RESUMO
Coronavirus disease 2019 (COVID-19) has caused a global pandemic since its onset in 2019, and the development of effective vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to induce potent and long-lasting immunity remains a priority. Herein, we prepared two Lactobacillus exopolysaccharide (EPS) nanoparticle adjuvants (NPs 7-4 and NPs 8-2) that were constructed by using sulfation-modified EPS and quaternization-modified chitosan. These two NPs displayed a spherical morphology with sizes of 39 and 47 nm. Furthermore, the zeta potentials of NPs 7-4 and NPs 8-2 were 50.40 and 44.40 mV, respectively. In vitro assays demonstrated that NPs could effectively adsorb antigenic proteins and exhibited a sustained release effect. Mouse immunization tests showed that the NPs induced the expression of cytokines and chemokines at the injection site and promoted the uptake of antigenic proteins by macrophages. Mechanically, the NPs upregulated the expression of pattern recognition receptors (toll-like receptors and nod-like receptors) and activated the immune response of T cells and the production of neutralizing antibodies. In addition, the NP adjuvants had favorable immune-enhancing effects in cats, which are of great significance for controlling the trans-host transmission and re-endemicity of SARS-CoV-2. Overall, we demonstrated that NP-adjuvanted SARS-CoV-2 receptor binding domain proteins could induce robust specific humoral and cellular immunity.
Assuntos
COVID-19 , Nanopartículas , Animais , Camundongos , Gatos , Vacinas contra COVID-19 , SARS-CoV-2 , Sulfatos/farmacologia , Adjuvantes Imunológicos/química , Nanopartículas/química , Adjuvantes Farmacêuticos/farmacologia , Imunidade Celular , Vacinas de Subunidades Antigênicas/farmacologiaRESUMO
Currently, certain cancer patients exhibit resistance to radiotherapy due to reduced DNA damage under hypoxic conditions and acquired immune tolerance triggered by transforming growth factor-ß1 (TGF-ß1) and membrane-localized programmed death ligand-1 (PD-L1). Meanwhile, cytoplasm-distributed PD-L1 induces radiotherapy resistance through accelerating DNA damage repair (DDR). However, the disability of clinically used PD-L1 antibodies in inhibiting cytoplasm-distributed PD-L1 limits their effectiveness. Therefore, a nanoadjuvant is developed to sensitize cancer to radiotherapy via multi-level immunity activation through depressing PD-L1 and TGF-ß1 by triphenylphosphine-derived metformin, and activating the cGAS-STING pathway by generating Mn2+ from MnO2 and producing more dsDNA via reversing tumor hypoxia and impairing DDR. Thus, Tpp-Met@MnO2@Alb effectively enhances the efficiency of radiotherapy to inhibit the progression of irradiated local and abscopal tumors and tumor lung metastases, offering a long-term memory of antitumor immunity without discernible side effects. Overall, Tpp-Met@MnO2@Alb has the potential to be clinically applied for overcoming radio-immunotherapy resistance.
Assuntos
Adjuvantes Farmacêuticos , Neoplasias Pulmonares , Neoplasias , Humanos , Antígeno B7-H1/antagonistas & inibidores , Imunoterapia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/terapia , Compostos de Manganês/farmacologia , Neoplasias/radioterapia , Neoplasias/terapia , Óxidos , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Adjuvantes Farmacêuticos/farmacologia , Adjuvantes Farmacêuticos/uso terapêutico , Nucleotidiltransferases/efeitos dos fármacos , Proteínas de Membrana/efeitos dos fármacosRESUMO
Sulfonamides are a conventional class of antibiotics that are well-suited to combat infections. However, their overuse leads to antimicrobial resistance. Porphyrins and analogs have demonstrated excellent photosensitizing properties and have been used as antimicrobial agents to photoinactivate microorganisms, including multiresistant Staphylococcus aureus (MRSA) strains. It is well recognized that the combination of different therapeutic agents might improve the biological outcome. In this present work, a novel meso-arylporphyrin and its Zn(II) complex functionalized with sulfonamide groups were synthesized and characterized and the antibacterial activity towards MRSA with and without the presence of the adjuvant KI was evaluated. For comparison, the studies were also extended to the corresponding sulfonated porphyrin TPP(SO3H)4. Photodynamic studies revealed that all porphyrin derivatives were effective in photoinactivating MRSA (>99.9% of reduction) at a concentration of 5.0 µM upon white light radiation with an irradiance of 25 mW cm-2 and a total light dose of 15 J cm-2. The combination of the porphyrin photosensitizers with the co-adjuvant KI during the photodynamic treatment proved to be very promising allowing a significant reduction in the treatment time and photosensitizer concentration by six times and at least five times, respectively. The combined effect observed for TPP(SO2NHEt)4 and ZnTPP(SO2NHEt)4 with KI seems to be due to the formation of reactive iodine radicals. In the photodynamic studies with TPP(SO3H)4 plus KI, the cooperative action was mainly due to the formation of free iodine (I2).
