topotecan

etoposide

doxorubicin

vincristine

Characterization of a novel topoisomerase I mutation from a camptothecin-resistant human prostate cancer cell line. In this study, we characterized the structure and function of topoisomerase I (top1) protein in the camptothecin (CPT)-resistant prostate cancer cell lines, DU-145/RC0.1 and DU-145/RC1 (RC0.1 and RC1, respectively). Both of the cell lines were previously selected by continuous exposure to 9-nitro-CPT. The RC0.1 and RC1 cells have high cross-resistance to CPT derivatives including SN-38 and topotecan , but are not cross-resistant to the non-top1 inhibitors etoposide , doxorubicin , and vincristine . Although the top1 protein levels were not decreased in the resistant cells compared with the parental cells, CPT-induced DNA cleavage was markedly reduced in the RC0.1 and RC1 nuclear extracts. The resistant-cell-line nuclear extracts also demonstrated top1 catalytic activity and resistance to CPT, in in vitro assays. Reverse transcription-PCR products from the resistant cell lines were sequenced, and revealed a point mutation resulting in a R364H mutation in the top1 of both RC0.1 and RC1. No wild-type top1 RNA or genomic DNA was detected in the resistant cell lines. Using a purified recombinant R364H top1, we found that the R364H mutant top1 was CPT resistant and fully active. In the published top1 crystal structure, the R364H mutation is close to the catalytic tyrosine and other well-known mutations leading to CPT resistance.


nifuratel

amoxicillin

bismuth

Nifuratel-containing initial anti-Helicobacter pylori triple therapy in children. Proton pump inhibitor-containing triple therapy with amoxicillin and metronidazole is recommended as initial treatment of Helicobacter pylori in childhood. However, eradication rate with this "classic" regimen is relatively low in Russia. ### aim To evaluate empiric nifuratel , amoxicillin , and bismuth triple therapy for H. pylori gastritis in childhood . ### Materials And Methods Pediatric outpatients with H. pylori-associated chronic gastritis who underwent endoscopy for dyspeptic symptoms received the combination of bismuth subcitrate (8 mg/kg/day, q.d.s.), nifuratel (30 mg/kg/day, q.d.s.), and amoxicillin (50 mg/kg/day, q.d.s.) for 10 days. H. pylori status was determined before and after the treatment (in 4-6 weeks) by modified Giemsa staining. ### results Seventy-three children (48 boys, 25 girls, age range 9-14) were entered. H. pylori was eradicated in 63 patients (86%; 95% confidence interval: 76.6-93.2; intention-to-treat and per protocol). There were no serious adverse reactions and were no withdrawals due to any side-effects. All of side-effects were self-limiting (dark stools, urine discoloration, blackening of the tongue, and others). ### conclusions The combination of nifuratel, bismuth subcitrate, and amoxicillin was an effective and tolerable regimen for H. pylori eradication.


anthracycline

etoposide

behenoyl cytarabine

Therapy-related myelodysplastic syndrome with monosomy 5 after successful treatment of acute myeloid leukemia (M2). We describe a patient who developed myelodysplastic syndrome over 2 years after achieving complete remission of acute myeloid leukemia (AML). The patient was treated in July 1998 with anthracycline , etoposide , and behenoyl cytarabine chemotherapy for AML ( French-American-British classification , M2 ; World Health Organization classification , AML with maturation ) and achieved complete remission . At presentation, no chromosomal abnormalities were detected. In December 2000, the patient's peripheral blood revealed pancytopenia, and his bone marrow was hypocellular with trilineage myelodysplasia and no blasts. Chromosomal analysis revealed complex karyotypic abnormalities, including monosomy 5. The patient was diagnosed with high-grade myelodysplastic syndrome (MDS)/refractory anemia with excess blasts (RAEB) subtype. The pancytopenia progressed rapidly, and he died 2 months after the diagnosis of MDS. Therapy-related MDS and AML (t-MDS/t-AML) developing after treatment for acute leukemia is unusual; the primary leukemia associated with most cases of t-MDS/t-AML is acute promyelocytic leukemia (APL). This unusual case suggests that AML excluding APL should be considered a primary hematologic malignancy for t-MDS/t-AML.


clopidogrel

aspirin

ASA

Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. We performed a meta-analysis of data from randomized trials to estimate the risk of all-cause mortality and bleeding (and especially gastrointestinal [GI] bleeding) in patients treated with low doses of acetylsalicylic acid (ASA) (75-325 mg/d), alone or in combination with other medications. ### methods We searched 10 electronic databases (until October 2010) and collected data on adverse events in randomized controlled studies that evaluated low doses of ASA, alone (35 trials) or in combination with anticoagulants (18 trials), clopidogrel (5 trials), or proton pump inhibitors (PPIs; 3 trials). We analyzed data using random-effects meta-analysis and meta-regression, applying Peto's odds ratio (OR) for adverse events. ### results Low doses of ASA alone decreased the risk for all-cause mortality (relative risk, 0.93, 95% confidence interval [CI], 0.87-0.99), largely because of effects in secondary prevention populations. The risk of major GI bleeding increased with low doses of ASA alone (OR, 1.55; 95% CI, 1.27-1.90), compared with inert control reagents. The risk increased when ASA was combined with clopidogrel , compared with aspirin alone ( OR , 1.86 ; 95 % CI , 1.49 - 2.31 ) , anticoagulants vs low doses of ASA alone ( OR , 1.93 ; 95 % CI , 1.42 - 2.61 ) , or in studies that included patients with a history of GI bleeding or of longer duration . Importantly, PPI use reduced the risk for major GI bleeding in patients given low doses of ASA (OR, 0.34; 95% CI, 0.21-0.57). ### conclusions In a meta-analysis, low doses of ASA increased the risk for GI bleeding; risk increased with accompanying use of clopidogrel and anticoagulant therapies, but decreased in patients who took PPIs.


Raloxifene

letrozole

Combined Raloxifene and Letrozole for Breast Cancer Patients.  Raloxifene , an anti-osteoporotic drug , is recently approved for prevention of breast cancer in postmenopausal women and thus the drug may be employed to combat the bony adverse effects of letrozole , another anticancer drug . However, the cytotoxic effect of their combination on human breast cancer (MCF-7) and human embryonic kidney (HEK) cell lines is not known. MCF-7 and HEK cell lines were treated with different graded doses of letrozole, raloxifene and their combination, then incubated for 24-48 h. MTT assay was performed to check the cytotoxicity of the drugs. The study indicates that the combination of letrozole and raloxifene possess additive effect in terms of cytotoxicity of cancer cell lines (MCF-7) and negligible effects in normal cell lines (HEK). Our study indicates that the addition of raloxifene doesn't interfere with anticancer efficacy of letrozole rather the combination acted additively for the treatment of breast cancer.


flutamide

leuprolide acetate

leuprolide acetate

Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial , we found that adding the antiandrogen flutamide to leuprolide acetate ( a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function ) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate . In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy. ### methods We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status. ### results Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of toxic effects was minimal; the only notable differences between the groups were the greater rates of diarrhea and anemia with flutamide. There was no significant difference between the two groups in overall survival (P=0.14). The estimated risk of death (hazard ratio) for flutamide as compared with placebo was 0.91 (90 percent confidence interval, 0.81 to 1.01). flutamide was not associated with enhanced benefit in patients with minimal disease. ### conclusions The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.


desogestrel

levonorgestrel

Contraceptives containing desogestrel or levonorgestrel have different effects on serum lipoproteins and post-heparin plasma lipase activities . We examined the effects of mono and polyphasic oral contraceptives containing desogestrel or levonorgestrel on serum lipoproteins, sex hormone binding globulin and post-heparin plasma lipase activities. ### design The women took either desogestrel or levonorgestrel during the first menstrual cycle on days 15-28. They then received monophasic ethinyloestradiol plus either desogestrel or levonorgestrel for three cycles. After this, the women took sequential pills containing ethinyloestradiol plus either desogestrel or levonorgestrel for the three following cycles. Fasting blood samples were drawn pretreatment and at the end of each treatment. ### patients The study group consisted of 30 apparently healthy women, aged 18-35. They were randomly divided into desogestrel and levonorgestrel groups, each consisting of 15 women. ### measurements Cholesterol, triglyceride and phospholipids were determined in whole serum and in all lipoprotein fractions (following isolation of lipoproteins by ultracentrifugation). Plasma apolipoprotein A-I concentration, post-heparin plasma lipase activities and serum sex hormone binding globulin were also measured. ### results desogestrel (150 micrograms/day) did not change serum total triglyceride concentration, whereas levonorgestrel (150 micrograms/day) decreased it. Except for monophasic ethinyloestradiol plus levonorgestrel, the oestrogen-containing combinations increased serum triglyceride level. Low density lipoprotein (LDL) cholesterol remained stable with all treatments, but the cholesterol/triglyceride ratio of LDL decreased during all combinations with ethinyloestradiol. levonorgestrel reduced total high density lipoprotein (HDL) cholesterol and both progestins reduced HDL2 cholesterol concentration. Addition of ethinyloestradiol reversed this change in the desogestrel but not in the levonorgestrel group. The polyphasic ethinyloestradiol plus levonorgestrel combination did not change total HDL cholesterol. Hepatic lipase was activated with either progestin when administered alone but its activity was suppressed below the baseline level when ethinyloestradiol was added. Conversely, both progestins suppressed sex hormone binding globulin levels, but addition of ethinyloestradiol caused marked increases above baseline. These increases were greater in women taking desogestrel than in those taking levonorgestrel. No treatment affected lipoprotein lipase activity significantly. ### conclusions Monophasic or polyphasic combinations of ethinyloestradiol and desogestrel do not have deleterious effects on serum lipoproteins. If levonorgestrel is used as the progestin component, polyphasic ethinyloestradiol plus levonorgestrel appears more favourable than monophasic ethinyloestradiol plus levonorgestrel.


