Apixaban

rivaroxaban

aspirin

clopidogrel

Oral anticoagulants in coronary heart disease (Section IV). Position paper of the ESC Working Group on Thrombosis - Task Force on Anticoagulants in Heart Disease. Until recently, vitamin K antagonists (VKAs) were the only available oral anticoagulants evaluated for long-term treatment of patients with coronary heart disease (CHD), particularly after an acute coronary syndrome (ACS). Despite efficacy in this setting, VKAs are rarely used because they are cumbersome to administer. Instead, the more readily manageable antiplatelet agents are the mainstay of prevention in ACS patients. This situation has the potential to change with the introduction of non-VKA oral anticoagulants (NOACs), which are easier to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. The NOACs include dabigatran, which inhibits thrombin, and apixaban, rivaroxaban and edoxaban, which inhibit factor Xa. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients , most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel . Although at the doses tested rivaroxaban was effective and apixaban was not, both agents increased major bleeding. The role for the NOACs in ACS management, although promising, is therefore complicated, because it is uncertain how they compare with newer antiplatelet agents, such as prasugrel, ticagrelor or vorapaxar, and because their safety in combination with these other drugs is unknown. Ongoing studies are also now evaluating the use of NOACs in non-valvular atrial fibrillation patients, where their role is established, with coexistent ACS or coronary stenting. Focusing on CHD, we review the results of clinical trials with the NOACs and provide a perspective on their future incorporation into clinical practice.


lidocaine

mepivacaine

Systemic and local effects of lidocaine or mepivacaine when used for intravenous regional anaesthesia of the distal limb in standing sedated horses . Local anaesthetics are being combined clinically with amikacin in intravenous regional limb perfusion (IVRLP), with limited knowledge on the analgesia provided and its onset and duration of action after tourniquet application and release. ### objective To evaluate the systemic clinical effect, limb withdrawal to nociceptive stimulation, and plasma and synovial fluid concentrations after IVRLP with lidocaine or mepivacaine in standing sedated horses. ### Study Design Prospective, controlled, randomised, cross-over study. ### methods Six healthy adult horses were sedated and received IVRLP with lidocaine, mepivacaine or saline (negative control), or perineural anaesthesia of the medial and lateral palmar and palmar metacarpal nerves (positive control) in one forelimb with a 3-week washout period between trials. Electrical and mechanical stimuli were used to test nociceptive threshold of the limb before and after IVRLP/perineural anaesthesia. For lidocaine and mepivacaine trials, blood was collected from the jugular vein and synovial fluid from the radiocarpal joint before, during and out to 24 hours after IVRLP. Drug concentrations were measured using high-performance liquid chromatography. ### results Nociceptive thresholds for lidocaine, mepivacaine and perineural anaesthesia trials were significantly increased compared with saline and baseline values at 10, 20 and 30 minutes, with no differences between anaesthetic trials. During this time, horses had lower heart rates than IVRLP with saline. After tourniquet release at 30 minutes, nociceptive thresholds for lidocaine and mepivacaine trials gradually returned to baselines, whereas perineural anaesthesia trial remained unchanged out to an hour. Plasma lidocaine and mepivacaine concentrations were ≤50 ng/mL while the tourniquet was in place, significantly increasing 10 minutes after tourniquet release. Maximal lidocaine and mepivacaine concentrations in synovial fluid were reached 25 minutes after IVRLP injection. ### Main Limitations amikacin was not included in the perfusate. ### conclusion Similar to perineural anaesthesia, IVRLP with lidocaine or mepivacaine provides anti-nociception to the distal limb in standing sedated horses while a tourniquet is applied with concentrations remaining below toxic levels in plasma and synovial fluid.


