Looking for combination of benznidazole and Trypanosoma cruzi-triosephosphate isomerase inhibitors for Chagas disease treatment

BACKGROUND The current chemotherapy for Chagas disease is based on monopharmacology with low efficacy and drug tolerance. Polypharmacology is one of the strategies to overcome these limitations. OBJECTIVES Study the anti-Trypanosoma cruzi activity of associations of benznidazole (Bnz) with three new synthetic T. cruzi-triosephosphate isomerase inhibitors, 2, 3, and 4, in order to potentiate their actions. METHODS The in vitro effect of the drug combinations were determined constructing the corresponding isobolograms. In vivo activities were assessed using an acute murine model of Chagas disease evaluating parasitaemias, mortalities and IgG anti-T. cruzi antibodies. FINDINGS The effect of Bnz combined with each of these compounds, on the growth of epimastigotes, indicated an additive action or a synergic action, when combining it with 2 or 3, respectively, and an antagonic action when combining it with 4. In vivo studies, for the two chosen combinations, 2 or 3 plus one fifth equivalent of Bnz, showed that Bnz can also potentiate the in vivo therapeutic effects. For both combinations a decrease in the number of trypomastigote and lower levels of anti-T. cruzi IgG-antibodies were detected, as well clear protection against death. MAIN CONCLUSIONS These results suggest the studied combinations could be used in the treatment of Chagas disease.

Synergistic antifungal activity of the lipophilic fraction of Hypericum carinatum and fluconazole

ABSTRACT Hypericum species, Hypericaceae, are recognized as a source of therapeutical agents. Purified fractions and isolated compounds have been shown antimicrobial activity. As the indiscriminate use of antifungals and the increase of infections caused by emerging species are leading to the search of new alternative treatments, the aim of this study was to continue the study with Hypericum carinatum Griseb. lipophilic fraction, rich in phloroglucinol derivatives, investigating the effect of its association with fluconazole against emerging yeasts (Candida krusei, C. famata, C. parapsilosis and Cryptococcus neoformans). The synergistic activity between H. carinatum lipophilic fraction and fluconazole was assessed by two methodologies for multiple dose–response analysis: checkerboard and isobologram. Regarding synergistic experiments, the effect of the association was higher than the effect of fluconazole alone against Candida krusei and C. famata isolates (MIC fluconazole decreased about eight and four folds, respectively), suggesting that, somehow, H. carinatum lipophilic fraction compounds are facilitating the action of this drug. On the other hand, when tested against Cryptococcus neoformans and C. parapsilosis, fluconazole showed better results than the association. Thus, against Candida krusei and C. famata, the lipophilic fraction of H. carinatum was able to reduce the MIC values of fluconazole and could be considered as a potential alternative to be used against emerging yeast species.

Synergy effects of octreotide combined with cisplatin and 5-fluorouracil on inhibition of lung adenocarcinoma cell line A549 / 国际肿瘤学杂志

Objective To investigate whether octreotide,as somatostatin analogue,can enhance the sensitivity of the human lung adenocarcinoma cell line A549 to chemotherapeutic drugs.Methods Different concentration of octretide,cisplatin and 5-Fluorouracil (5-Fu) was respectively acted on the lung adenocarcinoma cell line A549.The absorbance value was tested by colorimetry through MTT method to evaluate the effect of octreotide,cisplatin,5-Fu or the three drugs combined respectively after 48 hours.Each drug concentration had six holes and it repeated three times.The effects of combination therapy was analysed with isobologram.Results It was proved that octreotide could inhibit the proliferation of A549 cells in a dose-dependent manner at the concentration range of 1.3 mg/L ～ 166.7 mg/L.The inhibition rate was dose-dependent which was higher when octreotide combined with cisplatin and 5-Fu than it alone.It has statistically significant difference (P ＜ 0.05 ).The effect plots of IC50 were located in the synergy areas of isobologram.Conclusion It can be concluded that octreotide could inhibit the proliferation of A549 cells in vitro.This inhibition enhances when octreotide is combined with cisplatin and 5-Fu.Octreotide can enhance the susceptibility of A549 cells to cisplatin and 5-Fu.

Investigation into in vitro anti-leishmanial combinations of calcium channel blockers and current anti-leishmanial drugs

The need for drug combinations to treat visceral leishmaniasis (VL) arose because of resistance to antimonials, the toxicity of current treatments and the length of the course of therapy. Calcium channel blockers (CCBs) have shown anti-leishmanial activity; therefore their use in combination with standard drugs could provide new alternatives for the treatment of VL. In this work, in vitro isobolograms of Leishmania (Leishmania) chagasi using promastigotes or intracellular amastigotes were utilised to identify the interactions between five CCBs and the standard drugs pentamidine, amphotericin B and glucantime. The drug interactions were assessed with a fixed ratio isobologram method and the fractional inhibitory concentrations (FICs), sum of FICs (ΣFICs) and the overall mean ΣFIC were calculated for each combination. Graphical isobologram analysis showed that the combination of nimodipine and glucantime was the most promising in amastigotes with an overall mean ΣFIC value of 0.79. Interactions between CCBs and the anti-leishmanial drugs were classified as indifferent according to the overall mean ΣFIC and the isobologram graphic analysis.