clarithromycin

amoxicillin

gentamicin

furazolidone

metronidazole

levofloxacin

Antibiotics resistance of Helicobacter pylori in children with upper gastrointestinal symptoms in Hangzhou, China. The decreasing eradication rate of Helicobacter pylori is mainly because of the progressive increase in its resistance to antibiotics. Studies on antimicrobial susceptibility of H. pylori in children are limited. This study aimed to investigate the resistance rates and patterns of H. pylori strains isolated from children. ### Materials And Methods Gastric mucosa biopsy samples obtained from children who had undergone upper gastrointestinal endoscopy were cultured for H. pylori , and susceptibility to six antibiotics ( clarithromycin , amoxicillin , gentamicin , furazolidone , metronidazole , and levofloxacin ) was tested from 2012 - 2014 . ### results A total of 545 H. pylori strains were isolated from 1390 children recruited. The total resistance rates of H. pylori to clarithromycin, metronidazole, and levofloxacin were 20.6%, 68.8%, and 9.0%, respectively. No resistance to amoxicillin, gentamicin, and furazolidone was detected. 56.1% strains were single resistance, 19.6% were resistant to more than one antibiotic, 16.7% for double resistance, and 2.9% for triple resistance in 413 strains against any antibiotic. And the H. pylori resistance rate increased significantly from 2012-2014. There was no significant difference in the resistance rates to clarithromycin, metronidazole, and levofloxacin between different gender, age groups, and patients with peptic ulcer diseases or nonulcer diseases. ### conclusions Antibiotic resistance was indicated in H. pylori strains isolated from children in Hangzhou, and it increased significantly during the 3 years. Our data strongly support current guidelines, which recommend antibiotic susceptibility tests prior to eradication therapy.


guaifenesin

diphenhydramine

chlorpheniramine

Acute intoxication with guaifenesin, diphenhydramine, and chlorpheniramine. Mixed drug reactions are frequently encountered in emergency department overdose cases and also in fatal intoxications. Assessment of the relative contribution of each drug in producing adverse effects is often compounded by lack of case history and the paucity of cases reported in the literature. This report describes a fatal intoxication with three common over-the-counter medications: guaifenesin, diphenhydramine, and chlorpheniramine. A 48-year-old woman was found dead in the attic bedroom of her residence. Specimens obtained at autopsy for toxicologic analysis included heart blood, urine, bile, gastric contents, vitreous humor, and cerebrospinal fluid. The over-the-counter drugs were identified and quantitated by acid/neutral or basic liquid-liquid extraction followed by gas chromatographic analysis with nitrogen phosphorus detection. Concentrations of guaifenesin , diphenhydramine , and chlorpheniramine detected in the heart blood were 27.4 , 8.8 , and 0.2 mg/L , respectively . The cause of death was determined to be acute intoxication by the combined effects of guaifenesin, diphenhydramine, and chlorpheniramine, and the manner of death was determined to be suicide. To our knowledge, the blood guaifenesin concentration in this case is the highest reported concentration to date associated with an acute intoxication.


vincristine

actinomycin D

cyclophosphamide

doxorubicin

vincristine

doxorubicin

cyclophosphamide

ifosfamide

etoposide

[Ewing sarcoma]. Ewing sarcoma is the second most frequent primary bone cancer affecting children or young adults. Advances in molecular biology have revealed common chromosomal translocations such as EWS-FLI 1 among Ewing sarcoma and related diseases such as primitive neuroectodermal tumor (PNET), so these are considered as Ewing sarcoma family tumor (ESFT). Although fewer than 10% of patients with ESFT survived before establishment of modern multiagent chemotherapy, the multimodal therapeutic regimens including combination chemotherapy, radiotherapy, and surgery can cure 60% of patients with localized disease, due to the collaborative research in European-American or the international trials. The standard chemotherapy for localized ESFT now comprises vincristine , actinomycin D , cyclophosphamide and doxorubicin ( VACD ) in Europe or vincristine , doxorubicin , cyclophosphamide , ifosfamide and etoposide ( VDC-IE ) in North America . Meanwhile, those with metastatic disease have a much worse outcome with an approximately 10-30% 5-year event-free survival rate. New American-European collaborative trials such as EURO-E.W.I.N.G.99 are in progress for further improvement of the cure rate in localized and metastatic ESFT. In Japan, Japan Ewing Sarcoma Study Group (JESS) phase II clinical trial for localized ESFT, and some clinical trials including new drugs are ongoing and waiting for results.


Ceftriaxone

gentamicin

ceftriaxone

Ceftriaxone plus gentamicin or ceftriaxone alone for streptococcal endocarditis in Japanese patients as alternative first-line therapies . This study included 31 patients who had definite or possible infectious endocarditis as defined by the modified Duke's criteria Of these patients, 27 were treated with ceftriaxone plus gentamycin combination therapy and four with ceftriaxone monotherapy. Of these 31 cases, 29 had infections with Streptococcus species, and showed good responses to penicillin G and cefotaxime. Excluding one patient who died because of the underlying disease, all patients achieved clinical cure after treatment with either of the two regimens, showing no recurrence during a follow-up period of 6 months after completion of drug treatment. Although valve replacement was performed in 10 patients during the follow-up period, there were no recurrences in any of these patients 6 months postoperatively. ceftriaxone allows a simple regimen of once-daily administration. Although indications are limited, ceftriaxone therapy is feasible on an outpatient basis, offering favorable medical economics. Consistent with previous reports, the therapeutic effect of ceftriaxone was equivalent to that of penicillin G in this study, showing this agent to be an alternative first-line drug for infectious endocarditis.


acamprosate

naltrexone

Combined therapy : what does acamprosate and naltrexone combination tell us ? Relapse prevention treatment with both acamprosate and naltrexone has been shown to be efficacious in the treatment of alcoholism. Whereas both compounds act pharmacologically differently, there is up to now only limited evidence as to whether combined treatment is efficacious and pharmacologically safe. It remains to be answered whether data justify the combination of both drugs in clinical practice. ### methods Review of the three pre-clinical and four clinical studies that have been published to date on either combined tolerability or efficacy. ### results Data available up to now show no occurrence of severe adverse events during combined treatment. Diarrhoea and nausea were shown to be the most significant side-effects. Whereas pre-clinical studies regarding efficacy of combined treatment are not yet conclusive, clinical data show the superiority of combined treatment compared with both placebo and acamprosate monotherapy. The synergistic effect of combined treatment remained after 12 weeks of drug-free follow-up. ### conclusions The combination of acamprosate with naltrexone in a clinical sample seems to be efficacious and safe. Numerous alcohol dependent patients could benefit, particularly those that responded insufficiently on monotherapeutic treatment with either acamprosate or naltrexone.


atovaquone

pyrimethamine

Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM). Malignant pleural mesothelioma (MPM) is an aggressive cancer defined by loss-of-function mutations with few therapeutic options. We examined the contribution of the transcription factor Signal transducer and activator of transcription 3 (STAT3) to cell growth and gene expression in preclinical models of MPM. STAT3 is activated in a variety of tumors and is thought to be required for the maintenance of cancer stem cells. Targeting STAT3 using specific small hairpin RNAs (shRNAs) or with the pharmacologic inhibitors atovaquone or pyrimethamine efficiently reduced cell growth in established cell lines and primary-derived lines while showing minimal effects in nontransformed LP9 mesothelial cells. Moreover, atovaquone significantly reduced viability and tumor growth in microfluidic cultures of primary MPM as well as in an in vivo xenotransplant model. Biological changes were linked to modulation of gene expression associated with STAT3 signaling, including cell cycle progression and altered p53 response. Reflecting the role of STAT3 in inducing localized immune suppression , using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response , including upregulation of ICOSLG ( Inducible T-Cell Costimulator Ligand or B7H2 ) . Thus, our data strongly support a role for STAT3 inhibitors as anti-MPM therapeutics.


tenofovir

emtricitabine

raltegravir

TVR

A case of successful hepatitis C virus eradication by 24 weeks of telaprevir-based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon-α and ribavirin therapy. In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-α and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-α2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-α2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir , emtricitabine and raltegravir for patients with hemophilia . Furthermore, patients with undetectable HCV RNA at week 4 could be successfully treated with a 24-week regimen.


Ampicillin

Tobramycin

Bacteriophage typing and antibiotic sensitivity pattern of Staphylococcus aureus from clinical specimen in and around Solapur (South Maharashtra). Two hundred and eighty nine strains of Staphylococcus aureus isolated from pus and wound swabs (149), blood (36), urine (28), sputum (14), stool (12), throat swab (9) and CSF (4) were subjected for bacteriophage typing and antibiotic susceptibility pattern. 113 (39.11%) strains were typable. Among the typable strains, 16 (5.53%) belonged to phage group I, 33 (11.41%) strains belonged to phages group II, 38 (13.14%) belonged to phage group III, 26 (8.99%) strains belonged to the phages which have not been allocated to any group (Miscellaneous group) 176 (60.89%) strains were untypable. Only one (0.34%) strain was sensitive to all the drugs tested. Almost all the isolates were resistant to Ampicillin and Tobramycin ( 99.3 % each ) . 286 (98.96%) strains were found to be resistant to Penicillin and erythromycin followed by kanamycin 272 (94.11%) and gentamicin 263 (91.3%). 113 (39.1%) strains were Methicillin resistant Staphylococcus aureus (MRSA). All MRSA strains were resistant to all drugs tested except vancomycin. Resistance to most of the commonly used antimicrobial agents indicates a need to replace these drugs with other agents and maintenance of surveillance to detect changing patterns of resistance.


azithromycin

doxycycline

Topical azithromycin and oral doxycycline therapy of meibomian gland dysfunction:  a comparative clinical and spectroscopic pilot study. Meibomian gland dysfunction (MGD) is a common clinical problem that is often associated with evaporative dry eye disease. Alterations of the lipids of the meibomian glands have been identified in several studies of MGD. This prospective, observational, open-label clinical trial documents the improvement in both clinical signs and symptoms of disease as well as spectroscopic characteristics of the meibomian gland lipids after therapy with topical azithromycin ophthalmic solution and oral doxycycline treatment. ### methods Subjects with symptomatic MGD were recruited. Signs of MGD were evaluated with a slit lamp. Symptoms of MGD were measured by the response of subjects to a questionnaire. Meibum lipid-lipid interaction strength, conformation, and phase transition parameters, and meibum protein content were measured using Fourier transform infrared spectroscopy and principal component analysis. Terpenoids, short-chain CH3 moieties, lipid oxidation, wax, cholesterylesters and glycerides were measured with a proton nuclear magnetic resonance (H-NMR) spectrometer. ### results Topical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms and restored the lipid properties of the meibomian gland secretion toward normal . Compared with 4 weeks of azithromycin treatment reported in our previous study, oral doxycycline treatment was slightly less effective in improving foreign body sensation and the signs of plugging and secretion. In subjects with clinical evidence of MGD, changes in ordering of the lipids and phase transition temperature were brought closer to normal with azithromycin treatment than doxycycline treatment. Treatment with doxycycline but not azithromycin restored the Fourier transform infrared spectroscopy-principal component analysis scores and relative area of the H-NMR resonance at 1.26 ppm. Both doxycycline and azithromycin treatment restored the levels of the relative areas of the H-NMR resonance at 5.2 and 7.9 ppm to normal levels. The levels of meibum protein and meibum lipid oxidation were not influenced by azithromycin or doxycycline treatment. ### conclusions The mechanism of action of doxycycline may be different from that of azithromycin in therapy of MGD. It is notable that when carotenoids in meibum are low, as in MGD, the tear film is unstable and patients have the signs and symptoms of dry eyes. When carotenoids are restored with azithromycin and doxycycline treatment, tear film stability is restored and patients no longer have the signs and symptoms of dry eyes.