ampicillin

azithromycin

chloramphenicol

ciprofloxacin

doxycycline

erythromycin

furazolidone

levofloxacin

Emergence of trimethoprim-resistant Escherichia coli in healthy persons in the absence of prophylactic or therapeutic antibiotics during travel to Guadalajara, Mexico. Thirty-nine healthy US students without diarrheal disease and who had not received prophylactic or therapeutic antibiotics were monitored for emergence of trimethoprim-resistant gram-negative fecal flora for a 3-week period after arrival in Guadalajara, Mexico. During this time period, most students showed no change in total fecal gram-negative bacteria (p > 0.05) but showed an increasing level of trimethoprim (TMP) resistance (p < 0.01) among fecal coliforms. Escherichia coli was the TMP-resistant organism isolated in 18 of 39 (46%) healthy students. These 18 TMP-resistant E. coli were also resistant to ampicillin ( 44 % ) , azithromycin ( 11 % ) , chloramphenicol ( 39 % ) , ciprofloxacin ( 11 % ) , doxycycline ( 89 % ) , erythromycin ( 100 % ) , furazolidone ( 72 % ) , levofloxacin ( 17 % ) , trimethoprim-sulfamethoxazole ( 89 % ) and trovafloxacin ( 17 % ) . In the absence of prophylactic and therapeutic antibiotics, increased acquisition of TMP-resistant gram-negative fecal flora in this developing country is probably due to poor sanitary conditions and the recurrent and heavy exposure to antimicrobial-resistant indigenous flora as a result of contaminated food and drink.


VPA

fludarabine

flavopiridol

bortezomib

thalidomide

lenalidomide

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis. Epigenetic code modifications by histone deacetylase inhibitors have recently been proposed as potential new therapies for hematological malignancies. Chronic lymphocytic leukemia (CLL) remains incurable despite the introduction of new treatments. CLL B cells are characterized by an apoptosis defect rather than excessive proliferation, but proliferation centers have been found in organs such as the bone marrow and lymph nodes. In this study, we analyzed gene expression modifications in CLL B cells after treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. CLL B cells obtained from 14 patients were treated in vitro with a concentration of 1 mM VPA for 4 h. VPA effects on gene expression were thereafter studied using Affymetrix technology, and some identified genes were validated by real-time PCR and western blot. We observed that VPA induced apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. Furthermore , VPA significantly increased chemosensitivity to fludarabine , flavopiridol , bortezomib , thalidomide and lenalidomide . VPA inhibited the proliferation of CpG/IL2-stimulated CLL B cells and modulated many cell cycle messenger RNAs. In conclusion, exposure of CLL B cells to VPA induced apoptosis, potentiated chemotherapeutic agent effects and inhibited proliferation. These data strongly suggest the use of VPA in CLL treatment, particularly in combination with antileukemia agents.


pertuzumab

trastuzumab

docetaxel

Use of the tumor-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to combination therapy with pertuzumab , trastuzumab , and docetaxel for advanced HER2-positive breast cancer . The trastuzumab, pertuzumab, and docetaxel (TPD) regimen is strongly recommended as a treatment option for first-line therapy for advanced human epidermal growth factor receptor (HER) 2-positive breast cancer. Monitoring the host microenvironments in cancer plays a significant role in predicting prognoses and curative effects. It is important to clarify the role of immune related gene expression in tumor-infiltrating lymphocytes in the tumor microenvironment. In this study, we evaluated the impact of chemotherapy with a TPD regimen, on immune micro environments in HER2-positive breast cancer using immune related proteins as indicators. ### methods The subjects consisted of 30 patients who received the TPD regimen. The expression levels of estrogen receptor, progesterone receptor, Ki67, CD8, forkhead box protein (FOXP) 3, programmed death (PD) 1, programmed death ligand (PD-L) 1, CD163, phosphatase and tensin homolog and lymphocyte activation gene 3 were evaluated in biopsy specimens, by immunostaining. ### results CD8 ### conclusions This study shows with the TPD regimen, a high CFR leads to a high ORR and long PFS in HER2-positive breast cancer. CFR, therefore, may be one of the important prognostic factors for this disease.