Isobolographic Analysis of the Hypnotic Interaction Between Propofol and Thiopental

Introduction: Giving two intravenous anaesthetic agents simultaneously generally results in an additive effect. The aim of this study was to investigate the interaction between propofoland thiopental when given to patients who have had sedative premedication. Methods: Fifty patients were admitted into the study. All patients received oral midazolam 3.75mg and intravenous fentanyl 100mg before induction of anaesthesia. Twenty patients received an infusion of their propofol or thiopental while 30 patients received an infusion of an admixture of both drugs. Results: The interaction between propofol and thiopental was additive. The average dose at loss of the eyelash reflex for propofol and thiopental was 0.71mg kg-1 and 1.54mg kg-1 respectively. Premedication decreased the induction dose by 38.2%. Conclusion: Propofol and thiopental interact in an additive fashion when given at induction of anaesthesia

Interactions of propofol and remifentanil on bispectral index under 66% N2O: analysis by dose-effect curve, isobologram, and combination index / 대한마취과학회지

BACKGROUND: Propofol and remifentanil are usually co-administered and have shown synergistic effect for anesthesia. However, the synergistic effect of the two drugs on hypnosis measured by bispectral index (BIS) was controversial in previous studies. The aim of this study was to identify the interaction of propofol and remifentanil on BIS and the optimal dose combinations for hypnosis under 66% N2O during surgery. METHODS: Patients (age 55-75 and American Society of Anesthesiologists [ASA] 1-2) undergoing gastrectomy were enrolled in this study. Propofol and remifentanil were co-administered incrementally at 1 : 1 potent ratio (the P1R1 group), at 1 : 2 potent ratio (the P1R2 group), or at 2 : 1 potent ratio (the P2R1 group) using effect site target-controlled infusion and BIS was measured. 66% N2O was concomitantly administered to all groups. The dose-effect curves, the 90% effective dose (EC90) for adequate hypnosis (BIS 40), isobolograms and combination index were obtained by Calcusyn program (Biosoft) to reveal the interaction of propofol and remifentanil. RESULTS: The P2R1 group showed synergistic action on BIS. However, the other groups needed larger amount of each drug than the doses of additive action. The EC90 of the P2R1 group was propofol, 3.34 microg/ml and remifentanil, 2.41 ng/ml under 66% of N2O. CONCLUSIONS: Propofol dominant co-administration is needed for dose reduction in BIS guided hypnosis.

A quantitative analysis of interactions among ethanol, chloral hydrate and naloxone / 中国新药与临床杂志

AIM: To analyse quantitatively the interactions among ethanol, chloral hydrate and naloxone with isobologram, Q-test and multiple logistic regression methods. METHODS: The hypnotic effects of the three drugs on Kunming mice were observed. In two drugs interaction study, chloral hydrate and ethanol were given at different ratios (25∶75, 50∶50, 78∶22 and 80∶20). In three drugs interactions study, 15 min after treatment of naloxone at fixed dose (0.5 mg*kg-1 and 0.2 mg*kg-1) the mixture of chloral hydrate and ethanol (at 1∶1 and 1∶3 ratio) was given to induce sleep. The ED50 for hypnotic action (righting reflex loss) of chloral hydrate, ethanol, naloxone and their mixtures were calculated by use of isobologram, interaction Q-index test and multivariate logistic regression analysis. RESULTS: The mixtures of ethanol and chloral hydrate in all ratios revealed partial but significant synergism. But in addition with naloxone the three agents showed different natures of interactions according to different naloxone levels. CONCLUSION: There are synergistic interactions in hypnotic ED50s between ethanol and chloral hydrate at different ratios and antagonistic interaction in adding a fixed dose of naloxone. The results coincide with the pharmacologistic mechanism discussed in this paper.

Enhanced Growth inhibition by Combined Gene Transfer of p53 and p16INK4a in Adenoviral Vectors to Lung Cancer Cell Lines / 결핵

BACKGROUND: Two tumor suppressor genes, p53 and p16, which have different roles in controlling the cell cycle and inducing apoptosis, are frequently inactivated during carcinogenesis including lung cancer. Single tumor suppressor gene therapies using tither with p53 or p16 have been studied extensively. However, there is a paucity of reports regarding a combined gene therapy using these two genes. METHODS: The combined effect of p53 and p16 gene transfer by the adenoviral vector on the growth of lung cancer cell lines and its interactive mechanism was investigated. RESULTS: An isobologram showed that the co-transduction of p53 and p16 exhibited a synergistic growth inhibitory effect on NCI H358 and an additive effect on NCI H23. Cell cycle analysis demonstrated the induction of a synergistic G1/S arrest by a combined p53 and p16 transfer. This synergistic interaction was again confirmed in a soft agar clonogenic assay. CONCLUSION: These observations suggest the potential of a p53 and p16 combination gene therapy as another potent strategy in cancer gene therapy.