cefazolin

cephapirin

Use, misuse, and cost of parenteral cephalosporins at a county hospital. We reviewed total usage of parenteral cephalosporins at a county hospital during 1978 with regard to appropriateness, pattern of use, and cost. In addition, we determined the impact of replacing cephalothin with cephapirin in the hospital formulary. During the 12-month study 366 patients received 409 courses of parenteral cephalosporins: 167 received cefazolin, 160 received cephapirin, and 35 received a combination of cefazolin and cephapirin. The surgical service prescribed 87% of the cephapirin and 92% of the cefazolin. Parenteral cephalosporins were used 62% of the time for prophylaxis and 38% of the time for therapy. Usage was judged inappropriate in 47% of all courses based on our criteria; 25% of the therapeutic courses were judged inappropriate, compared to 60% of the prophylactic courses. Pharmacy costs of cefazolin used as prophylaxis were more than twice the cost for cephapirin . Cost of a mean therapeutic course for cefazolin was 43% higher than for cephapirin. Antibiotic audits and continued education combined with judicial substitution of therapeutic equivalents should limit the inappropriate use and expense of parenteral cephalosporins for large as well as small hospitals.


lactose

lactose

xylose

[Effect of lactic acid bacteria isolated from Tibetan Plateau on silage fermentation quality of Elms nutans]. In order to detect the effect of lactic acid bacteria isolated from Tibetan Plateau on silage fermentation quality of Elms nutans. ### methods We used 3 isolated lactic acid bacteria with better growth at low temperatures of 10 and 15 degrees C at ensiling of Elymus nutans. Subsequently, effects of the selected lactic acid bacteria on fermentation profiles of Elymus nutans silages stored at 15 and 25 degrees C were evaluated by using the same species of commercial inoculants as the control. ### results PP-6 isolated from Tibetan Plateau could ferment raffinose , lactose , sorbitol , melibiose and sucrose , and LS-5 could ferment cottonseed sugar , laetrile , rhamnose , lactose , sorbitol , xylose , arabinose , melibiose and sucrose , but the same species of commercial strains could not use these sugars . Inoculation of these three strains into Elymus nutans at 15 and 25 degrees C ensiled for 50 d, we found that LS-5 significantly reduced silage pH, propionic acid concentration and ratio of ammonia nitrogen/total nitrogen at 15 degrees C (P < 0.05), salvaged more water-soluble carbohydrate and crude protein; Application of LP-2 and PP-6 as a combined inoculant to Elymus nutans significantly improved lactic acid concentration (P < 0.05), resulting in a lower ratio of ammonia nitrogen/total nitrogen, saved more crude protein and significantly reduced neutral detergent fiber content (P < 0.05) as compared with the commercial strains. ### conclusion The three isolated strains can improve silage quality of Elymus nutans growing on the Qinghai-Tibetan Plateau at low temperature, but these strains have no obvious advantages at 25 degrees C in comparison with the commercial inoculants.


rapamycin

doxycycline

Targeting cellular metabolism using rapamycin and/or doxycycline enhances anti-tumour effects in human glioma cells. Glioma is the most common highly aggressive, primary adult brain tumour. Clinical data show that therapeutic approaches cannot reach the expectations in patients, thus gliomas are mainly incurable diseases. Tumour cells can adapt rapidly to alterations during therapeutic treatments related to their metabolic rewiring and profound heterogeneity in tissue environment. Renewed interests aim to develop effective treatments targeting angiogenesis, kinase activity and/or cellular metabolism. mTOR (mammalian target of rapamycin), whose hyper-activation is characteristic for many tumours, promotes metabolic alterations, macromolecule biosynthesis, cellular growth and survival. Unfortunately, mTOR inhibitors with their lower toxicity have not resulted in appreciable survival benefit. Analysing mTOR inhibitor sensitivity, other metabolism targeting treatments and their combinations could help to find potential agents and biomarkers for therapeutic development in glioma patients. ### methods In vitro proliferation assays, protein expression and metabolite concentration analyses were used to study the effects of mTOR inhibitors, other metabolic treatments and their combinations in glioma cell lines. Furthermore, mTOR activity and cellular metabolism related protein expression patterns were also investigated by immunohistochemistry in human biopsies. temozolomide and/or rapamycin treatments altered the expressions of enzymes related to lipid synthesis, glycolysis and mitochondrial functions as consequences of metabolic adaptation; therefore, other anti-metabolic drugs (chloroquine, etomoxir, doxycycline) were combined in vitro. ### results Our results suggest that co-targeting metabolic pathways had tumour cell dependent additive/synergistic effects related to mTOR and metabolic protein expression patterns cell line dependently. Drug combinations , especially rapamycin + doxycycline may have promising anti-tumour effect in gliomas . Additionally, our immunohistochemistry results suggest that metabolic and mTOR activity alterations are not related to the recent glioma classification, and these protein expression profiles show individual differences in patients' materials. ### conclusions Based on these, combinations of different new/old drugs targeting cellular metabolism could be promising to inhibit high adaptation capacity of tumour cells depending on their metabolic shifts. Relating to this, such a development of current therapy needs to find special biomarkers to characterise metabolic heterogeneity of gliomas.


prednisolone

cyclophosphamide

vincristine

prednisone

methotrexate

psoralen-ultraviolet-A

procarbacine

citrovorum

Cutaneous immunoblastic T-cell lymphoma. The case of a 69-year-old male patient with an unusual type of malignant lymphoma is presented. Clinically, it was at first characterized by follicular papules and erythematous patches, later, by the development of cutaneous tumors and enlarged lymph nodes, and by a severe, finally excruciating pruritus. Treatment with PUVA ( psoralen-ultraviolet-A ) combined with 40 - -80 mg prednisolone and then with chemotherapy [ COPP regimen ( cyclophosphamide , vincristine , procarbacine , prednisone ) , high-dosage methotrexate followed by citrovorum factor rescue ] was not successful . The patient died of pneumonia 2.5 years after the onset of the first clinical symptoms. An immunoblastic infiltrate was observed histologically and electromicroscopically in the initial lesions of the skin. Therefore, the diagnosis of a cutaneous immunoblastic T-cell lymphoma was tentatively made at the beginning, which was later confirmed in numerous biopsies and laboratory investigations. Immunocytologically and enzymecytochemically, the infiltrating cells were shown to be immature T cells; in the lymph nodes, numerous immunoblasts and large Sézary cells was observed in the peripheral blood, though there were no very large Sézary cells or blast cells. In the autopsy, a systemic involvement with an atypical lymphoid infiltration was found in numerous internal organs. The special nature of this case justifies its classification as high-grade malignant lymphoma and its differentiation from normal cases of mycosis fungoides. In contrast, mycosis fungoides generally fulfils criteria typical of low-grade malignant lymphomas.


bevacizumab

cetuximab

Association of Primary Tumor Site With Mortality in Patients Receiving Bevacizumab and Cetuximab for Metastatic Colorectal Cancer. Biologic therapy (BT) (eg, bevacizumab or cetuximab) is increasingly used to treat metastatic colorectal cancer (mCRC). Recent investigations have suggested that right- or left-sided primary tumor origin affects survival and response to BT. ### objective To evaluate the association of tumor origin with mortality in a diverse population-based data set of patients receiving systemic chemotherapy (SC) and bevacizumab or cetuximab for mCRC. ### Design Setting And Participants This population-based nonconcurrent cohort study of statewide California Cancer Registry data included all patients aged 40 to 85 years diagnosed with mCRC and treated with SC only or SC plus bevacizumab or cetuximab from January 1 , 2004 , through December 31 , 2014 . Patients were stratified by tumor origin in the left vs right sides. ### interventions Treatment with SC or SC plus bevacizumab or cetuximab. ### Main Outcomes And Measures Mortality hazards by tumor origin (right vs left sides) were assessed for patients receiving SC alone or SC plus bevacizumab or cetuximab. Subgroup analysis for patients with wild-type KRAS tumors was also performed. ### results A total of 11 905 patients with mCRC (6713 men [56.4%] and 5192 women [43.6%]; mean [SD] age, 60.0 [10.9] years) were eligible for the study. Among these, 4632 patients received SC and BT. Compared with SC alone, SC plus bevacizumab reduced mortality among patients with right- and left-sided mCRC, whereas SC plus cetuximab reduced mortality only among patients with left-sided tumors and was associated with significantly higher mortality for right-sided tumors (hazard ratio [HR], 1.31; 95% CI, 1.14-1.51; P < .001). Among patients treated with SC plus BT, right-sided tumor origin was associated with higher mortality among patients receiving bevacizumab (HR, 1.31; 95% CI, 1.25-1.36; P < .001) and cetuximab (HR, 1.88; 95% CI, 1.68-2.12; P < .001) BT, compared with left-sided tumor origin. In patients with wild-type KRAS tumors (n = 668), cetuximab was associated with reduced mortality among only patients with left-sided mCRC compared with bevacizumab (HR, 0.75; 95% CI, 0.63-0.90; P = .002), whereas patients with right-sided mCRC had more than double the mortality compared with those with left-sided mCRC (HR, 2.44; 95% CI, 1.83-3.25, P < .001). ### Conclusions And Relevance Primary tumor site is associated with response to BT in mCRC. Right-sided primary tumor location is associated with higher mortality regardless of BT type. In patients with wild-type KRAS tumors, treatment with cetuximab benefited only those with left-sided mCRC and was associated with significantly poorer survival among those with right-sided mCRC. Our results underscore the importance of stratification by tumor site for current treatment guidelines and future clinical trials.