Assuntos
Iodo , Staphylococcus aureus Resistente à Meticilina , Fotoquimioterapia , Porfirinas , Infecções Estafilocócicas , Humanos , Fármacos Fotossensibilizantes/farmacologia , Staphylococcus aureus , Porfirinas/farmacologia , Antibacterianos/farmacologia , Sulfanilamida/farmacologia , Adjuvantes Imunológicos/farmacologia , Adjuvantes Farmacêuticos/farmacologia , Iodo/farmacologiaRESUMO
The poor cancer immunotherapy outcome has been closely related to immunosuppressive tumor microenvironment (TME), which usually inactivates the antitumor immune cells and leads to immune tolerance. Metalloimmunotherapy by supplementing nutritional metal ions into TME has emerged as a potential strategy to activate the tumor-resident immune cells. Herein, we engineered a magnesium-contained nano-aluminum adjuvant (NanoAlum) through hydrolyzing a mixture of Mg(OH)2 and Al(OH)3, which has highly similar components to commercial Imject Alum. Peritumoral injection of NanoAlum effectively neutralized the acidic TME while releasing Mg2+ to activate the tumor-resident T cells. Meanwhile, NanoAlum also blocked the autophagy pathway in tumor cells and subsequently induced cell apoptosis. The in vivo studies showed that merely peritumoral injection of NanoAlum successfully inhibited the growth of solid tumors in mice. On this basis, NanoAlum combined with chemical drug methotrexate or immunomodulatory adjuvant CpG further induced potent antigen-specific antitumor immunity. Overall, our study first provides a rational design for engineering tumor-targeted nanomodulator from clinical adjuvants to achieve effective cancer metalloimmunotherapy against solid tumors.
Assuntos
Alumínio , Neoplasias , Animais , Camundongos , Alumínio/farmacologia , Alumínio/uso terapêutico , Adjuvantes Imunológicos/farmacologia , Neoplasias/tratamento farmacológico , Imunoterapia , Linfócitos T , Adjuvantes Farmacêuticos/farmacologia , Microambiente TumoralRESUMO
The decades-long effort to deliver peptide drugs orally has resulted in several clinically successful formulations. These formulations are enabled by the inclusion of permeation enhancers that facilitate the intestinal absorption of peptides. Thus far, these oral peptide drugs have been limited to peptides less than 5 kDa, and it is unclear whether there is an upper bound of protein size that can be delivered with permeation enhancers. In this work, we examined two permeation enhancers, 1-phenylpiperazine (PPZ) and sodium deoxycholate (SDC), for their ability to increase intestinal transport of a model macromolecule (FITC-Dextran) as a function of its size. Specifically, the permeability of dextrans with molecular weights of 4, 10, 40, and 70 kDa was assessed in an in vitro and in vivo model of the intestine. In Caco-2 monolayers, both PPZ and SDC significantly increased the permeability of only FD4 and FD10. However, in mice, PPZ and SDC behaved differently. While SDC improved the absorption of all tested sizes of dextrans, PPZ was effective only for FD4 and FD10. This work is the first report of PPZ as a permeation enhancer in vivo, and it highlights the ability of permeation enhancers to improve the absorption of macromolecules across a broad range of sizes relevant for protein drugs.
Assuntos
Adjuvantes Farmacêuticos/farmacologia , Ácido Desoxicólico/farmacologia , Absorção Intestinal/efeitos dos fármacos , Substâncias Macromoleculares/administração & dosagem , Substâncias Macromoleculares/metabolismo , Piperazinas/farmacologia , Administração Oral , Animais , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Humanos , Camundongos , PermeabilidadeRESUMO
Fucoxanthin (Fx) is a carotenoid derived from marine organisms that exhibits anticancer activities. However, its role as a potential drug adjuvant in breast cancer (BC) treatment is still poorly explored. Firstly, this study investigated the cytotoxic effects of Fx alone and combined with doxorubicin (Dox) and cisplatin (Cis) on a panel of 2D-cultured BC cell lines (MCF7, SKBR3 and MDA-MB-231) and one non-tumoral cell line (MCF12A). Fucoxanthin induced cytotoxicity against all the cell lines and potentiated Dox cytotoxic effects towards the SKBR3 and MDA-MB-231 cells. The combination triggering the highest cytotoxicity (Fx 10 µM + Dox 1 µM in MDA-MB-231) additionally showed significant induction of cell death and genotoxic effects, relative to control. In sequence, the same combination was tested on 3D cultures using a multi-endpoint approach involving bioactivity assays and microscopy techniques. Similar to 2D cultures, the combination of Fx and Dox showed higher cytotoxic effects on 3D cultures compared to the isolated compounds. Furthermore, this combination increased the number of apoptotic cells, decreased cell proliferation, and caused structural and ultrastructural damages on the 3D models. Overall, our findings suggest Fx has potential to become an adjuvant for Dox chemotherapy regimens in BC treatment.