doxycycline

rifampicin

levofloxacin

amikacin

[Diagnosis and treatment of seven patients with brucellosis in non-pastoral areas]. To explore how to diagnose and treat brucellosis accurately and timely in patients with fever of unkown origin in non-pastoral areas. The epidemiological history, clinical symptoms, complete blood counts, procalcitonin and treatment efficacy of 7 patients with brucellosis were analyzed retrospectively. Some characteristic manifestations should be differentiated from tuberculosis. The clinical symptoms were relieved after combination of doxycycline , rifampicin , levofloxacin and amikacin for 6 weeks , only one patient with bone destruction needed orthopedic surgery . The overall response rate was 6/7. No relapse occurred during half year follow-up.


enalapril

nitrendipine

hydrochlorothiazide

Validated LC-MS/MS method for the simultaneous determination of enalapril maleate , nitrendipine , hydrochlorothiazide , and their major metabolites in human plasma . Hypertension is a major risk factor for atherosclerosis and ischemic heart disease. Most hypertensive patients need a combination of antihypertensive agents to achieve therapeutic goals. A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometric method was developed and validated for simultaneous determination of enalapril maleate (ENA) and its major metabolite enalaprilat (ENAT), nitrendipine (NIT) and its major metabolite dehydronitrendipine (DNIT), and hydrochlorothiazide (HCT) in human plasma using felodipine as an internal standard (IS). The drugs were extracted from plasma using one-step protein precipitation. Chromatographic separation was performed on a Symmetry C


exemestane

toremifene

fulvestrant

[An Elderly Patient with Metastatic Breast Cancer Who Developed Severe Adverse Events such as Stomatitis and Interstitial Pneumonia after Everolimus plus Exemestane Treatment]. An 80-year-old woman was diagnosed with right breast cancer with clinical Stage IIIA 6 years previously. She underwent mastectomy and axillary lymph node dissection. The pathological diagnosis was invasive micropapillary carcinoma with lymph node involvement. Immunohistochemically, the tumor was positive for estrogen receptor and progesterone receptor, and negative for HER2. Postoperatively, the patient was treated with adjuvant chemotherapy consisting of cyclophosphamide, epirubicin, 5-fluorouracil, and paclitaxel, followed by endocrine therapy with letrozole. Four years after surgery , she experienced a recurrence of breast cancer in the thoracic wall , and was treated with exemestane , toremifene , and fulvestrant for 1 year and 5 months . However, she developed carcinomatous pleurisy and was treated with eribulin. This last treatment was ineffective. Subsequently, she received combination therapy with everolimus and exemestane. Although the pleural effusion reduced markedly after 5 weeks, stomatitis, diarrhea, melena, and interstitial pneumonia occurred as adverse events. The symptoms improved after drug discontinuation and steroid therapy. The combination therapy with everolimus and exemestane is a prospective therapy for hormone-resistant recurrent breast cancer, but the management of adverse events is very important.


doxazosin

atenolol

Long-term efficacy of doxazosin plus atenolol in the management of severe and sustained arterial hypertension and reversibility of the cardiac damage induced by chronic cathecolamine excess . Herein we report on a young girl with recurrent, functioning paraganglioma of the organ of Zuckerkandl and severe and sustained arterial hypertension (systolic pressure >200, diastolic pressure >120 mmHg); with evidence of cardiac damage induced by chronic cathecolamine excess. She promptly and steadily improved after the institution of doxazosin (6 mg/day) plus atenolol (50 mg bid) treatment. This case demonstrates that a correct therapeutic strategy in the long-term management of patients with inoperable catecholamine-producing neuroendocrine tumors (pheochromocytomas and paragangliomas) can maintain arterial pressure in the normal range and reverse the cardiac damage induced by chronic cathecolamine excess.