Vinorelbine

Gemcitabine

Sequential therapy with Vinorelbine followed by Gemcitabine in patients with metastatic non small cell lung cancer (NSCLC), performance status (PS) 2, or elderly with comorbidities--a multicenter phase II trial. High risk patients with metastatic non small cell lung cancer (NSCLC) including patients with performance status (PS) 2 or elderly with comorbidities do poorly on combination chemotherapy regimens. We evaluated a sequential treatment with Vinorelbine followed by Gemcitabine to determine its effect on survival and the toxicity in this patient population . ### methods Forty-two evaluable patients, median age 75, 21 patients with PS 2 and 21 patients with PS 0 or 1, 37 patients with stage IV and five patients with stage III B NSCLC entered the trial. They received vinorelbine 30 mg/m2, i.v., on days 1+8 every 3 weeks followed by gemcitabine 1000 mg/m2, i.v., on days 1+8 every 3 weeks, each for two cycles for stable disease or one cycle after best response. Then stable patients continued until progressive disease on vinorelbine or gemcitabine according to the patient's preference. ### results A total of 126 cycles of vinorelbine were administered to 42 patients, median of three cycles per patient and 74 cycles of gemcitabine, median of 1.0 cycle per patient. Sixteen patients (38%) achieved PR, 11 patients on vinorelbine, 5 patients on gemcitabine; 12 patients (26%) had stable disease, 7 patients on vinorelbine, 5 patients on gemcitabine. Of 24 patients with progressive disease on vinorelbine, 3 patients (12.5%) responded to gemcitabine. Median time-to-first progression was 3.5 months, median survival was 8 months, 1-year survival was 12 patients (28.5%). No grade 3 or 4 toxicities were reported. ### conclusion This sequential treatment offers excellent palliative treatment with minimal toxicity for high-risk patients with metastatic NSCLC.


etoposide

colchicine

Apoptosis in Hep2 cells treated with etoposide and colchicine . When malignant cells undergo apoptosis, they exhibit many distinct patterns of behavior, with blebbing being one of the most spectacular and mysterious features. Despite huge advancements in our understanding of cell death, the mechanisms of apoptosis associated blebbing have not been elucidated. In order to verify the putative involvement of actin and tubulin in this process, Hep2 cells were treated with a combination of etoposide (10 microg/ml) and colchicine (0.2 microg/ml) for 24 h. Blebbing was analyzed using immunofluorescence staining of actin and tubulin, and the course of apoptosis was followed by time-lapse videomicroscopy, immunofluorescence detection of caspase-3 and cytokeratin fragment 18. The results indicate that microfilaments (actin) and not microtubules (tubulin) are involved in blebbing of Hep2 cells. Furthermore, despite the different mechanisms by which both chemicals act, their combined effects are not additive, but rather eliminate each other.


carboplatin

paclitaxel

Phase II study of carboplatin and weekly paclitaxel combination chemotherapy in advanced non-small cell lung cancer: a Kansai Clinical Oncology Group study.  The objective of this phase II study was to evaluate the efficacy and toxicity of carboplatin and weekly paclitaxel combination chemotherapy in previously untreated , advanced non-small cell lung cancer ( NSCLC ) . Patients received paclitaxel at a dose of 70 mg/m(2) on days 1, 8, 15, and carboplatin with the target dose of area under the curve (AUC) of 6 on day 1 every 28 days. Forty-six patients were enrolled. A median of four cycles (range, 1-13) were administered. Complete response was observed in one patient (2.2%) and partial response in 23 patients (50%), yielding an overall intent-to-treat response rate of 52.2% (95% confidence interval, 37.8-66.6%). The median survival time was 395 days and 1-year survival rate was 51.4%. Toxicities were mild. Twelve patients (26%) had grade 3 and three patients (7%) had grade 4 neutropenia. Grade 3 thrombocytopenia was seen in four patients (8%). Massive hematoemesis due to duodenal ulcer was observed in one patient, but no other patients experienced grade 3 or more non-hematological toxicities. There was no treatment-related death. carboplatin and weekly paclitaxel combination chemotherapy is an efficacious and feasible regimen in patients with advanced NSCLC, and this treatment will be a reasonable alternative to the conventional triweekly regimen of paclitaxel and carboplatin.


vincristine

cyclophosphamide

doxorubicin

prednisone

doxorubicin

ranimustine

prednisone

etoposide

carboplatin

prednisone

vindesine

A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma: Japan Clinical Oncology Group Study 9303. This phase II trial was performed to evaluate the efficacy of a new granulocyte colony-stimulating factor (G-CSF)-supported multi-agent chemotherapy protocol, LSG15, for aggressive adult T-cell leukaemia-lymphoma (ATL). Ninety-six previously untreated patients with aggressive ATL were enrolled and grouped as: acute type (58), lymphoma type (28) and unfavourable chronic type (10). Therapy consisted of seven cycles of VCAP ( vincristine , cyclophosphamide , doxorubicin and prednisone ) , AMP ( doxorubicin , ranimustine and prednisone ) and VECP ( vindesine , etoposide , carboplatin and prednisone ) . G-CSF was administered during the intervals between chemotherapy until neutrophil reconstitution was achieved. Eighty-one per cent of the 93 eligible patients responded [95% confidence interval (CI), 71.1-88.1%], with 33 patients obtaining complete response (35.5%) and 42 obtaining partial response (45.2%). The median survival time (MST) after registration was 13 months and the median follow-up duration of the 20 surviving patients was 4.2 years (range 2.8-5.6). Overall survival at 2 years was estimated to be 31.3% (95% CI, 22.0-40.5%). Grade 4 haematological toxicity of neutropenia and thrombocytopenia were observed in 65.3% and 52.6% of the patients respectively, but grade 4 non-haematological toxicity was observed in only one patient. LSG15 is feasible with mild non-haematological toxicity and improved the clinical outcome of ATL patients. MST and overall survival at 2 years were superior to those obtained by our previous trials.


naproxen

dexamethasone

Effects of certain antiarthritic agents on the synthesis of type II collagen and glycosaminoglycans in rat chondrosarcoma cultures. Cartilage destruction is a characteristic feature of osteoarthritis. Treatment with certain nonsteroidal anti-inflammatory drugs could exacerbate cartilage destruction by impairing the synthesis of cartilage matrix proteins, type II collagen and proteoglycan. In order to monitor the changes occurring in cartilage collagen synthesis, we developed a type II collagen specific ELISA. The effects of antiarthritic agents on type II collagen and glycosaminoglycan synthesis were examined in rat chondrosarcoma cultures. Drugs were added to the monolayer cultures and 4 days later the total type II collagen, as determined by the type II collagen ELISA, and glycosaminoglycan content, as measured by dimethyl-methylene blue dye binding assay, was measured. All drugs except tiaprofenic acid decreased type II collagen synthesis by at least 40% at 100 micrograms/ml. tiaprofenic acid at 1 microgram/ml increased type II collagen content by 54% of the controls. Glycosaminoglycan synthesis was decreased by acetylsalicylic acid, diclofenac and tiaprofenac acid, at 50 micrograms/ml or above. Indomethacin , naproxen and dexamethasone had no effect . Interestingly, tenidap stimulated the glycosaminoglycan synthesis by 32% at 100 micrograms/ml. We show that the combination of chondrosarcoma cultures, type II collagen specific ELISA and dimethylmethylene blue dye binding assay serves as a useful model for screening the effects of agents capable of modulating type II collagen and glycosaminoglycan synthesis.


trastuzumab

lapatinib

Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo. HER2 amplification occurs in 18% to 27% of gastric and gastroesophageal junction cancers. lapatinib, a potent ATP-competitive inhibitor simultaneously inhibits both EGFR and HER2. To explore the role of HER family biology in upper gastrointestinal cancers, we evaluated the effect of lapatinib, erlotinib, and trastuzumab in a panel of molecularly characterized human upper gastrointestinal cancer cell lines and xenografts. ### Experimental Design EGFR and HER2 protein expression were determined in a panel of 14 human upper gastrointestinal cancer cell lines and HER2 status was assessed by fluorescent in situ hybridization. Dose-response curves were generated to determine sensitivity to lapatinib, erlotinib, and trastuzumab. In HER2-amplified cells , the combination of trastuzumab and lapatinib was evaluated using the median effects principal . The efficacy of lapatinib, trastuzumab, or the combination was examined in HER2-amplified xenograft models. ### results lapatinib had concentration-dependent antiproliferative activity across the panel with the greatest effects in HER2-amplified cells. There was no association between EGFR protein expression and sensitivity to any of the HER-targeted agents. Cell cycle analysis revealed that lapatinib induced G(1) arrest in sensitive lines and phosphorylated AKT and phosphorylated ERK were decreased in response to lapatinib as well. The combination of lapatinib and trastuzumab was highly synergistic in inhibiting cell growth with a combination index of <1. The combination also induced greater decreases in AKT and ERK activation, G(0)-G(1) cell cycle arrest, and increased rates of apoptosis. In vivo studies showed that the combination of lapatinib and trastuzumab had greater antitumor efficacy than either drug alone. ### conclusion Together, these data suggest that lapatinib has activity in HER2-amplified upper gastrointestinal cancer and supports the ongoing clinical investigation of lapatinib in patients with HER2-amplified disease.


voriconazole

hydrochlorothiazide

Inflammation Due to Voriconazole-induced Photosensitivity Enhanced Skin Phototumorigenesis in Xpa-knockout Mice. voriconazole is an antifungal agent and used as a prophylactic measure, especially in immunocompromised patients. However, there have been several reports of its adverse reactions, namely photosensitivity with intense inflammatory rashes and subsequent skin cancer development. To assess the effects of photosensitizing drugs voriconazole and hydrochlorothiazide ( HCTZ ) on the enhancement of UV-induced inflammatory responses and UV-induced tumorigenesis , we utilized Xpa-knockout mice , which is DNA repair-deficient and more susceptible to UV-induced inflammation and tumor development than wild-type mice . Administration of voriconazole prior to broadband UVB exposure significantly upregulated multiple inflammatory cytokines compared with the vehicle- or HCTZ-administered groups. voriconazole administration along with chronic UVB exposure produced significantly higher number of skin tumors than HCTZ or vehicle in Xpa-knockout mice. Furthermore, the investigation of UVB-induced DNA damage using embryonic fibroblasts of Xpa-knockout mice revealed a significantly higher 8-oxo-7,8-dihydroguanine level in cells treated with voriconazole N-oxide, a voriconazole-metabolite during UV exposure. The data suggest that voriconazole plus UVB-induced inflammatory response may be related to voriconazole-induced skin phototumorigenesis.