Assuntos
Adjuvantes Farmacêuticos/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Xantofilas/farmacologia , Técnicas de Cultura de Células , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , HumanosRESUMO
The limitations of cisplatin, a standard chemotherapy for lung cancer, have been documented with serious adverse effects and drug resistance. To address the need for novel therapy, this study firstly reveals the potential of peptide from Lentinus squarrosulus (Mont.) as a chemotherapeutic adjuvant for cisplatin treatment. The purified peptide from L. squarrosulus aqueous extracts was obtained after eluting with 0.4 M NaCl through FPLC equipped with anion exchange column. Preincubation for 24 h with 5 µg/mL of the peptide at prior to treatment with 5 µM cisplatin significantly diminished %cell viability in various human lung cancer cells but not in human dermal papilla and proximal renal cells. Flow cytometry indicated the augmentation of cisplatin-induced apoptosis in lung cancer cells pretreated with peptide from L. squarrosulus. Preculture with the peptide dramatically inhibited colony formation in lung cancer cells derived after cisplatin treatment. Strong suppression on integrin-mediated survival was evidenced with the diminution of integrins (ß1, ß3, ß5, α5, αV) and down-stream signals (p-FAK/FAK, p-Src/Src, p-Akt/Akt) consequence with alteration of p53, Bax, Blc-2 and Mcl-1 in cisplatin-treated lung cancer cells preincubated with peptide from L. squarrosulus. These results support the development of L. squarrosulus peptide as a novel combined chemotherapy with cisplatin for lung cancer treatment.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Lentinula/química , Neoplasias Pulmonares/tratamento farmacológico , Peptídeos/uso terapêutico , Extratos Vegetais/uso terapêutico , Adjuvantes Farmacêuticos/farmacologia , Adjuvantes Farmacêuticos/uso terapêutico , Western Blotting , Linhagem Celular Tumoral , Sinergismo Farmacológico , Citometria de Fluxo , Humanos , Peptídeos/isolamento & purificação , Peptídeos/farmacologia , Extratos Vegetais/farmacologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Centella asiatica (CA) is commonly used herbal medicine for treatment of epilepsy. CA has CYP2C9, CYP2D6 and CYP3A4 enzymes inhibition property and used as an adjuvant therapy with conventional antiepileptic drugs (AEDs). That may be responsible for herb-drug interaction. AIM OF THE STUDY: The present study was planned to evaluate interactions profile of hydroalcoholic extract Centella asiatica (HECA) with antiepileptic drugs in experimental models of epilepsy in rats. MATERIALS AND METHODS: Wistar rats (175-200 g) were used. In the pharmacodynamic interaction study, seizures were induced using pentylenetetrazole (PTZ) (60 mg/kg, i.p.) and maximal electroshock seizure (MES) (70 mA for 0.2 s). The therapeutic and sub-therapeutic doses of valproate (VPA) and phenytoin (PHT) were co-administrated with HECA in PTZ and MES model of seizures respectively. Behavioural parameters were assessed using elevated plus maze test and passive avoidance paradigm. Rat brain oxidative stress parameters were also assessed. In the pharmacokinetic interaction study, the serum levels of the VPA and PHT were estimated at different time intervals by HPLC and pharmacokinetic parameters were analyzed by WinNonlin software. RESULTS: The VPA and PHT produced complete protection against seizures in their therapeutic doses but not with sub-therapeutic doses. However, co-administration of HECA with a sub-therapeutic dose of VPA and PHT enhanced the protection of seizures and significantly (p < 0.001) attenuated the seizure induced oxidative stress and cognitive impairment. It also significantly increased (p < 0.001) serum levels of VPA and PHT. The alterations in pharmacokinetic parameters (maximum serum concentration, area under the curve, clearance) of AEDs were also found with co-administration of HECA. CONCLUSION: The results suggested that co-administration of HECA could improve the therapeutic efficacy of VPA and PHT. But, alteration in pharmacokinetic parameters revel that needs critical medical supervision to avoid any toxic reactions.
