Trend Analysis of Combined Drugs Creation （for Example Acetylsalicylic Acid）

The pharmaceutical market of Ukraine in January 2015 was registered 71 drug based acetylsalicylic acid （ASA）, for which 52% combined. The most common combinations of ASA with acetaminophen and caffeine （45.9%）, magnesium hydroxide （18.9%）, bisoprolol （10.8%）, ascorbic acid （8.1%）, clopidogrel （5.4%）. Comparing markets combined drugs ASA of Ukraine, the Russian Federation, 28 EU countries, Norway, Switzerland, India, Syria, Australia and the USA identified the active pharmaceutical ingredients, combined with ASA in a single dosage form. The analysis of questionnaires 40 pharmacists pharmacies Temopil, Khmelnytsky and Kyiv regions of Ukraine noted that the biggest demand is mono-drugs ASA, Citramon, Askofen and Cardiomagnyl Methods of pharmacoeconomic studies proved efficient use Upsaryn UPSA with vitamin C tabl. spike, tuba in box number 20 BMS （France）, Citramon tablets number 6 PJSC ＂Monfarm＂ （Ukraine） and Cardiomagnyl tabl. film-coated shell 75 mg in bottle number 100 Nycomed Austria （Austria）. On the basis of six State Forms of drugs in Ukraine （2009-2014） was found that the combination of drugs based on ASA is recommended to use of ascorbic acid （Aspiryn C, Asprovit C, Upsarin UPSA with vitamin C）, dipyridamole （Agrenox）, magnesium hydroxide （Cardiomagnyl, Cardiomagnyl Forte）. Some of the standard combination of ASA （combination of paracetamol and caffeine） are not in form. For optimize State Form of drugs by improving health system in Ukraine can be useful pharmacoeconomic analysis of combination therapies with the current official system to note the combination of ASA with statins, esomeprazole, isosorbide.

Effect of cerebralcare granule®combined with donepezil on Alzheimer’s disease

Background:The current prevalence of Alzheimer’s disease(AD)in the elderly has risen from 1%at 65 to 40%to 50%at 95,and the overall proportion is rising.Emerging evidence suggests that ros-driven oxidative stress is a crucial mediator of the aging process.Thus,in recent years,oxidative damage and inflammation have become targets for exploring pharmacological strategies for treating age-related diseases.Methods:In C57BL/6J mice,to determine whether the mechanism of action of cerebralcare granule®(CG)combined with donepezil(Don)treatment is better than dementia alone,we constructed a mouse model and treated it with CG in combination with Don.Results:A combination of Don and CG significantly reduces the damage caused by lipid peroxidation in the hippocampus of AD mice,reduces oxidative damage,and reduces inflammation,increases the activity of antioxidant enzymes,which is finally manifested as the improvement effect on the learning and memory impairment of AD mice.Conclusion:CG combined with Don has a better effect on improving cognitive and behavioral deficits caused by D-galactose in AD mice than Don alone.The mechanism may be related to reducing inflammation via the NF-κB pathway,resisting oxidative damage and increasing acetylcholine levels.

A proteomic landscape of pharmacologic perturbations for functional relevance

Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds. The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells. Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol, as well as the noncanonical targets of clinically approved tamoxifen, lovastatin, and their derivatives. Furthermore, the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints. This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.

Portable and automated analyzer for rapid and high precision in vitro dissolution of drugs

We developed a novel portable and automated dissolution test analyzer for rapid and high precision in vitro dissolution testing of drugs.The analyzer consists of a flow-through-cell drug dissolution system,an automated sequential sampling system,a high-speed capillary electrophoresis(HSCE)system,and a data acquisition system.Combining the high-temporal resolution flow-gating sampling approach with HSCE,which has outstanding advantages of efficient separation and resolution,the analyzer can achieve rapid analysis and exhibits the ability in miniaturization for on-site assessment of different active pharmaceutical ingredients.To integrate the flow-through-cell dissolution system with HSCE,a specially designed flow-gating-injection(FGI)interface was employed.The performance of the analyzer was investigated by analyzing the dissolution of immediate-release drugs including single dose(amoxicillin dispersible tablets)and fixed dose combination(amoxicillin and clavulanate potassium)drug tablets with the high-temporal resolutions of 12 s and 20 s,respectively.The dissolution profiles of different active pharmaceutical ingredients could be simultaneously and automatically monitored with high repeatability and accuracy.The analyzer was successfully utilized for the pharmaceutical quality control and bio-relevant dissolution testing,as well as in vivo-in vitro correlation analysis.Our portable analyzer is miniaturized,convenient and of low-cost,and will provide a valuable tool for dissolution testing in pharmaceutical research and development.