Sorafenib

bevacizumab

ixabepilone

gemcitabine

capecitabine

tamoxifen

Sorafenib in breast cancer treatment: A systematic review and overview of clinical trials. To evaluate the current role of sorafenib, an oral multikinase inhibitor in the treatment of breast cancer. ### methods An extensive search of the literature until March 2016 was carried out in Medline and clinicaltrials.gov, by using the search terms "sorafenib" and "breast cancer". Papers found were checked for further relevant publications. Overall, 21 relevant studies were found, 18 in advanced breast cancer (16 in stage IV and two in stages III-IV) and three in early breast cancer. ### results Among studies in advanced breast cancer, there were two trials with sorafenib as monotherapy, four trials of sorafenib in combination with taxanes, two in combination with capecitabine, one with gemcitabine and/or capecitabine, one with vinorelbine, one with bevacizumab, one with pemetrexed and one with ixabepilone, three trials of sorafenib in combination with endocrine therapy and two trials in women with brain metastases undergoing whole brain radiotherapy. In addition, there was one trial of sorafenib added to standard chemotherapy in the adjuvant setting, and two trials in the neoadjuvant setting. In general, sorafenib was well tolerated in breast cancer patients, though its dosage had to be adjusted in some trials, and discontinuation rates were high, particularly for the combination of sorafenib with anastrozole. Sorafenib monotherapy and combinations with taxanes , bevacizumab and ixabepilone showed inadequate efficacy , while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising . ### conclusion At present, sorafenib should not be used for the treatment of breast cancer outside of clinical trials and more clinical data are needed in order to support its standard use in breast cancer therapy.


paclitaxel

cisplatin

carboplatin

Current status of taxane and platinum-based chemotherapy in ovarian cancer. Before 1993, the standard of care for the chemotherapeutic management of advanced ovarian cancer was cisplatin or carboplatin combined with a classic alkylating agent (typically cyclophosphamide). Studies in the 1990s have changed this standard to one of the platinum-containing agents combined with a taxane, paclitaxel, or docetaxel. This article reviews the pertinent studies regarding paclitaxel combined with cisplatin or carboplatin , discusses the remaining controversies surrounding how best to combine these agents , and provides opinions regarding the discordant outcomes noted in studies of the paclitaxel-platinum doublet . A separate article discusses the docetaxel-platinum doublet and how that might be considered an appropriate option for first-line therapy in patients with advanced, newly diagnosed ovarian cancer.


neomycin

lactitol

[Lactitol and neomycin: monotherapy or combined therapy in the prevention and treatment of hepatic encephalopathy?]. The beneficial effect of disaccharides, lactulose and lactitol, in prevention and treatment of hepatic encephalopathy is well established but their use in combination with neomycin is still controversial. We studied in vitro the fecal bacterial growth, acid and gas formation in presence of lactitol (beta-galactoside-sorbitol) and neomycin alone or in combination. The results indicate that neomycin only inhibits the growth of susceptible bacteria ( E. coli , Staph . aureus ) which , conversely , are poor lactitol fermenters . The resistant organisms (Lactobacillus acidophilus, Clostridium perfringens) that are efficient disaccharide fermenters continue to metabolize lactitol still when antibiotic is added. Addition of lactitol 10% increased the inhibitory effect of neomycin on bacterial growth by 25-50% within 60-70 min. These preliminary data suggest that lactitol and neomycin may have additional or synergistic effects in vivo when used together in presence of favourable intestinal microbial environment.


cis-platinum

carboplatin

oxaliplatin

Hyperthermia

[Effects of hyperthermia combined platinum-based drugs on ovarian cancer cell lines SKOV3]. To investigate the effects and mechanisms of hyperthermia combined with various platinum-based drugs cis-platinum (DDP), carboplatin (CBP), oxaliplatin (OXA) on the proliferation and apoptosis of ovarian cancer cell lines SKOV3. ### methods SKOV3 cells were treated with different concentrations of anticancer drugs DDP (final concentration respectively 0, 1.25, 2.5, 5.0, 10.0, 20.0 microg/mL), CBP and OXA (both final concentration respectively 0, 2.5, 5.0, 10.0, 20.0, 40 microg/mL) at a temperature of 42 degrees C for hyperthermia or 37 degrees C for normal temperature. Methyl thiazolyl tetrazolium (MTT) method was used to test growth ratios of ovarian cancer cell lines SKOV3. Real-time PCR was adopted to detect the expression level of excision repair cross-complementing group 1 (ERCC1) and Survivin mRNA in SKOV3 cells. ### results DDP, CBP and OXA inhibited the growth of SKOV3 in a dose-dependent manner (P < 0.05). Hyperthermia could increase the sensitivity of SKOV3 to cis-platinum , carboplatin and oxaliplatin ( P < 0.05 ) . The half inhibitory concentration (IC50) values of DDP, CBP and OXA were (7.271 +/- 0.096) microg/mL, (37.609 +/- 0.779) microg/mL and (28.328 +/- 0.698) microg/mL respectively. When combined with hyperthermia, the IC50 values of DDP, CBP, and OXA were (2.075 +/- 0.244) microg/mL, (19.591 +/- 0.453) microg/mL, (19.089 +/- 0.424) microg/mL (P < 0.05). The increased sensitivity index was 2.075 +/- 0.244 for cis-platinum, 1.92 +/- 0.044 for carboplatin, 1.484 +/- 0.039 for oxaliplatin. After the treatment of hyperthermia, the expression of ERCC1 and Survivin mRNA showed downward trend. ERCC1 decreased more significantly in the group of hyperthermia combined with carboplatin, and Survivin decreased more significantly in the group of hyperthermia combined with oxaliplatin (P < 0.05). ### conclusion Hyperthermia can enhance the sensitivity of ovarian cancer SKOV3 cells to platinum-based drugs, which may be related to the down regulation of ERCC1 and Survivin expression.


oxaliplatin

leucovorin

Quality of Life Outcomes From a Phase 2 Trial of Short-Course Radiation Therapy Followed by FOLFOX Chemotherapy as Preoperative Treatment for Rectal Cancer.  A prospective phase 2 trial of short-course ( SC ) radiation therapy ( RT ) with 25 Gy over 5 fractions , followed by 4 cycles of 5-fluorouracil , oxaliplatin , and leucovorin ( mFOLFOX6 ) before surgery was recently completed at our institution . We present here the patient-reported quality of life (QOL) outcomes from this trial. ### Methods And Materials Eighty patients with cT3/T4, any N, any M rectal adenocarcinoma planned for resection were enrolled between 2009 and 2012. The QOL data were obtained prospectively using the Functional Assessment of Cancer Therapy-Colon (FACT-C) questionnaire before RT, before surgery, and 1 year after surgery. The previously validated minimally importance difference (MID) method was used to measure clinically significant QOL changes in FACT-C scores for each patient across time points. We examined the role of ostomy on QOL. We also compared QOL with disease outcomes and physician-reported toxicity. ### results The FACT-C questionnaire was completed by 97% of patients before RT, 85% immediately before surgery, and 62% 1 year after surgery. There was no statistically significant change in mean FACT-C scores from before treatment to after treatment. The majority of patients had either no change or an increase in QOL 1 year after treatment using the MID method. There were significant changes in QOL between patients with ostomy versus no ostomy 1 year after treatment for functional well-being (FWB) (14.81 vs 20.52, P=.018) and the colorectal cancer subscale (CCS) using the MID method (P=.004). Patients without ostomy reported stable changes in bowel control 1 year after surgery. There was no statistically significant correlation between QOL and disease recurrence, pathologic complete response, pathologic T stage downstaging, or acute/late toxicity. ### conclusions SC-RT and sequential mFOLFOX6 as preoperative therapy for rectal cancer results in stable patient-reported QOL outcomes 1 year after treatment. These findings in conjunction with previously reported oncologic outcomes support further evaluation of this regimen in a phase 3 setting.


trastuzumab

capecitabine

Cisplatin

[ A case of advanced gastric cancer successfully treated with trastuzumab , capecitabine , and Cisplatin therapy followed by curative resection ] . We report a case of human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer successfully treated with combination therapy of trastuzumab, capecitabine, and cisplatin, followed by a curative resection. A 23-year-old woman was diagnosed with advanced type 3 gastric cancer, and the clinical findings were T3N0M0, StageIIA. A laparoscopic exploration revealed that it was a CY1 unresectable StageIV cancer. Initially, docetaxel, cisplatin, and S-1 therapy was chosen. However, the patient's HER2 status proved to be positive (IHC 3+), and so trastuzumab, capecitabine and cisplatin therapy was administered. After four cycles, the tumor significantly decreased in size, suggesting a partial response(PR). A further laparoscopic exam showed no apparent dissemination or metastatic cancer cells. We performed a curative resection consisting of a laparoscopic distal gastrectomy and D2 lymphadenectomy. The patient's postoperative course has been uneventful. She has been alive for 4 months and is receiving adjuvant chemotherapy comprising trastuzumab and S-1.