Assuntos
Anticonvulsivantes/farmacologia , Centella/química , Epilepsia/tratamento farmacológico , Interações Ervas-Drogas , Fenitoína/farmacologia , Extratos Vegetais/farmacologia , Ácido Valproico/farmacologia , Adjuvantes Farmacêuticos/química , Adjuvantes Farmacêuticos/farmacocinética , Adjuvantes Farmacêuticos/farmacologia , Animais , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacocinética , Comportamento Animal/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Inibidores das Enzimas do Citocromo P-450/farmacologia , Modelos Animais de Doenças , Eletrochoque/efeitos adversos , Epilepsia/induzido quimicamente , Glutationa/metabolismo , Malondialdeído/metabolismo , Ayurveda , Metanol/química , Estresse Oxidativo/efeitos dos fármacos , Pentilenotetrazol/toxicidade , Fenitoína/sangue , Fenitoína/farmacocinética , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Folhas de Planta/química , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Ácido Valproico/sangue , Ácido Valproico/farmacocinéticaRESUMO
INTRODUCTION: Aromatase inhibitor (AI)-associated bone loss increases the risk of bone fracture and reduces patients' quality of life, making it a critical issue worldwide. We conducted a prospective non-randomized clinical trial (UMIN-CTR, UMIN 000016173) to assess the effect of denosumab on bone loss in patients treated with adjuvant AI and have previously reported the results at 12 and 24 months. This study aimed to present the results at 36 months of treatment with denosumab for osteopenia in breast cancer patients who were undergoing treatment with adjuvant AI; 36 months is the longest denosumab treatment period reported so far. MATERIALS AND METHODS: Patients received 60-mg denosumab subcutaneously every 6 months. Daily supplements containing 500-mg elemental calcium and at least 400 international units of vitamin D were highly recommended throughout the study period. The levels of bone mineral density (BMD) and bone turnover markers, serum tartrate-resistant acid phosphatase isoform 5b, and bone alkaline phosphatase were determined at baseline and 6, 12, 18, 24, and 36 months. RESULTS: At 36 months, the bone mineral density of the lumbar spine, right femoral neck, and left femoral neck were found to increase by 8.8% (95% confidence interval CI 7.6-10.1), 4.3% (95% CI 3.0-5.5), and 3.1% (95% CI 2.1-4.1), respectively. No non-traumatic clinical fractures occurred in patients receiving AI and denosumab. CONCLUSION: Twice-yearly administration of denosumab to the breast cancer patients treated with adjuvant AI, regardless of the skeletal site, resulted in consistent increases in BMD without severe adverse events at 36 months.
Assuntos
Adjuvantes Farmacêuticos/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Denosumab/uso terapêutico , Adjuvantes Farmacêuticos/farmacologia , Idoso , Idoso de 80 Anos ou mais , Fosfatase Alcalina/sangue , Inibidores da Aromatase/farmacologia , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Neoplasias da Mama/sangue , Denosumab/efeitos adversos , Denosumab/farmacologia , Feminino , Fraturas Ósseas/sangue , Fraturas Ósseas/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Fosfatase Ácida Resistente a Tartarato/sangueRESUMO
Breast cancer is one of the most common cancers in women and is associated with a high mortality rate. The majority of deaths resulting from breast cancer are attributable to metastatic growth; in addition, chemoresistance is a major concern in the treatment of patients with breast cancer. However, limited drugs are available for the treatment of metastatic breast cancer. In this study, the chemoadjuvant effects of a methanolic extract from the leaves of Pseudolysimachion rotundum var. subintegrum (NC13) and an active component isolated from the plant, verminoside (Vms), were evaluated. Furthermore, their potent anti-metastatic activities were validated in vitro and in vivo in animal models. The anti-metastatic and chemosensitizing activities of NC13 and Vms on cisplatin treatment were found to be partly mediated by suppression of the epithelial-mesenchymal transition of cancer cells. Collectively, our results implied that NC13 and its bioactive component Vms could be developed as effective chemoadjuvants in combination with conventional therapeutics.