low-molecular-weight heparin

aspirin

unfractionated heparin

Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin.  To evaluate the use of low-molecular-weight heparin ( LMWH ) in combination with low-dose aspirin ( LDA ) for the treatment of antiphospholipid antibody (APA)-associated recurrent pregnancy loss and to compare the results with the use of unfractionated heparin ( UFH ) plus LDA . ### design Prospective, controlled, multicenter pilot study. ### setting Two academically based reproductive health centers. ### Patient S Patients with three or more pregnancy losses and positive APA. ### Intervention S Patients were treated with LMWH and LDA (n = 25) or UFH and LDA (n = 25). ### Main Outcome Measure S Fetal outcome and maternal complications from treatments were compared between the two treatment groups. ### Result S Of the 25 patients in the LMWH group, 21 (84%) delivered a viable infant and 4 (16%) miscarried. Of the 25 patients in the UFH group, 20 (80%) delivered a viable infant and 5 (20%) miscarried. These differences were not statistically significant. No major bleeding episodes occurred during pregnancy or at the time of delivery. No cases of deep venous thrombosis, thrombocytopenia, pre-eclampsia, gestational diabetes, or bone fractures were noted in either of the two groups. ### Conclusion S In this pilot study, the use of LDA in combination with LMWH during pregnancy for the prevention of recurrent pregnancy loss in women with antiphospholipid syndrome seems to be as safe as UFH plus LDA. Large, randomized trials will be required to determine differences in outcome with LMWH and LDA compared with treatment with UFH combined with LDA in this group of patients.


neostigmine

dexmedetomidine

dexmedetomidine

neostigmine

Addition of dexmedetomidine and neostigmine to 1.5 % lidocaine and triamcinolone for epidural block to reduce the duration of analgesia in patients suffering from chronic low back pain. Lower back pain is one of the leading causes of disability in the world. The aim of this study was to evaluate the effect of supplementation of dexmedetomidine and neostigmine with lidocaine 1.5% and triamcinolone for epidural block in increasing the duration of analgesia among patients suffering from chronic low back pain. In this double-blind, randomized clinical trial, 33 patients with chronic low back pain were included in three groups of 11 patients for epidural blockage. triamcinolone (40 mg/ml) was added to lidocaine 1.5% solution (2 cc/segment) for all three groups. In group N, neostigmine was used at a dose of 1 mg (mg), followed by group D (dexmedetomidine 35 μg [0.5 μg/kg]), and grou [ND (neostigmine 0.5 mg, and 35 μg dexmedetomidine, all of which were added to the triamcinolone and lidocaine solution in each group. Medications were injected into the epidural space using an interlaminar approach. Subsequently, scores of pain and duration of analgesia were recorded in questionnaires and analysed using SPSS version 23. One month after the injections, pain scores recorded in the N group were 7.6±1.4, followed by 5.88±1.2 in group D and 5.42 ±1.1 in group ND. Therefore , the pain scores were significantly higher in the neostigmine group than the other two groups ( p = 0.02 ) , but no significant difference was found between the two groups that received dexmedetomidine and a combination of dexmedetomidine + neostigmine . Three months after the injections, there was a significant difference in pain scores between the two groups (P = 0.01). Both neostigmine and dexmedetomidine were capable of reducing the pain of patients with chronic low back pain after epidural block. However, neostigmine's impact is lower compared to dexmedetomidine. The combination of the two drugs also reduced the pain scores of the patients after the intervention.


gemcitabine

docetaxel

[ Two cases of complete response to combination chemotherapy of gemcitabine and docetaxel for recurrent ovarian cancer ] . The established standard treatment for advanced ovarian cancer is carboplatin and paclitaxel. However, more than 70% of patients have recurrent disease. The standard therapy for recurrent ovarian cancer has not been confirmed. It was reported that docetaxel had a 30-40% of response rate in patients with recurrent ovarian cancer, and that gemcitabine had a 13-22% response rate. The combination chemotherapy of gemcitabine and docetaxel is also applied to non-small cell lung cancer. We use a regimen of 800 mg/m2 of gemcitabine on day 1 and day 8 in combination with 70 mg/m2 of docetaxel on day 8 with a 3-week interval. We treated 2 patients with recurrent ovarian cancer who responded completely to combination chemotherapy with gemcitabine and docetaxel.