Sulpiride

hydroxyzine

Sulpiride plus hydroxyzine decrease tinnitus perception . The aim of the study is to confirm the effectiveness of sulpiride and hydroxyzine in tinnitus patients. The administration of sulpiride, a D2 antagonist of dopamine receptors, together with hydroxyzine, a subcortical sedative, covers the areas of tinnitus perception. ### methods A prospective, randomized, single blinded, placebo-control study was done in general otorhinolaryngology consultations for 2002-2004 in Seville and Zaragoza (Spain). One hundred and fifty patients consulted for subjective tinnitus. They were included randomly in three groups of 50. A group took sulpiride (50 mg/8 h) alone, other the same dose of sulpiride plus hydroxyzine (25 mg/12 h), and the third placebo (lactose), for 1 month. One hundred and twenty-two patients completed the study. Clinical history, tonal audiometry, tympanometry, and tinnitometry were done in the beginning and end of the study. Subjective Grading of Tinnitus Perception and visual analogical scale (0-10) were done for result evaluation. ### results Based on the Subjective Grading of Tinnitus Perception, tinnitus perception diminished by 56% in patients treated with sulpiride and by 81% in patients treated with sulpiride plus hydroxyzine. Based on the visual analogical scale, tinnitus perception diminished from 7.8 to 6.3 in the patients treated with sulpiride, and from 7.8 to 5.1 in those treated with sulpiride plus hydroxyzine. ### conclusions sulpiride plus hydroxyzine decreases tinnitus perception. Tinnitus auditolimbic dopaminergic pathway opens wide therapeutical implications.


anastrozole

tamoxifen

' Arimidex ' ( anastrozole ) versus tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer -- efficacy overview . ATAC, a randomized, double-blind trial, compared tamoxifen (20 mg) with anastrozole ('Arimidex') (1 mg) alone, and the combination of anastrozole plus tamoxifen (combination), as adjuvant endocrine treatment for postmenopausal patients with early breast cancer. Patients with operable invasive breast cancer following completion of primary therapy, who were candidates to receive adjuvant endocrine therapy, were eligible for this study. Primary endpoints were disease-free survival (DFS) and tolerability. Other endpoints included time to recurrence (TTR: censoring non-breast cancer deaths before recurrence) and the incidence of contralateral breast cancer. A total of 9366 patients were included in this study (N=3125, 3116 and 3125 for anastrozole, tamoxifen and the combination, respectively). Median duration of therapy was 30.7 months and median follow-up was 33.3 months. The total numbers of events were 317, 379 and 383 for anastrozole, tamoxifen and the combination, respectively. DFS was significantly improved in the overall population for anastrozole versus tamoxifen (hazard ratio (HR)=0.81, 95% confidence interval (CI) (0.71-0.96), P=0.013). anastrozole showed improved TTR compared with tamoxifen (HR=0.79, CI (0.67-0.94), P=0.008), which improved even further in the ER+ and/or PR+ subgroup (HR=0.73, CI (0.59-0.90), P=0.003). The incidences of hot flushes, thromboembolic events, ischaemic cerebrovascular events, vaginal bleeding/discharge and endometrial cancer were significantly reduced with anastrozole compared with tamoxifen (P<0.03 for all). Musculoskeletal disorders and fractures were significantly reduced in patients receiving tamoxifen compared with those on anastrozole (P<0.03 for both). No increase in hip fractures was seen for anastrozole versus tamoxifen (11 versus 13, respectively). Combination treatment was equivalent to tamoxifen in terms of both efficacy and tolerability. anastrozole showed superior efficacy to tamoxifen for DFS, TTR and contralateral breast cancer. Early findings show anastrozole to be an effective and well-tolerated endocrine option for the treatment of postmenopausal patients with early breast cancer. For the first time a choice now exists for adjuvant endocrine treatment for postmenopausal women with hormone responsive tumours. Longer follow-up will further define the benefit/risk of anastrozole adjuvant therapy.


tissue plasminogen activator

heparin

prostaglandin E1

Successful treatment of an infant with veno-occlusive disease developed after allogeneic bone marrow transplantation by tissue plasminogen activator, heparin and prostaglandin E1. A 15-month-old boy with severe aplastic anemia developed veno-occlusive disease (VOD) after allogeneic bone marrow transplantation (BMT), in which the preparative regimen included 50 mg/kg/day cyclophosphamide and anti-lymphocyte globulin for 4 consecutive days. The diagnosis was made based on clinical symptoms and data including, hepatomegaly, right upper quadrant abdominal pain, jaundice, ascites, coagulopathy and thrombocytopenia which was refractory to transfusions of platelet concentrate. We gave 2 , 3 , 5 and 5 mg/day/body of recombinant tissue plasminogen activator ( tPA ) followed by heparin and prostaglandin E1 ( PGE1 ) effectively and without significant side effect on days 9 , 10 , 13 and 14 , respectively . Clinical and biochemical improvement was steady and dramatic. We suggest that tPA following continuous heparin and PGE1 infusion may be useful in the treatment of VOD even in infantile cases.


Roxithromycin

clarithromycin

Roxithromycin and clarithromycin , 14-membered ring macrolides , potentiate the antitumor activity of cytotoxic agents against mouse B16 melanoma cells . We previously reported antiangiogenic activity of roxithromycin and clarithromycin, 14-membered ring macrolide antibiotics. In the present study, we examined the antitumor effects of roxithromycin and clarithromycin, alone and in combination with several cytotoxic drugs, on mouse B16BL6 melanoma cells in vivo and in vitro. Both roxithromycin and clarithromycin potentiated the inhibition of tumor growth induced by cyclophosphamide, cis-diamminedichloroplatinum(II), Adriamycin and vindesine in vivo. However, neither roxithromycin nor clarithromycin, altered the cytotoxicity of 4-hydroperoxycyclophosphamide, cis-diamminedichloroplatinum(II), Adriamycin or vindesine in an in vitro cell proliferation assay. These results suggest that the antiangiogenic activity of roxithromycin and clarithromycin may provide beneficial effects in combination with cytotoxic therapies against solid tumors.


etoposide

vinblastine

doxorubicin

etoposide

bleomycin

dacarbazine

Primary systemic treatment of advanced Hodgkin's disease with EVA (etoposide, vinblastine, doxorubicin): 10-year follow-up. The most commonly used regimen for the treatment of advanced Hodgkin's disease (HD) is ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Two of these components, bleomycin and dacarbazine, have defined toxicities such as pulmonary fibrosis and nausea/vomiting, and also uncertain single-drug activity. The EVA regimen ( etoposide , vinblastine , doxorubicin ) is an attempt to substitute a known active agent , etoposide , for bleomycin and dacarbazine . ### Patients And Methods A series of 51 patients with advanced HD without prior systemic therapy were treated. The series included 12 stage II patients with bulky (>10 cm) mediastinal tumors, 10 of whom received complementary radiation therapy. The remaining patients received EVA only. Response, duration of response, survival, toxicity and the efficacy of salvage therapy were evaluated in all patients. The median follow-up time was 111 months and permitted an assessment of the long-term effects of treatment and natural history of a cohort of treated patients. ### results EVA achieved a complete response (or clinical complete response) in 48/51 patients (94%). Of these 48 responders, 16 relapsed in a median of 11 months (range 3-48 months). In follow-up, 32/51 patients had no evidence of relapsed HD, although three died from other causes (two from vascular events and one from large cell lymphoma), resulting in progression-free survival for the entire group of 57% at 111 months. Eight of the 16 were alive and free from disease at follow-up at 111 months. In the entire series, only seven patients (14%) died of HD. 37 patients (73%) continued free from disease. There was no pulmonary toxicity. ### conclusions The EVA regimen appears to have an overall survival (OS) outcome comparable to ABVD, but without the lung toxicity. The high salvage rate of second-line therapy, in most instances at conventional dosage, suggests an absence of cross-resistance to alkylating agents in patients treated with EVA.


gemcitabine

vinorelbine

irinotecan

Chemoresistance in non-small cell lung cancer.  The treatment of advanced non-small-cell lung cancer ( NSCLC is based on the combination of platin and one of the following agents : taxanes , gemcitabine , vinorelbine or irinotecan . There are no significant differences in efficacy among these combinations suggesting that the maximum efficacy has been reached. In this review, we will consider the mechanisms of chemoresistance of the five groups of cytotoxic drugs commonly used in the treatment of advanced NSCLC as well as the clinical studies which have assessed the value of chemoresistance markers. Breast Cancer Related Protein (BRCP) expression has been related to irinotecan and cisplatin (CDDP) resistance. DNA repair capacity influences response to CDDP and ERCC1 gene stands out as a predictive marker of CDDP sensitivity. Preliminary studies indicate that high tubulin III and stathmin mRNA levels correlate with response to paclitaxel and vinorelbine and that high expression of class III tubulin by tumor cells assessed immunohistochemically in patients receiving a taxane-based regimen is associated with a poor response to chemotherapy, and a shorter progression-free survival. High expression levels of ribonucleotide reductase has also been related to response to gemcitabine. Uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) genotype has been reported to be associated with time to progression and survival in patients treated with irinotecan. These data suggest that pharmacogenomic strategies may be used for developing customized chemotherapy in prospective studies. Adjuvant chemotherapy which had recently shown its usefulness in limited lung cancer represents another area of investigation for pharmacogenomic studies.


Carvedilol

imatinib

Carvedilol in glioma treatment alone and with imatinib in vitro. The purpose of the study was to investigate whether carvedilol has an antiproliferative effect alone and whether carvedilol provides an additive, synergistic or antagonistic effect on imatinib mesylate-induced cytotoxicity in both C6 glioma monolayer and spheroid culture. The C6 rat glioma chemoresistant experimental brain tumour cell line, that is notoriously difficult to treat with combination chemotherapy, was used both in monolayer and spheroid cultures. We treated C6 glioma cells with carvedilol alone and a combination of carvedilol and imatinib mesylate at a concentration of 10 microM. Following treatment, we evaluated cell proliferation index, bromodeoxyuridine labelling index (BrDU-LI), cell cycle distributions, apoptotic cell percentages, cAMP levels and three dimensional cell morphology at monolayer cultures. In addition BrDU-LI, volume and morphology of spheroids were also assessed. Carvedilol and imatinib mesylate alone reduced cell number , BrDU-LI , cAMP levels and spheroid volume . carvedilol and imatinib mesylate arrested cells at G0/G1 phase in a time-dependent manner and time-independent manner, respectively. carvedilol increased apoptosis rate only at the 24th h, but imatinib mesylate did for all time intervals. Interestingly carvedilol, drug with well-known protective effect on mitochondria, induced severe mitochondria damage, and imatinib mesylate induced autophagy confirmed only by transmission electron microscopy. These results suggest that carvedilol showed antitumour activity against rat C6 glioma cells and a combination of carvedilol with imatinib mesylate resulted in enhanced in vitro antitumour activity.