Assuntos
Adjuvantes Farmacêuticos/farmacologia , Antineoplásicos/administração & dosagem , Neoplasias da Mama/metabolismo , Cisplatino/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Iridoides/farmacologia , Fitoterapia/métodos , Extratos Vegetais/farmacologia , Veronica/química , Aloenxertos , Animais , Neoplasias da Mama/dietoterapia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Dieta , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica/tratamento farmacológico , Folhas de Planta/químicaRESUMO
CD8+ T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1, an interaction acts like brakes to prevent T cell overreaction under normal conditions but is exploited by tumor cells to escape the immune surveillance. Immune checkpoint inhibitors have revolutionized cancer therapeutics by removing such brakes. Unfortunately, only a minority of cancer patients respond to immunotherapies presumably due to inadequate immunity. Antitumor immunity depends on the activation of the cGAS-STING pathway, as STING-deficient mice fail to stimulate tumor-infiltrating dendritic cells (DCs) to activate CD8+ T cells. STING agonists also enhance natural killer (NK) cells to mediate the clearance of CD8+ T cell-resistant tumors. Therefore STING agonists have been intensively sought after. We previously discovered that manganese (Mn) is indispensable for the host defense against cytosolic dsDNA by activating cGAS-STING. Here we report that Mn is also essential in innate immune sensing of tumors and enhances adaptive immune responses against tumors. Mn-insufficient mice had significantly enhanced tumor growth and metastasis, with greatly reduced tumor-infiltrating CD8+ T cells. Mechanically, Mn2+ promoted DC and macrophage maturation and tumor-specific antigen presentation, augmented CD8+ T cell differentiation, activation and NK cell activation, and increased memory CD8+ T cells. Combining Mn2+ with immune checkpoint inhibition synergistically boosted antitumor efficacies and reduced the anti-PD-1 antibody dosage required in mice. Importantly, a completed phase 1 clinical trial with the combined regimen of Mn2+ and anti-PD-1 antibody showed promising efficacy, exhibiting type I IFN induction, manageable safety and revived responses to immunotherapy in most patients with advanced metastatic solid tumors. We propose that this combination strategy warrants further clinical translation.
Assuntos
Imunidade/efeitos dos fármacos , Imunoterapia , Manganês/farmacologia , Proteínas de Membrana/metabolismo , Neoplasias/imunologia , Neoplasias/terapia , Nucleotidiltransferases/metabolismo , Adjuvantes Farmacêuticos/farmacologia , Adulto , Idoso , Animais , Apresentação de Antígeno/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Células Dendríticas/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Interferon Tipo I/metabolismo , Células Matadoras Naturais/imunologia , Pulmão/patologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neoplasias/patologia , Tamanho do Órgão/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacosRESUMO
There is a growing consensus that the antioxidant and anti-inflammatory properties of melatonin are of great importance in preserving the body functions and homeostasis, with great impact in the peripartum period and adult life. Melatonin promotes adaptation through allostasis and stands out as an endogenous, dietary, and therapeutic molecule with important health benefits. The anti-inflammatory and antioxidant effects of melatonin are intertwined and are exerted throughout pregnancy and later during development and aging. Melatonin supplementation during pregnancy can reduce ischemia-induced oxidative damage in the fetal brain, increase offspring survival in inflammatory states, and reduce blood pressure in the adult offspring. In adulthood, disturbances in melatonin production negatively impact the progression of cardiovascular risk factors and promote cardiovascular and neurodegenerative diseases. The most studied cardiovascular effects of melatonin are linked to hypertension and myocardial ischemia/reperfusion injury, while the most promising ones are linked to regaining control of metabolic syndrome components. In addition, there might be an emerging role for melatonin as an adjuvant in treating coronavirus disease 2019 (COVID 19). The present review summarizes and comments on important data regarding the roles exerted by melatonin in homeostasis and oxidative stress and inflammation related pathologies.
Assuntos
Adjuvantes Farmacêuticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Melatonina/administração & dosagem , Melatonina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Adjuvantes Farmacêuticos/administração & dosagem , Adjuvantes Farmacêuticos/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , COVID-19 , Homeostase/efeitos dos fármacos , Humanos , Melatonina/farmacologia , PandemiasRESUMO
The lack of novel classes of antibiotics as well as the constant increase of multidrug resistant bacteria are leaving the clinicians disarmed to treat bacterial infections, especially those caused by Gram-negative pathogens. Among all the investigated solutions, the design of adjuvants able to enhance antibiotics activities appears to be one of the most promising. In this context, a polyamino-isoprenyl derivative has been recently identified to be able to potentiate, at a very low concentration the activity of doxycycline against P. aeruginosa bacterial strains by increasing its intracellular concentration. On the other hand, since aerosol therapy allows a rapid drug administration and targets the respiratory system by avoiding the first pass effect and minimizing undesirable systemic effects, we have developed the first adjuvant/antibiotic combination in an aerosolized form and demonstrated the feasibility of such an approach. Thus, combination aerosol droplets have been demonstrated in sizes suitable for inhalation (3.4 and 4.4 µm mass median aerodynamic diameter and 54 and 60% of the aerodynamic particle size distribution less than 5 µm, as measured for the adjuvant NV716 and doxycycline, respectively and with properties (stoichiometric 1:1 ratio of NV716 salt to drug) that would support further development as an inhaled dosage form. Taken together, our results suggest that these molecules could be successfully delivered at the requested concentration in the lungs and then able to decrease drug consumption as well as increase treatment efficacy.