trilostane

dexamethasone

Hormonal changes in postmenopausal women with breast cancer treated with trilostane and dexamethasone . Postmenopausal women with metastatic breast cancer were treated with trilostane, initially 240 mg daily increasing after 3 days to 480 mg daily and after a further three days to 960 mg daily. After 3 days at this dose dexamethasone 1 mg daily was added and this combination was continued until disease progression occurred. Partial remission was seen in 26% and stabilization of previously progressive disease in a further 13% of the first twenty-three patients studied. During therapy with trilostane alone significant increases in DHEAS, androstenedione, 17-hydroxypregnenolone, progesterone, testosterone and oestradiol were seen. A significant fall in oestrone concentration occurred at the same time. After dexamethasone was added the elevated steroid concentrations fell back to the baseline while oestrone remained depressed below this and testosterone was also significantly lowered. No change was seen in cortisol or ACTH concentration while patients were on trilostane alone but cortisol levels were undetectable after dexamethasone was added though, in most patients, ACTH remained detectable. There was no change in the ratio of delta 5:delta 4 steroids at any stage of therapy but a highly significant increase in the androstenedione: oestrone ratio was seen. We conclude that in long-term use in vivo it is difficult to demonstrate that trilostane inhibits 3 beta-hydroxysteroid dehydrogenase but it may produce inhibition of aromatase.


oxaliplatin

leucovorin

Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: a trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer. Isolated hepatic metastases of colorectal cancer constitute a frequent and serious therapeutic problem that has led to the evaluation of hepatic arterial infusion (HAI) of different drugs. oxaliplatin combined with fluorouracil (FU) and leucovorin is effective in the treatment of colorectal cancer. In this context, a phase II study was conducted to evaluate concomitant administration of oxaliplatin by HAI and intravenous (IV) FU plus leucovorin according to the LV5FU2 protocol (leucovorin 200 mg/m(2), FU 400 mg/m(2) IV bolus, FU 600 mg/m(2) 22-hour continuous infusion on days 1 and 2 every 2 weeks). ### Patients And Methods Patients had metastatic colorectal cancer that was restricted to the liver and inoperable. The patients were not to have previously received oxaliplatin. After surgical insertion of a catheter in the hepatic artery , patients were treated with oxaliplatin 100 mg/m(2 ) HAI combined with FU + leucovorin IV according to the LV5FU2 protocol . Treatment was continued until disease progression or toxicity. Response was evaluated every 2 months. ### results Twenty-eight patients were included, and 26 patients were treated. Two hundred courses of therapy were administered, and the median number of courses received was eight courses (range, zero to 20 courses). The most frequent toxicity consisted of neutropenia. The main toxicity related to HAI was pain. The intent-to-treat objective response rate was 64% (95% CI, 44% to 81%; 18 of 28 patients). With a median follow-up of 23 months, the median overall and disease-free survival times were 27 and 27 months, respectively. ### conclusion The combination of oxaliplatin HAI and FU + leucovorin according to the LV5FU2 protocol is feasible and effective in patients presenting with isolated hepatic metastases of colorectal cancer.