Twenty-eight Cases of Diabetic Foot Ulcer and Gangrene Treated with the Chinese Herbal Medicine Combined with Injection of Ahylsantinfarctase

Since 1995, the Chinese herbal medicine for supplementing qi and activating blood circulation combined with injection of ahylsantinfarctase into the femoral artery has been used in 28 cases of diabetes complicated with gangrene and ulcer of the foot, with quite good therapeutic effects as reported in the following.……

CP-25 monotherapy and combined administration ameliorate progression of animal arthritis model by inhibition on GRK2 translocation

OBJECTIVE Increased efficacy without increased toxicity is expected when treating rheumatoid arthritis(RA).However,there are many difficulties associated with currently available RA treatments.Reportedly,CP-25,a new compound developed by our group,significantly inhibits the progression of arthritis in animal models through reducing membrane expression of GRK2.This study observed CP-25 monotherapy and combined administration with MTX/LEF in treating animal arthritis model and investigated possible mechanisms.METHODS We set up AA rat and collageninduced arthritis(CIA)mice model.Experimental groups were divided into normal group,vehicle group,monotherapy groups and CP-25-combined MTX/LEF groups.We focused on the role of GRK2 on macrophage polarization and fibro⁃blast-like synoviocytes(FLS)proliferation.We measured cytokine levels,phosphorylation and protein expression,and interactions between proteins.Targeted disruption of GRK2 in FLS and macrophages through GRK2 siRNA and CRIS⁃PR/Cas9.RESULTS Equivalent therapeutic effects were observed between CP-25-combination groups and high-dose MTX/LEF groups.In the vehicle group,GRK2 membrane expression increased leading to the decreased GRK2-p-ERK interactions in FLS(leading to the phosphorylation of ERK related with FLS over-proliferation),and increased GRK2-EP4 interaction in macrophage(leading to the abnormal PGE2-EP4-cAMP-CREB signal related with imbalance of macro⁃phage polarization).CONCLUSION CP-25 monotherapy and combined administration with MTX/LEF ameliorate the progression of animal arthritis model.CP-25 inhibited p-ERK by reducing the membrane expression of GRK2 in FLS from AA rats.CP-25 restored normal PGE2-EP4-cAMP-CREB signal through inhibiting GRK2 transferring to membrane.These results highlighted CP-25 a kind of potential for treating patients with RA.

Application of the Drugs for Expelling the Pathogenic Wind in Treatment of Chronic Diarrhea

Chronic diarrhea can be divided into four types:retention of dampness leading to blockage of qi,invasion of the intestines by pathogenic wind,damp-retention due to deficiency of the spleen, andstagnation of the liver-qi with deficiency of thespleen.

Thymoquinone anticancer activity is enhanced when combined with royal jelly in human breast cancer

BACKGROUND Breast cancer is the most common cause of the majority of cancer-related deaths in women,among which triple-negative breast cancer is the most aggressive type of breast cancer diagnosed with limited treatment options.Thymoquinone(TQ),the main bioactive constituent of Nigella sativa,has been extensively studied as a potent anticancer molecule against various types of cancers.Honeybee products such as the royal jelly(RJ),the nutritive secretion fed to honeybee queens,exhibit a variety of biological activities besides its anticancer effect.However,the anticancer activity of the combination of TQ and RJ against breast cancer is still unknown.AIM To investigate cytotoxicity of RJ in FHs 74 Int cells and the anticancer effects of TQ,RJ,and their combinations in the MDA-MB-231 cell line.METHODS Cells were treated with TQ,RJ,and their combinations for 24 h.Using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,we determined the half-maximal inhibitory concentration of TQ.Trypan blue and 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays were then performed to assess the cell viability in response to different treatment conditions.Cell death and cycle regulation were investigated using propidium iodide deoxyribonucleic acid staining followed by flow cytometry in response to a single dose of TQ,RJ,and their combination.Immunostaining for cleaved caspase 3 and Ki67 expression was used to determine apoptosis induction and changes in cell proliferation.RESULTS TQ alone inhibited cell viability in a dose-dependent manner at concentrations below and above the half-maximal inhibitory concentration.RJ exhibited relatively nontoxic effects against MDA-MB-231 cells and FHs 74 Int small intestinal cells at concentrations below 5μg/mL.High doses of RJ(200μg/mL)had greater toxicity against MDA-MB-231 cells.Interestingly,the inhibition of cell viability was most pronounced in response to 15μmol/L TQ and 5μg/mL RJ.A dose of 15μmol/L TQ caused a significant increase in the PreG1 population,while a more pronounced effect on cell viability inhibition and PreG1 increase was observed in response to TQ and RJ combinations.TQ was the main inducer of caspase 3-dependent apoptosis when applied alone and in combination with RJ.In contrast,no significant regulation of Ki67 expression was observed,indicating that the decrease in cell viability was due to apoptosis induction rather than to inhibition of cell proliferation.CONCLUSION This study is the first to report enhanced anticancer effects of TQ and RJ combination against MDA-MB-231 breast cancer cells,which could confer an advantage for cancer therapy.