Assuntos
Adjuvantes Farmacêuticos/farmacologia , Antibacterianos/farmacologia , Doxiciclina/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Adjuvantes Farmacêuticos/administração & dosagem , Administração por Inalação , Aerossóis , Antibacterianos/administração & dosagem , Doxiciclina/administração & dosagem , Farmacorresistência Bacteriana Múltipla , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Poliaminas/administração & dosagem , Poliaminas/farmacologia , Infecções por Pseudomonas/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/isolamento & purificação , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologiaRESUMO
The widespread adaptation of a new generation of direct-acting antiviral agents (DAAs) unveils a superlative effect in the eradication of the hepatitis C virus (HCV). However, this therapy has been reported to exhibit vigorous side effects that pose a risk in fleet recovery. This study was conducted to investigate the efficacy of DAAs: sofosbuvir (SOF) and ribavirin (RBV), along with black cumin (BLC) and ascorbate (ASC), as adjuvants on hematological parameters; oxidative stress markers such as total antioxidant status (TAS), superoxide dismutase (SOD), reduced (GSH) and oxidized (GSSG) glutathione (GSH), gamma-glutamyl transferase (GGT), and malondialdehyde (MDA); liver function markers such as aspartate transaminase (AST), alanine aminotransferase (ALT), bilirubin, and alkaline phosphatase (ALP); and viral load with determined genotypes. HCV-infected patients (n = 30) were randomly divided into two equal groups: control group (n = 15) and treatment group (n = 15). The control group was subjected only to SOF and RBV (400 mg each/day). Synergistically, the treatment group was administered with adjuvant therapy of BLC (250 mg/day) and ASC (1000 mg/day) along with DAAs (400 mg each/day) for 8 weeks. All selected patients were subjected to sampling at pre- and posttreatment stages for the assessment of defined parameters. The data revealed that the BLC/ASC adjuvant therapy boosted the efficacy of DAAs by reducing the elevated levels of liver markers such as AST, ALT, ALP, and bilirubin in the treatment group compared with those in the control group (P > 0.05). The adjuvant therapy synchronously showed an ameliorating effect on hematological parameters. The SOF/RBV with adjuvant therapy also demonstrated an increasing effect in the activity of SOD, TAS, and GSH and a decreasing effect for GSSG, GGT, and malondialdehyde (MDA; P > 0.05) followed by curtailing a RT-PCR-quantified viral load. Our findings provide evidence that systemic administration of BLC/ASC efficiently alleviates hematological, serological, and antioxidant markers as well as the viral load in hepatitis C patients. This highlights a potentially novel role of BLC and ASC in palliating hepatitis C.
Assuntos
Adjuvantes Farmacêuticos/uso terapêutico , Antioxidantes/uso terapêutico , Antivirais/uso terapêutico , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Nigella sativa/química , Adjuvantes Farmacêuticos/farmacologia , Antioxidantes/farmacologia , Antivirais/farmacologia , Ácido Ascórbico/efeitos adversos , Biomarcadores/sangue , Glutationa/sangue , Hepacivirus/genética , Hepatite C Crônica/sangue , Hepatite C Crônica/fisiopatologia , Hepatite C Crônica/virologia , Humanos , Testes de Função Hepática , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Superóxido Dismutase/metabolismo , gama-Glutamiltransferase/sangueRESUMO
The latest WHO report estimates about 1.6 million global deaths annually from TB, which is further exacerbated by drug-resistant (DR) TB and comorbidities with diabetes and HIV. Exiguous dosing, incomplete treatment course, and the ability of the tuberculosis bacilli to tolerate and survive current first-line and second-line anti-TB drugs, in either their latent state or active state, has resulted in an increased prevalence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant TB (TDR-TB). Although a better understanding of the TB microanatomy, genome, transcriptome, proteome, and metabolome, has resulted in the discovery of a few novel promising anti-TB drug targets and diagnostic biomarkers of late, no new anti-TB drug candidates have been approved for routine therapy in over 50 years, with only bedaquiline, delamanid, and pretomanid recently receiving tentative regulatory approval. Considering this, alternative approaches for identifying possible new anti-TB drug candidates, for effectively eradicating both replicating and non-replicating Mycobacterium tuberculosis, are still urgently required. Subsequently, several antibiotic and non-antibiotic drugs with known treatment indications (TB targeted and non-TB targeted) are now being repurposed and/or derivatized as novel antibiotics for possible use in TB therapy. Insights gathered here reveal that more studies focused on drug-drug interactions between licensed and potential lead anti-TB drug candidates need to be prioritized. This write-up encapsulates the most recent findings regarding investigational compounds with promising anti-TB potential and drugs with repurposing potential in TB therapy.