methysergide

clonidine

haloperidol

atropine

Neuronal mechanisms involved in drug-induced jumping behavior in mice. Previously we have found that lithium chloride (250 mg/kg i.p.) plus haloperidol (4 mg/kg i.p.), or apomorphine (0.25 mg/kg i.p.) plus thyrotropin releasing hormone (TRH, 20 mg/kg i.p.), elicited a jumping behavior which involves dopaminergic and cholinergic inhibition, and noradrenergic activation. Pretreatment with antiserotonergic agents such as methysergide (5 and 10 mg/kg i.p.) and cyproheptadine (5 mg/kg i.p.) enhanced the jumping behavior induced by these drugs. 5-Methoxy-N,N-dimethyltryptamine (5-MDMT, 5 mg/kg i.p.), a serotonergic receptor agonist, inhibited the jumping behavior. Muscimol, a GABA receptor agonist, at 2 mg/kg, potentiated jumping. GABA receptor antagonists such as bicuculline (4 mg/kg i.p.) and picrotoxin (0.2 and 1 mg/kg i.p.) depressed jumping. An antihistamine agent, diphenhydramine (5 mg/kg i.p.), also potentiated the jumping behavior. Furthermore methysergide ( 10 mg/kg i.p . ) , but not muscimol ( 2 mg/kg i.p . ) elicited jumping behavior when combined with clonidine ( 0.5 mg/kg i.p . ) , TRH ( 20 mg/kg i.p . ) , haloperidol ( 4 mg/kg i.p . ) or atropine ( 5 mg/kg i.p . ) . These results suggest that in addition to dopaminergic, cholinergic and noradrenergic mechanisms, serotonergic inhibition may be directly contributing to the initiation of jumping behavior, whereas GABAergic activation appears to be a modulating factor in this behavior.


doxorubicin

flavopiridol

Synergistic anti-tumor efficacy of doxorubicin and flavopiridol in an in vivo hepatocellular carcinoma model. A previous study showed that flavopiridol increased doxorubicin sensitivity in hypoxic hepatocellular carcinoma (HCC) cells by increasing apoptosis through suppressing hypoxia-inducible N-myc downstream-regulated gene-1 (NDRG1) expression. However, this has not been investigated in an in vivo HCC model. Therefore, we aimed to elucidate whether the combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model. ### methods An HCC mouse model was established by implanting C3H/He mouse with MH134 cells. Then , doxorubicin with or without flavopiridol was injected . The anti-tumor efficacy was assessed by evaluating tumor volumes, and the underlying mechanism was investigated by quantifying apoptotic cells, the Ki-67 proliferation index, and microvessel densities (MVDs). Immunohistochemistry of NDRG1 was performed to determine the underlying mechanism. ### results Tumor growth was significantly suppressed in the doxorubicin + flavopiridol combination group compared to the other three groups. The percentage of apoptotic cells was significantly higher, and Ki-67-positive proliferating cells were significantly lower in the combination group compared to the other groups; however, MVDs were not significantly different across the groups. Increased apoptosis by flavopiridol occurred by suppressing hypoxia-inducible NDRG1 expression. ### conclusions These results show that a combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model. This synergistic effect of combination therapy was attributed to increased apoptosis and decreased proliferation of tumor cells rather than decreased angiogenesis. These findings suggest that flavopiridol might be an effective adjuvant therapy to doxorubicin-resistant HCC cells by inducing apoptosis through suppression of NDRG1 expression.


bicalutamide

tremelimumab

Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer. CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor-specific immune response elicited by androgen deprivation. We report here the results of a phase I trial evaluating a humanized monoclonal antibody targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen deprivation using an antiandrogen. Eligible patients were those with PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not previously treated with androgen deprivation, and without radiographic evidence of metastatic disease. Subjects were treated in two cycles , 3 months apart , in which they received bicalutamide 150 mg daily days 1 - 28 and tremelimumab on day 29 . The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose. Eleven patients were enrolled and completed at least 1 year of follow-up. Dose-limiting toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA doubling time were observed in a period shortly after completing treatment; however, three patients experienced a prolongation in PSA doubling time detectable several months after completing treatment. The identification of delayed, prolonged favorable changes in serum PSA suggests that future studies could explore this combination in studies evaluating time to disease progression.