cytarabine

sorafenib

A phase I/II study of sorafenib in combination with low dose cytarabine in elderly patients with acute myeloid leukemia or high-risk myelodysplastic syndrome from the National Cancer Institute of Canada Clinical Trials Group: trial IND.186. sorafenib is active in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The National Cancer Institute of Canada (NCIC) Clinical Trials Group initiated a phase I/II study of the combination of sorafenib with cytarabine in older patients with AML or high-risk MDS who were unsuitable for intensive chemotherapy. FLT3 mutational status was determined in all patients. Twenty-one patients were enrolled (four MDS, 17 AML) with a median age of 77 years. The recommended phase II dose ( RP2D ) was cytarabine 10 mg bid days 1 - 10 and sorafenib 600 mg/day days 2 - 28 . Dose-limiting toxicities were fatigue, sepsis and skin rash. Of 15 evaluable patients treated at the RP2D, two patients responded. The overall response rate for eligible patients was 10%. FLT3 mutations were found in only three patients. We conclude that this combination of sorafenib and cytarabine has limited activity in this unselected cohort of elderly patients with AML/MDS in which FLT3 mutations seemed underrepresented.


panitumumab

cetuximab

Panitumumab in patients with KRAS wild-type colorectal cancer after progression on cetuximab. cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type meta-static colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab . ### Patients And Methods We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve patients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies. ### results We treated twenty patients for a median of two cycles (range 1-4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. panitumumab was well tolerated. Thirteen patients (65%) had grade 1-2 dry skin or rash, and three patients had treatment-related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies. ### conclusions panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab. Discussion Both cetuximab and panitumumab competitively inhibit ligand binding to EGFR, thereby promoting receptor internalization and blocking receptor-mediated signaling. Although the two agents have never been compared directly in a randomized clinical trial, they produce similar response rates when used alone as well as in combination with cytotoxic agents. cetuximab is a chimeric antibody with approximately 30% murine protein, while panitumumab is a fully human monoclonal antibody. Correspondingly, rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). However, the potential efficacy of panitumumab in patients who have developed disease progression on cetuximab has been an open question. Metges et al. (PANERB trial) prospectively treated 32 KRAS wild-type metastatic colorectal cancer patients with cetuximab and irinotecan followed by panitumumab monotherapy after progression. Remarkably, the authors reported an objective response rate of 22% to panitumumab, including a disease control rate (objective response plus stable disease) of 73% in 11 patients who had previously responded to cetuximab and irinotecan. In contrast, we found no responders and a stable disease rate of 45% with a median duration of only 1.7 months in our trial of 20 patients. Moreover, no patients had detectable anti-cetuximab antibodies at baseline. It is not clear to what extent the PANERB trial included patients without objective disease progression on cetuximab or for whom cetuximab-containing regimens may have been ceased due to toxicity in the absence of disease progression. In both circumstances, retreatment with panitumumab may be expected to demonstrate some degree of clinical activity. In our study, disease progression after at least 4 weeks of cetuximab documented radiographically or by increased carcinoembryonic antigen (CEA) levels was required for inclusion in order to ensure that the study population demonstrated unequivocal evidence of progression on cetuximab. While it remains possible that a small subset of patients may benefit from panitumumab after progression on cetuximab, our results suggest that this approach should not be adopted until predictive biomarkers for panitumumab response in this setting have been discovered and validated. Until then, patients who develop progression on cetuximab should be enrolled in trials of novel agents.


ritonavir

ombitasvir

dasabuvir

cyclosporine

tacrolimus

Pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when coadministered with ABT-450, ombitasvir, and dasabuvir. ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 ( 150 mg coadministered with ritonavir 100 mg once daily ) , ombitasvir ( 25 mg once daily ) , and dasabuvir ( 400 mg twice daily ) on the pharmacokinetics , safety , and tolerability of a single dose of cyclosporine ( 30 mg ) or tacrolimus ( 2 mg ) in healthy volunteers ( N = 12 per study ) . In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C₂₄), and area under the concentration-time curve from time 0 to infinity (AUC(∞)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C₂₄ and AUC(∞) were 17-fold and 57-fold, respectively, of either agent alone. cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen.


estrone

diethylstilbestrol

Novel approaches to the analysis of steroid estrogens in river sediments. A wide range of estrogenic contaminants has been detected in the aquatic environment. Among these, natural and synthetic steroid estrogens, typically present in municipal sewage-treatment plant (STP) effluents, are the most potent. In this study a new GC-MS method has been developed for direct analysis of five major steroid estrogens ( estrone , 17beta-estradiol , 17alpha-ethinylestradiol , dienestrol , and diethylstilbestrol ) in river sediments . Four GC-MS systems used for analysis of underivatized analytes in purified extracts were compared. Relatively low detection limits (1.5-5 ng g(-1) dried sediment) and good repeatability of GC splitless injection (RSD 1-2%) were achieved by use of a system combining low-pressure gas chromatography with a single-quadrupole mass analyzer (LP-GC-MS). Use of orthogonal gas chromatography (GCxGC) hyphenated with high-speed time-of-flight mass spectrometry (HSTOF-MS) enabled not only significantly better resolution of target analytes, and their unequivocal identification, but also further improvement (decrease) of their detection limits. In addition to these outcomes, use of this unique GCxGC-TOF-MS system enabled identification of several other non-target chemicals, including pharmaceutical steroids, present in purified sediment extracts.


dihydroartemisinin

artesunate

artemether

[Research progress of effect of artemisinin family drugs on T lymphocytes immunomodulation]. artemisinin was isolated from traditional Chinese herb Artemisia annua for treating malaria. A series of derivatives , like dihydroartemisinin , artesunate , artemether , artether , had the same core chemical structure , and sesquiterpene lactone containing peroxide bridge constitute the basic chemical structure . Besides anti-malaria,artemisinin family drugs were found to ameliorate many different diseases,which have attracted wide attention in recent years. Among different diseases,artemisinin family drugs were found to have T lymphocytes immunomodulation effects,including activation,proliferation,differentiation,apoptosis and subsets function. Because T cell immunologic response is the key point of many diseases,and impact the pathogenic process,therapeutic effect and prognosis,the drug studies with it as the target have become hotspots in recent years. Studies of artemisinin family drug on T cell immunomodulation were still at the initial stage and involved in different disease; furthermore,T cell immune process involves complicated molecular mechanism,it is imperative to summarize the advance of current studies for further systematic explanation and exploration of their characteristics and mechanisms. This article will summarize the research progress of artemisinin family drugs for malaria,autoimmune disease,hypersensitivity reaction,tumor,schistosomiasis and AIDS relating to T cell immune modulation,so as to provide basic and professional reference for related research and application.


dipyridamole

aspirin

dipyridamole

Effect of dipyridamole and aspirin on vein graft patency after coronary bypass operations.  Antiplatelet therapy with dipyridamole , 100 mg q.i.d . , starting 2 days before surgery , followed by aspirin , 325 mg t.i.d . plus dipyridamole , 75 mg t.i.d . , 7 hours after surgery was assessed in the prevention of saphenous vein bypass graft occlusion . Early (less than or equal to 1 month) and late (1 year) occlusions were reduced both on a per patient and a per distal anastomosis basis. Bleeding complications were not increased. Graft occlusion in high-risk situations (low-flow grafts and endarterectomy) was reduced, but not eliminated, by this antiplatelet regimen. The authors recommend this combination of dipyridamole before surgery, adding aspirin after surgery, to prevent coronary artery bypass graft occlusion.


cyclophosphamide

methotrexate

fluorouracil

Toxicity patterns following stepwise combinations of cyclophosphamide , methotrexate and fluorouracil . The contribution of the agents used in the CMF regimen, i.e., cyclophosphamide (CY), methotrexate (MTX) and fluorouracil (FUra), to the development of toxicity was determined in tumor-bearing WAG/Rij rats. Data from untreated (U) rats were compared with data from rats treated with single-agent therapy (C-, M- and F-treatment groups), with data from double-agent therapy (CM-, MF- and CF-treatment groups) and with data from the triple combination: the CMF-treatment group. Doses of agents of interest were the same in all treatment groups. The sequence of administration was (1) CY; (2) MTX and (3) FUra which is similar to clinical treatment with CMF. Systemic levels of CY, MTX and FUra were comparable to those found in patients treated according to the CMF regimen. Toxicity was evaluated by body-weight changes, water and food consumption, white blood cell (WBC) and platelet cell (Pts) counts. With the exception of WBC and Pts nadirs, estimated toxicity parameters reflected toxicity over the whole treatment period of 14 days. The toxicity was generally mild and well tolerated, with one fatality in the M-treatment group. CY was the main contributor to toxicity; it caused both myelotoxicity and gastro-intestinal toxicity. The contribution of FUra was judged to be negligible. MTX + FUra did not increase host toxicity in a synergistic or even an additional fashion. The absence of addition or synergism of toxic side-effects can be explained both by site-specific interactions at the pharmacodynamic level and by interactions at the pharmacokinetic level.


lapatinib

capecitabine

Lapatinib plus capecitabine for HER2-positive advanced breast cancer: a multicentre study of Anatolian Society of Medical Oncology (ASMO). lapatinib is the first dual tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2/neu) and epidermal growth factor receptor (EGFR). The present study evaluated the efficacy and tolerability of the combination of lapatinib and capecitabine in patients with metastatic breast cancer (MBC) who progressed after therapy with trastuzumab, a taxane and/or anthracycline. A total of 203 patients with a median age of 48 years (range: 25-82 years) were evaluated retrospectively in 11 centres between September 2007 and May 2011. All the patients had HER2-positive MBC progressing after trastuzumab and chemotherapy including an anthracycline and/or taxane. All patients were treated with the combination of lapatinib ( 1250 mg/day , continuously ) and capecitabine ( 2000 mg/m(2 ) on days 1 through 14 of a 21-day cycle ) . Data on demographics, clinical outcome, and toxicity were collected for descriptive analyses. The median follow-up was 10·7 months (range: 1-40 months). An overall response rate (ORR) of 33·4% was achieved including 7 complete responses (CR, 3·4%), 61 partial responses (PR, 30·0%), and 44 stable disease (37·9%). Clinical benefit rate of 71·3% was achieved. Median progression-free survival (PFS) was 7 months (95% CI: 6-10 months), with a median overall survival (OS) of 15 months (95% CI: 12-18 months). The most common side effects were hand-foot syndrome (46·8%), nausea (42·3%), fatigue (42·2%), anorexia (38·5%), diarrhea (31·5%), and rash (29·6%). Grade 3-4 toxicities were identified as hand foot syndrome (7·9%), diarrhea (6·9%), fatigue (5·9%), and rash (5·4%). There were no symptomatic cardiac events. lapatinib and capecitabine combination therapy is effective and well tolerated in patients with MBC who had progressive disease after trastuzumab, taxane, and/or anthracycline therapy, as evidenced by this retrospective evaluation. Toxicity was mild to moderate with low grade 3-4 toxicity.