Assuntos
Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Reposicionamento de Medicamentos , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adjuvantes Farmacêuticos/química , Adjuvantes Farmacêuticos/farmacologia , Adjuvantes Farmacêuticos/uso terapêutico , Animais , Antituberculosos/química , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos/tendências , Quimioterapia Combinada/tendências , Humanos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêuticoRESUMO
BACKGROUND: Piper chaba Hunt. is used as an ingredient in Thai traditional preparation for arthritis. Its isolated compound is piperine which shows anti-inflammatory activity. Piperine produces a burning sensation because it activates TRPV1 receptor. The TRPV1 activation involved with the analgesic and adjuvant effect. P. chaba Hunt. has not been reported about TRPV1 activation and adjuvant effect. The aim of this study was to investigate the effect of P. chaba extract and piperine on TRPV1 receptor, which is considered as a target for analgesic and their adjuvant effects to support the development of an analgesic drug from herbal medicine. METHODS: The effect of P. chaba extract and piperine on HEK cells expressing TRPV1 channel was examined by calcium imaging assay. Adjuvant effects of P. chaba extract and piperine were investigated by a fluorescein isothiocyanate (FITC)-induced contact hypersensitivity (CHS) model in mice. RESULTS: P. chaba extract induced calcium influx with EC50 value of 0.67 µg/ml. Piperine induced calcium influx with EC50 value of 0.31 µg/ml or 1.08 µM. For mouse CHS model, we found that 1% piperine, 5% piperine, 1% P. chaba extract and 5% P. chaba extract significantly enhanced sensitization to FITC as revealed by ear swelling responses. CONCLUSION: P. chaba extract and piperine activated TRPV1 channel and enhanced contact sensitization to FITC.
Assuntos
Adjuvantes Farmacêuticos/farmacologia , Alcaloides/farmacologia , Benzodioxóis/farmacologia , Piper , Piperidinas/farmacologia , Extratos Vegetais/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Canais de Cátion TRPV/metabolismo , Adjuvantes Farmacêuticos/química , Alcaloides/química , Animais , Benzodioxóis/química , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Piperidinas/química , Extratos Vegetais/química , Alcamidas Poli-Insaturadas/química , TailândiaRESUMO
BACKGROUND: Adrenaline (Adr) and dexmedetomidine (Dex) are commonly used adjuvants of local anesthetics; however, the difference in the improvement of analgesia of local anesthetics between the 2 adjuvants remains unclear. OBJECTIVE: The objective of this experimental research was to evaluate the cutaneous analgesic effect of mexiletine (Mex) by coadministration with Dex or Adr. METHODS: The effect of a nociceptive block was assessed based on the inhibition of the cutaneous trunci muscle reflex in response to skin pinpricks in rats. The analgesic activity of Mex alone and Mex coadministered with Dex or Adr was evaluated after subcutaneous injections. Subcutaneous injections of drugs or combinations include Mex 0.6, 1.8, and 6.0 µmol; Adr 13.66 nmol; Dex 1.05600 nmol; saline; and Mex 1.8 and 6.0 µmol, respectively, combined with Dex 0.01056, 0.10560, and 1.05600 nmol or Adr 0.55, 2.73, and 13.66 nmol, with each injection dose of 0.6 mL. RESULTS: Subcutaneous injections of Mex elicited dose-related cutaneous analgesia. Compared with Mex (1.8 µmol), adding Dex or Adr to Mex (1.8 µmol) solutions for skin nociceptive block potentiated and prolonged the action. Mex (6.0 µmol) combined with Dex or Adr extended the duration of cutaneous analgesia when compared with Mex (6.0 µmol) alone. A high dose of Adr is more effective with Mex 1.8 µmol than that of Dex, whereas medium and low doses were less effective. Mex 6.0 µmol combined with any dose of Adr is superior to that of Dex. CONCLUSIONS: Both Dex and Adr improve the sensory block and enhance the nociceptive block duration of Mex. But in most cases, Adr is superior to Dex. It may be that different mechanisms of action of the 2 adjuvants lead to the differences.
