suggestthat new studies using association or coadministration of these drugs withstandard drugs may be promising in animal models.

In vitro investigations into the use of antimicrobials in combination to maintain efficacy of fluoroquinolones in poultry.

The aim of this study was to determine if apramycin, colistin or lincomycin-spectinomycin, in combination with enrofloxacin, was able prevent the emergence of mutants with reduced susceptibility to fluoroquinolone antibiotics in vitro. MICs were determined for enrofloxacin alone and in combination for panels of Campylobacter (n=37), Escherichia coli (n=52) and Salmonella (n=52) isolates. MIC results suggested that apramycin, colistin and lincomycin-spectinomycin worked in an additive/indifferent way when each was combined with enrofloxacin. Apramycin was considered the most promising antibiotic for combination-therapy in conjunction with enrofloxacin, and further evaluations (MBCs, MPCs and time-kill-curves) were performed for this combination for selected isolates. Results suggest combination-therapy of enrofloxacin with apramycin increases the efficacy, as well as decreasing the emergence and survival of bacteria with mutational resistance to fluoroquinolone antibiotics. Such combination-therapy, minimising the development of mutational resistance, may have relevance for Campylobacter, E. coli and Salmonella infections in poultry.

Benefit of initial dual-therapy on stroke prevention in Chinese hypertensive patients: a real world cohort study.

AIMS: Studies have shown that combination anti-hypertensive therapy is superior to mono-therapy in blood pressure control and prevention of cardiovascular events. However, whether such advantage exists in the prevention of stroke in Chinese hypertensive patients remains unclear. This study aimed to compare the impact of initial combination versus mono-therapy on stroke events in a large cohort of Chinese hypertensive patients. METHODS AND RESULTS: Hypertensive patients with uncontrolled blood pressure and without a history of stroke were screened from the Shanghai Community-dwelling Hypertensive Population Follow-up Database. Based on the initial treatment, individuals were divided into an initial mono-therapy group and initial dual combination group. Patients were followed for 42 months. 32,682 and 4,926 patients were included in the initial mono- and dual-therapy group. The achieved target blood pressure control rates of mono vs. combination groups at 6, 12, 24, and 42 months of follow-up, were 59.47% vs. 60.05%, 78.23% vs. 77.06%, 85.51% vs. 84.02%, and 86.90% vs. 85.44%, respectively. Their corresponding incidence densities of stroke were 0.792 vs. 0.489, 1.49 vs. 1.15, 2.79 vs. 2.38, and 4.25 vs. 4.32 (cases per 100 person-year), respectively. The 6-month incidence of stroke in dual-therapy group was significantly lower than mono-therapy group (adjusted HR 0.64; 95% CI: 0.30-0.93). However, no significant group differences in the incidence density were observed at 12, 24, and 42 months. CONCLUSIONS: Our study demonstrates that, for patients with uncontrolled hypertension, initial dual therapy is more effective in the prevention of stroke during the first 6 months of treatment, but not thereafter. Combination antihypertensive therapy may be a beneficial initial strategy for early stroke prevention.

Optimisation of prescription in patients with long-term treatment-resistant schizophrenia.

OBJECTIVE: The aim of this clinical review was to investigate the effectiveness and safety of the practice of antipsychotic poly-pharmacy (AP) in the long-term management of hospitalised patients with insufficient response to antipsychotic monotherapy. METHOD: The databases Medline, PsycINFO, Embase and Scopus were searched. Studies were required to include inpatients with long-term, treatment-resistant schizophrenia on maintenance AP. The search was restricted to systematic review studies. RESULTS: The review yielded four studies of interest that showed no categorical advantage for maintenance AP for the population of interest. However, clozapine combination faired marginally well. Particular weaknesses of the present literature are low number of participants, and inadequate monitoring of potential adverse effects. The evidence on the risks and benefits of maintenance AP is not generally considered adequate to warrant a recommendation for its use in routine clinical practice in psychiatry. CONCLUSIONS: This review provides a synthesis of the evidence on the maintenance use of AP for hospitalised patients with long-term, treatment-resistant schizophrenia. The results show both no support for AP with some marginal benefit for clozapine combination therapy, and methodological weaknesses of the included studies. These findings have clinical implications for treatment decisions and suggest that sufficiently powered studies are needed.

An evaluation of treatment strategies for head and neck cancer in an African American population / Evaluación de las estrategias del tratamiento para el cáncer de cabeza y cuello en una población afroamericana

OBJECTIVE: This study evaluated treatment strategies for head and neck cancers in a predominantly African American population. METHODS: Data were collected utilizing medical records and the tumour registry at the Howard University Hospital. Kaplan-Meier method was used for survival analysis and Cox proportional hazards regression analysis predicted the hazard of death. RESULTS: Analysis revealed that the main treatment strategy was radiation combined with platinum for all stages except stage I. Cetuximab was employed in only 1% of cases. Kaplan-Meier analysis revealed stage II patients had poorer outcome than stage IV while Cox proportional hazard regression analysis (p = 0.4662) showed that stage I had a significantly lower hazard of death than stage IV (HR = 0.314; p = 0.0272). Contributory factors included tobacco and alcohol but body mass index (BMI) was inversely related to hazard of death. CONCLUSIONS: There was no difference in survival using any treatment modality for African Americans.

OBJETIVO: Este estudio evaluó las estrategias del tratamiento para los cánceres de cabeza y cuello en una población predominantemente afroamericana. MÉTODOS: Se recopilaron datos utilizando historias clínicas y el registro de tumores del Hospital Universitario Howard. Se utilizó el método de Kaplan-Meier para el análisis de supervivencia, y el análisis de regresión de riesgos proporcionales de Cox para predecir los riesgos de muerte. RESULTADOS: El análisis reveló que la estrategia principal para el tratamiento fue la radiación combinada con platino para todas las etapas, excepto la etapa I. Se empleó cetuximab en sólo 1% de los casos. El análisis de Kaplan-Meier reveló que los pacientes de etapa II tuvieron resultados más pobres que los de la etapa IV, mientras que el análisis de regresión de riesgos proporcionales de Cox (p = 0.4662) mostró que la etapa I tenía un riesgo de muerte significativamente menor que la etapa IV (HR = 0.314; p = 0.0272). Los factores contribuyentes incluyeron el tabaco y el alcohol, pero el índice de masa (IMC) fue inversamente proporcional al riesgo de muerte. CONCLUSIONES: No hubo diferencias en la supervivencia con ninguna de las modalidades de tratamiento para los afroamericanos.