CLINICAL OBSERVATION ON 40 CASES OF ANKYLOSING SPONDYLITIS TREATED WITH ACUPUNCTURE AND CHINESE DRUGS

Objective： To observe the clinical therapeutic effect of acupuncture plus Chinese herbal medicines for ankylceing Methods： A total of 80 cases of AS patients were evenly and randomly divided into treatment group and control group. In treatment group, patients were treated with acupuncture of Jiaji （夹脊 EX-B 2） and oral administration of Yishen Tongdu Won （益肾通督丸,Bolus for Reinforcing the Kidney and Dredging Governor Vessesl） and those of control group treated with oral administration of Sulfasalazin （0.5 g, twice daily）. Before and after treatment, the thoracic-dilaion scale, Schober test, Bath ankylceing spondylitis disease activity index （BASDAI）, Bath ankylosing spondylitis functional index （BASFI）, erythrocyte sedimentation rate （ESR） and C-reaction protein （CRP） were detected separately. Results： After 6 months of treatment, of the both 40cases in treatment and control groups, 27 （67.5%） and 13 （32.5%） were improved remarkably, 11 （27.5%） and 16 （40.0%） effective, and 2 （5.0%） and 11 （27.5%） failed, with the effective rates being 95.0% and 72.5% separately. The therapeutic effect of treatment group was significantly superior to that of control group （P〈 0.05）. After treatment, the thoracicdilaion scale and Schober test values increased significantly （ P〈 0.05）, while BASDAI, BASFI, ESR and CRP lowered considerably （P〈0.01, P〈0.05）. Comparison between two groups indicated that after treatment, the decreased values of BASDAI, BASFI, ESR and CRP of treatment group were significantly lower than those of control group （ P〈 0.01 ）, while those of the thoracio-dilaion scale and Schober test of treatment group were significantly higher than those of control group （ P 〈 0.05, P 〈 0.01 ）. Results displayed that both acupuncture combined with Chinese drugs and Sulfasalazin could lower BASDAI, BASFI, ESR and CRP, raise the thoracic-dilaion scale and Schober test values considerably in AS patients, and the therapeutic effect of combined acupunclure and Chinese drugs was apparently superior to that of Westem medicine. Conclusion： Joint application of acupuncture and Chinese drugs is superior to Western medicine in the therapeutic effect for AS and has fewer side effects.

The Antagonistic Action of Heat-Clearing and Detoxifying Chinese Drugs on Endotoxins

In the recent decade, interest in treatment and prevention of many critical, severe and acute diseases caused by bacterial endotoxins has been aroused along with the advance of the knowledge on the nature of the endotoxin and the conditions involved. In abroad, attention has been mainly payed to raising antisera and monocolonal antibodies against the endotoxin and the induced mediators. However, the allergic reactions and the cost are still the problems. Till now, there is no drug that can antagonize endotoxin with high effectiveness and low toxicity. Clinical treatments are still confined in inhibiting or killing the pathogen, and correcting the internal environmental disturbance. Being less toxic and rich in resources with low cost and less side-effects, screening of effective Chinese drugs for antagonizing endotoxin is of important and practical significance. Endotoxin belongs to the category of toxic evils, or more precisely, the heat toxin in TCM. Therefore the application of heat-clearing and detoxifying Chinese drugs to antagonizing endotoxins is consistent with the theory of TCM. Some achievements in this field are reported as follows.

Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is one of the most lethal malignant tumours worldwide.The mortality-to-incidence ratio is up to 91.6%in many countries,representing the third leading cause of cancer-related deaths.Systemic drugs,including the multikinase inhibitors sorafenib and lenvatinib,are first-line drugs used in HCC treatment.Unfortunately,these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance.Thus,novel pharmacological alternatives are urgently needed.For instance,immune checkpoint inhibitors have provided new approaches targeting cells of the immune system.Furthermore,monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients.In addition,drug combinations,including first-line treatment and immunotherapy,as well as drug repurposing,are promising novel therapeutic alternatives.Here,we review the current and novel pharmacological approaches to fight HCC.Preclinical studies,as well as approved and ongoing clinical trials for liver cancer treatment,are discussed.The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.

Immunotherapy for recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is presented frequently in late stages that are not amenable for curative treatment.Even for patients who can undergo resection for curative treatment of HCC,up to 50%recur.For patients who were not exposed to systemic therapy prior to recurrence,recurrence frequently cannot be subjected to curative therapy or local treatments.Such patients have several options of immunotherapy(IO).This includes programmed cell death protein 1(PD-1)and cytotoxic T-lymphocyte associated protein 4 treatment,combination of PD-1 and vascular endothelial growth factor inhibitor or single agent PD-1 therapy when all other options are deemed inappropriate.There are also investigational therapies in this area that explore either PD-1 and tyrosine kinase inhibitors or a novel agent in addition to PD-1 with vascular endothelial growth factor inhibitors.This minireview explored IO options for patients with recurrent HCC who were not exposed to systemic therapy at the initial diagnosis.We also discussed potential IO options for patients with recurrent HCC who were exposed to first-line therapy with curative intent at diagnosis.

Cocktail hepatocarcinoma therapy by a super-assembled nano-pill targeting XPO1 and ATR synergistically

Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier.Herein,a two-step super-assembled strategy was performed to unify the pharmacokinetics of a peptide and a small molecular compound.In this proof-of-concept study,the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1(XPO1)and ataxia telangiectasia mutated-Rad3-related(ATR),and then a super-assembled nano-pill(gold nano drug carrier loaded AZD6738 and 97110 amino acids of apoptin(AP)(AA@G))was constructed through camouflaging AZD6738(ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle.As expected,both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest,promoting DNA damage and inhibiting DNA repair of hepatoma cell.This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential,but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds,thereby extending the scope of drugs for developing the advanced combination therapy.

Standard triple therapy for Helicobacter pylori infection in China: A meta-analysis

AIM: To assess the efficacy and safety of standard triple therapy compared with other pre-existing and new therapies in China.

Immuno-oncology combinations： raising the tail of the survival curve

There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer,immune checkpoint inhibitors also appears to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.

Azithromycin-containing versus standard triple therapy for Helicobacter pylori eradication:A meta-analysis

AIM： To evaluate whether adding azithromycin to firstline Helicobacter pylori （H pylorl） eradication improved eradication and reduced side effects. METHODS： Eligible articles were identified by searches of electronic databases. We included all randomized trials that compared azithromycin-containing with standard triple-therapy regimens for first-line treatment of H pylori infection. Statistical analysis was performed with Review Manager 5.0.10. Sub-analyses were also performed. RESULTS： We identified 14 randomized trials （1431 patients）. Pooled Hpylori eradication rates were 72.01% （95% CI： 58.09%-85.93%） and 69.78% （95% CI： 66.47%-73.09%） for patients with or without azithromycin by intention-to-treat analysis, and the odds ratio （OR） was 1.17 （95% CI： 0.64-2.14）. The occurrence of side effects differed significantly and was 15.81% （95% CI： 12.50%-19.12%） and 25.20% （95% CI： 21.44%-28.96%） for treatment with or without azithromycin, respectively, and the summary OR was 0.58 （95% CI： 0.41-0.82）. Furthermore, the azithromycin-containing group had a lower occurrence of diarrhea, nausea and taste disturbance. CONCLUSION： Our review suggests that azithromycincontaining triple-therapy regimens could be equally effective in eradication of Hpylori compared with standard first-line triple-therapy regimens.

Immune therapies in pancreatic ductal adenocarcinoma: Where are we now?