Assuntos
Adjuvantes Farmacêuticos/farmacologia , Anestésicos Locais/farmacologia , Dexmedetomidina/farmacologia , Epinefrina/farmacologia , Mexiletina/farmacologia , Dor Nociceptiva/tratamento farmacológico , Adjuvantes Farmacêuticos/administração & dosagem , Analgesia/métodos , Anestesia Local/métodos , Anestésicos Locais/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Dexmedetomidina/administração & dosagem , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Epinefrina/administração & dosagem , Injeções Subcutâneas , Masculino , Mexiletina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Reflexo/efeitos dos fármacos , Pele/efeitos dos fármacosRESUMO
Colorectal cancer (CRC) is one of the most widespread and deadly types of neoplasia around the world, where the inflammatory microenvironment has critical importance in the process of tumor growth, metastasis, and drug resistance. Despite its limited effectiveness, 5-fluorouracil (5-FU) is the main drug utilized for CRC treatment. The combination of 5-FU with other agents modestly increases its effectiveness in patients. Here, we evaluated the anti-inflammatory Trimethylglycine and the Signal transducer and activator of transcription (STAT6) inhibitor AS1517499, as possible adjuvants to 5-FU in already established cancers, using a model of colitis-associated colon cancer (CAC). We found that these adjuvant therapies induced a remarkable reduction of tumor growth when administrated together with 5-FU, correlating with a reduction in STAT6-phosphorylation. This reduction upgraded the effect of 5-FU by increasing both levels of apoptosis and markers of cell adhesion such as E-cadherin, whereas decreased epithelial-mesenchymal transition markers were associated with aggressive phenotypes and drug resistance, such as ß-catenin nuclear translocation and Zinc finger protein SNAI1 (SNAI1). Additionally, Il-10, Tgf-ß, and Il-17a, critical pro-tumorigenic cytokines, were downmodulated in the colon by these adjuvant therapies. In vitro assays on human colon cancer cells showed that Trimethylglycine also reduced STAT6-phosphorylation. Our study is relatively unique in focusing on the effects of the combined administration of AS1517499 and Trimethylglycine together with 5-FU on already established CAC which synergizes to markedly reduce the colon tumor load. Together, these data point to STAT6 as a valuable target for adjuvant therapy in colon cancer.
Assuntos
Adjuvantes Farmacêuticos/uso terapêutico , Carcinogênese/patologia , Colite/complicações , Neoplasias do Colo/tratamento farmacológico , Fluoruracila/uso terapêutico , Glicina/uso terapêutico , Pirimidinas/uso terapêutico , Fator de Transcrição STAT6/metabolismo , Adjuvantes Farmacêuticos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caderinas/metabolismo , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Colite/patologia , Neoplasias do Colo/etiologia , Neoplasias do Colo/patologia , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Fluoruracila/farmacologia , Glicina/farmacologia , Humanos , Inflamação/patologia , Camundongos Endogâmicos BALB C , Monócitos/metabolismo , Fosforilação/efeitos dos fármacos , Pirimidinas/farmacologia , beta Catenina/metabolismoRESUMO
Despite major advances in the last 10 years, whether in terms of prevention or treatment, the 5 year survival rate remains relatively low for a large number of cancers. These therapeutic failures can be the consequence of several factors associated with the cellular modifications or with the host by itself, especially for some anticancer drugs such as cisplatin, which induces a nephrotoxicity. In the strategy of research for active molecules capable both of exerting a protective action against the deleterious effects of cisplatin and exerting a chemosensitizing action with regard to cancer cells, we tested the potential effects of Ephedra alata Decne extract (E.A.) rich in polyphenolic compounds towards a 4T1 breast cancer model in vitro and in vivo. We showed that E.A. extract inhibited cell viability of 4T1 breast cancer cells and induced apoptosis in a caspase-dependent manner, which involved intrinsic pathways. Very interestingly, we observed a synergic antiproliferative and pro-apoptotic action with cisplatin. These events were associated with a strong decrease of breast tumor growth in mice treated with an E.A./cisplatin combination and simultaneously with a decrease of hepato- and nephrotoxicities of cisplatin.
Assuntos
Adjuvantes Farmacêuticos/farmacologia , Neoplasias da Mama/patologia , Cisplatino/farmacologia , Ephedra/química , Neoplasias Mamárias Animais/patologia , Animais , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Feminino , Concentração Inibidora 50 , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , Fenóis , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
Background Hypertension is a cardiovascular disease which has become a major health problem in Indonesia. Left ventricle hypertrophy is one of the cardiac complications of hypertension that is characterized by thickening of the left ventricle and increasing the mass of cardiac muscle. Methods This study was an experimental study with a posttest group design. Twenty-four mice were divided into four groups. The normal group was given distilled water, the negative control group was given L-NAME 1.75 mg/25 g BW/day, the positive control group was given L-NAME 1.75 mg/25 g BW/day + captopril 0.04875 mg/30 g BW/day, and the adjuvant captopril group was given L-NAME 1.75 mg/25 g BW/day + captopril 0.04875 mg/30 g BW/day + curcuma extract 31.25 mg/30 g BW for 30 days. Results The results of one-way analysis of variance (ANOVA) test analysis on the adjuvant treatment of the captopril group revealed no significant effect on cardiac muscle mass (p > 0.05), while the thickness of the left ventricle was significant (p < 0.05). Conclusions Captopril-Curcuma group resulted in a decrease of cardiac muscle and the thickness of the left ventricle in male mice with hypertension.