histamine

pyrilamine

ranitidine

morphine

naloxone

Interaction between histamine and morphine at the level of the hippocampus in the formalin-induced orofacial pain in rats.  The present study explored the interaction between histaminergic and opioidergic systems at the level of the hippocampus in modulation of orofacial pain by intra-hippocampal microinjections of histamine , pyrilamine ( an antagonist of histamine H(1 ) receptors ) , ranitidine ( an antagonist of histamine H(2 ) receptors ) , morphine ( an opioid receptor agonist ) and naloxone ( an opioid receptor antagonist ) in separate and combined treatments . Orofacial pain was induced by subcutaneous (sc) injection of formalin (50 μl, 1%) in the upper lip region and the time spent face rubbing was recorded in 3 min blocks for 45 min. Formalin (sc) produced a marked biphasic (first phase: 0-3 min, second phase: 15-33 min) pain response. Histamine and morphine suppressed both phases of pain. Histamine increased morphine-induced antinociception. pyrilamine and ranitidine had no effects when used alone, whereas pretreatments with pyrilamine and ranitidine prevented histamine- and morphine-induced antinociceptive effects. naloxone alone non-significantly increased pain intensity and inhibited the antinociceptive effects of morphine and histamine. The results of the present study indicate that at the level of the hippocampus, histamine through its H(1) and H(2) receptors, mediates orofacial region pain. Moreover, morphine via a naloxone-reversible mechanism produces analgesia. In addition, both histamine H(1) and H(2) receptors, as well as opioid receptors may be involved in the interaction between histamine and morphine in producing analgesia.


curcumin

doxorubicin

Curcumin Rescues Doxorubicin Responsiveness via Regulating Aurora a Signaling Network in Breast Cancer Cells. Insensitivity towards anthracycline drugs like doxorubicin poses a significant challenge in the treatment of breast cancer. Among several factors, Aurora A (a mitotic serine threonine kinase) plays crucial roles in acquiring non-responsiveness towards doxorubicin. However, the mechanisms underlying need to be elucidated. The present study was therefore designed to evaluate the underlying mechanisms of Aurora A mediated doxorubicin insensitivity in MCF-7Dox/R, an isolated resistant-subline of MCF-7 (breast adenocarcinoma cell line). Effect of curcumin , a natural phytochemical in restoring doxorubicin sensitivity by targeting Aurora A was assessed furthermore . ### methods A doxorubicin resistant subline (MCF-7Dox/R) was isolated from the parental MCF-7 cells by treating the cell with gradual step-wise increasing concentration of the drug. Expressions of Aurora A and its target proteins (Akt, IκBα and NFκB) were assessed in both parental and MCF-7Dox/R cells. Both the cell lines were pretreated with curcumin prior to doxorubicin treatment. Cellular proliferation rate was measured using BrdU (5-bromo-2'-deoxyuridine) assay kit. Intracellular doxorubicin accumulation was estimated spectrofluorimetrically. Cellular uptake of curcumin (spectrophotometric and spectrofluorimetric method) and its nuclear localization was confirmed by confocal microscopic study. Protein expressions were determined by western blot analysis. Localization of Aurora A was ascertained by immunofluorescence assay. To explore the possible outcome of impact of curcumin on Aurora A, cell-cycle distribution and apoptosis were performed subsequently. ### results Higher expressions of Aurora A in MCF-7Dox/R cells led to phosphorylation of Akt as well as IκBα. Phosphorylated IκBα preceded release of NFκB. Phospho-Akt, NFκB consequentially decreased doxorubicin accumulation by enhancing the expressions of ABCG2 and Pgp1 respectively. curcumin by regulating Aurora A and its target molecules sensitized resistant subline towards doxorubicin mediated G2/M-arrest and apoptosis. ### conclusion Molecular targeting of Aurora A by curcumin restores chemosensitivity by increasing the efficacy of doxorubicin in breast cancer..


carbamazepine

phenytoin

Pharmacokinetic interactions between contraceptives and antiepileptic drugs. The occurrence of bi-directional drug interactions between antiepileptic drugs (AEDs) and combined oral contraceptives (OCs) pose potential risks of un-intended pregnancy and as well as seizure deterioration. It is well established that several of the older AEDs ( carbamazepine , phenytoin and phenobarbital ) , are strong inducers of the hepatic cytochrome P450 ( CYP ) 3A4 enzyme system , and are associated with increased the risk of contraceptive failure . In addition, it is demonstrated that also some of the newer AEDs, oxcarbazepine and topiramate influence on the pharmacokinetics of OCs, which is thought to be due to a more selective induction of subgroups of the hepatic enzyme system. Estrogens containing OCs induce the glucuronosyltransferase and may reduce the plasma levels and the effect of AEDs cleared by glucuronidation. This has been most intensively studied for lamotrigine but also other AEDs, which undergoes glucuronidation processes, such as valproate and oxcarbazepine, may be affected by OCs. The magnitude of the drug-drug interactions show in general wide inter-individual variability and the change in the elimination rate is often unpredictable and can be influenced by a number of co-variants such as co-medication of other drugs, as well as genetic and environmental factors. It is therefore recommended that change in OC use is assisted by AED monitoring whenever possible.


olaparib

carboplatin

paclitaxel

Phase Ib with expansion study of olaparib plus weekly (Metronomic) carboplatin and paclitaxel in relapsed ovarian cancer patients.  Our goals were to : establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer ; evaluate dose-limiting toxicities ; and evaluate efficacy at the maximum tolerated dose . ### methods In this open-label, single-arm, investigator-initiated trial (ClinicalTrials.gov NCT01650376), patients with high-grade serous ovarian cancer who failed primary platinum and taxane therapy received oral olaparib tablets twice daily days 1-3 each week combined with fixed-dose metronomic carboplatin AUC2 and paclitaxel 60 mg/m ### results The maximum tolerated dose of olaparib tablets was 150 mg twice daily with metronomic carboplatin and paclitaxel. 54 women were enrolled, 14 in phase Ib and 40 in the expansion phase. The median number of prior therapeutic regimens was 3. Response included 13 complete remission (24%) and 16 partial remission (30%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for an overall response rate of 54% (95% CI 40% to 67%). Of 47 patients who underwent ### conclusions olaparib 150 mg tablet twice daily can be safely administered in combination with metronomic carboplatin and paclitaxel in pre-treated relapsed ovarian cancer with 24% complete remission. ### Trial Registration Number NCT01650376.


Abiraterone

pregnenolone

Abiraterone acetate: a promising drug for the treatment of castration-resistant prostate cancer.  Abiraterone acetate ( CB7630 ) , a pregnenolone analog , is an orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis , CYP17 , and blocks the synthesis of androgens in the testes , adrenal glands and prostate without causing adrenal insufficiency . In clinical studies, abiraterone acetate is well tolerated and shows promising clinical activity in castration-resistant prostate cancer. The recommended Phase II dose of abiraterone acetate is 1000 mg orally daily in combination with prednisone 5 mg twice daily. Side effects are minimal and mostly associated with secondary mineralocorticoid excess, owing to a compensatory increase in upstream steroids, such as deoxycorticosterone and corticosterone. These include hypertension, hypokalemia and edema and are easily manageable with a selective mineralocorticoid antagonist, such as eplerenone, or low-dose corticosteroids. Currently, abiraterone acetate is being tested in a Phase III trial for men with progressive castration-resistant prostate cancer who are chemotherapy naive. A Phase III trial for patients following prior chemotherapy has been completed and is awaiting analysis.


mefloquine

halofantrine

primaquine

atovaquone

artesunate

Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum. The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, primaquine, atovaquone and artesunate were evaluated against Plasmodium falciparum isolates from children with uncomplicated malaria from Libreville (Gabon), using an isotopic, micro, drug susceptibility test. The IC(50) values for ferrochloroquine were in the range 0.43-30.9 nM and the geometric mean IC(50) for the 103 isolates was 10.8 nM (95% CI 8.6-13.5 nM), while the geometric means for chloroquine, quinine, mefloquine, amodiaquine and primaquine were 370 nM, 341 nM, 8.3 nM, 18.1 nM and 7.6 microM, respectively. Ferrochloroquine was active against P. falciparum isolates, 95% of which showed in vitro resistance to chloroquine. Weak positive significant correlations were observed between the responses to ferrochloroquine and that to chloroquine, amodiaquine and quinine, but too low to suggest cross-resistance. There was no significant correlation between the response to ferrochloroquine and those to mefloquine , halofantrine , primaquine , atovaquone or artesunate . Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.


decitabine

cytarabine

aclarubicin

Efficacy and safety of decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin in newly diagnosed elderly patients with acute myeloid leukemia. This prospective phase II, open label, study was designed to assess the efficacy and safety of D-CAG induction treatment for elderly patients with newly diagnosed AML. ### Experimental Design All patients in this study were treated with decitabine of 15 mg/m2 for 5 days and G-CSF for priming , in combination with cytarabine of 10-mg/m2 q12h for 7 days and aclarubicin of 10 mg/day for 4 days ( D-CAG ) . ### results Among 85 evaluable patients, overall response rate (ORR) and complete remission (CR) were 82.4% and 64.7%, respectively, after 1 cycle of therapy. The ORR in patients aged <70 years was 83.0% and 81.6% in patients aged ≥70 years. There was a significantly longer median overall survival (OS) in patients with response (16 months) than in those without response (7 months, p< 0.0001). The OS for patients aged ≥70 years and 60-69 years was 10 months and 12 months, respectively (p=0.4994). The two-year OS probability was 19.2% and the twenty-month survival rate was 33.8%. Induction mortality of D-CAG treated elderly patients with AML is 4.4%. ### conclusion D-CAG regimen was well tolerated and showed a promising clinic efficacy in elderly patients with AML (≥70 years).