Pancreatic ductal adenocarcinoma(PDAC)is one of the deadliest cancers,mostly due to its resistance to treatment.Of these,checkpoint inhibitors(CPI)are inefficient when used as monotherapy,except in the case of a rare subset of tumors harboring microsatellite instability(<2%).This inefficacy mainly resides in the low immunogenicity and non-inflamed phenotype of PDAC.The abundant stroma generates a hypoxic microenvironment and drives the recruitment of immunosuppressive cells through cancerassociated-fibroblast activation and transforming growth factorβsecretion.Several strategies have recently been developed to overcome this immunosuppressive microenvironment.Combination therapies involving CPI aim at increasing tumor immunogenicity and promoting the recruitment and activation of effector T cells.Ongoing studies are therefore exploring the association of CPI with vaccines,oncolytic viruses,MEK inhibitors,cytokine inhibitors,and hypoxia-and stroma-targeting agents.Adoptive T-cell transfer is also under investigation.Moreover,translational studies on tumor tissue and blood,prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.

Type 2 diabetes mellitus affects eradication rate of Helicobacter pylori

AIM: To study the eradication rate of Helicobacter pylori (Hp) in a group of type 2 diabetes and compared it with an age and sex matched non-diabetic group.METHODS: 40 diabetic patients (21 females, 19 males;56±7 years) and 40 non-diabetic dyspeptic patients (20females, 20 males; 54±9 years) were evaluated. Diabetic patients with dyspeptic complaints were referred for upper gastrointestinal endoscopies; 2 corpus and 2 antral gastric biopsy specimens were performed on each patient. Patients with positive Hp results on histopathological examination comprised the study group. Non-diabetic dyspeptic patients seen at the Gastroenterology Outpatient Clinic and with the same biopsy and treatment protocol formed the control group.A triple therapy with amoxycillin (1 g b.i.d), clarithromycin (500 mg b.i.d) and omeprazole (20 mg b.i.d.) was given to both groups for 10 days. Cure was defined as the absence of Hp infection assessed by corpus and antrum biopsies in control upper gastrointestinal endoscopies performed 6weeks after completing the antimicrobial therapy.RESULTS: The eradication rate was 50 % in the diabetic group versus 85 % in the non-diabetic control group (P＜0.001).CONCLUSION: Type 2 diabetic patients showed a significantly lower eradication rate than controls which may be due to changes in microvasculature of the stomach and to frequent antibiotic usage because of recurrent bacterial infections with the development of resistant strains.

Drug-drug cocrystals:Opportunities and challenges

Recently,drug-drug cocrystal attracts more and more attention.It offers a low risk,low-cost but high reward route to new and better medicines and could improve the physiochemical and biopharmaceutical properties of a medicine by addition of a suitable therapeutically effective component without any chemical modification.Having so many advantages,to date,the reported drug-drug cocrystals are rare.Here we review the drug-drug cocrystals that reported in last decade and shed light on the opportunities and challenges for the development of drug-drug cocrystals.

Key factors and potential drug combinations of nonalcoholic steatohepatitis:Bioinformatic analysis and experimental validation-based study

Background:Nonalcoholic fatty liver disease and its advanced stage,nonalcoholic steatohepatitis(NASH),are the major cause of hepatocellular carcinoma(HCC)and other end-stage liver disease.However,the potential mechanism and therapeutic strategies have not been clarified.This study aimed to identify potential roles of mi RNA/m RNA axis in the pathogenesis and drug combinations in the treatment of NASH.Methods:Microarray GSE59045 and GSE48452 were downloaded from the Gene Expression Omnibus and analyzed using R.Then we obtained differentially expressed genes(DE-genes).DAVID database was used for Gene Ontology(GO)analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment pathway analysis.Protein-protein interaction(PPI)networks were used for the identification of hub genes.We found upstream regulators of hub genes using mi RTar Base.The expression and correlation of key mi RNA and its targets were detected by q PCR.Drug Pair Seeker was employed to predict drug combinations against NASH.The expression of mi RNA and hub genes in HCC was identified in the Cancer Genome Atlas database and Human Protein Atlas database.Results:Ninety-four DE-genes were accessed.GO and KEGG analysis showed that these predicted genes were linked to lipid metabolism.Eleven genes were identified as hub genes in PPI networks,and they were highly expressed in cells with vigorous lipid metabolism.hsa-mi R-335-5 p was the upstream regulator of 9 genes in the 11 hub genes,and it was identified as a key mi RNA.The hub genes were highly expressed in NASH models,while hsa-mi R-335-5 p was lowly expressed.The correlation of mi RNA-m RNA was established by q PCR.Functional verification indicated that hsa-mi R-335-5 p had inhibitory effect on the development of NASH.Finally,drug combinations were predicted and the expression of mi RNA and hub genes in HCC was identified.Conclusions:In the study,potential mi RNA-m RNA pathways related to NASH were identified.Targeting these pathways may be novel strategies against NASH.