docetaxel

topotecan

gemcitabine

[Chemotherapy in germinal and epithelial ovarian cancer]. Generically, ovarian cancer represents a group of tumors with diverse biological and clinical behavior. Thus, germinal cells ovarian tumors, in the vast majority of patients are successfully treated utilizing traditional based on cisplatin chemotherapy. Epithelial ovarian cancer, that accounts for 90% of these cases, although sensitive to chemotherapy has not shown satisfactory results. In the search better tumoral response in the treatment of epithelial ovarian cancer new drugs have surged that promise good results , including docetaxel , topotecan and gemcitabine , both as single agents, or in combination with other therapies utilizing monoclonal antibodies.


ropivacaine

hydromorphone

ketorolac

Peri-operative pain management in children with cerebral palsy: comparative efficacy of epidural vs systemic analgesia protocols. Selective Dorsal Rhizotomy (SDR) is the only surgical intervention with class I evidence supporting permanent reduction in spasticity for children with cerebral palsy (Paediatr Anaesth, 12, 2002, 296; Neurosurg Focus, 21, 2006, e2). Postoperatively, adequate analgesia can be difficult to achieve (J Neurosurg, 105, 2006, 8; Childs Nerv Syst, 17, 2001, 556; Pediatr Neurosurg, 43, 2007, 107; Anesth Analg, 79, 1994, 340; Reg Anesth Pain Med, 24, 1999, 438; Pediatr Anesth, 19, 2009, 1213). This study examines a novel regimen utilizing the combination of epidurally infused ropivacaine - hydromorphone and scheduled ketorolac . This regimen was compared to a protocol utilizing systemic fentanyl and diazepam. ### methods Following IRB approval, 31 patients receiving epidural analgesia were compared with 41 patients who received systemic analgesia. All surgeries were performed by one surgeon with standardized anesthetic and nursing care. Studied outcomes included: pain scores; episodes of severe pain; nausea, itching; oxygen desaturation; and ICU admission. Data were analyzed using Mann-Whitney U-test, CHI square, and Fisher exact test where indicated with P < 0.05 considered significant. ### results Studied groups had similar demographics, biometrics and disease burdens. Patients in the epidural group had statistically and clinically significant reductions in peak recorded pain scores for each 4-h period in the first 24 postoperative hours. Severe pain (score >5) was markedly reduced in the epidural group with 9% of epidural patients vs. 68% of systemic patients experiencing at least one episode. Fewer epidural patients experienced oxygen desaturation during the first two postoperative days (6.5% vs. 41%, 6.5% vs. 39%). ### conclusion Epidural analgesia resulted in substantial improvements in pain control and safety. The data supports the superiority of a multimodal analgesia approach centered on epidural analgesia. A similar protocol should be considered following simple laminectomies or procedures associated with lower-extremity muscle spasm.


tegafur

gimeracil

A phase II study of S-1 in patients with metastatic breast cancer--a Japanese trial by the S-1 Cooperative Study Group, Breast Cancer Working Group.  S-1 is a newly developed novel oral dihydrouracil dehydrogenase inhibiting fluoropyrimidine drug consisting of 1 M tegafur ( FT ) , 0.4 M 5-chloro-2 , 4-dihydroxypyrimidine ( gimeracil ) , and 1 M potassium oxonate ( oteracil ) , with efficient antitumor activity and low gastrointestinal toxicity which is widely used in Japan against advanced gastric , head and neck cancers . We investigated its clinical efficacy against metastatic breast cancer. ### methods A non-blind phase II study was carried out to evaluate the efficacy and toxicity in metastatic breast cancer patients. Patients with measurable metastasis foci (n=111) were enrolled, and 108 patients were regarded as eligible. S-1 was administered orally at a standard dose of 80 mg/m2/day b.i.d. One course consisted of 28 consecutive days of administration followed by a 14-day rest, and courses were repeated up to six times. ### results Among the eligible patients, 10 had a complete response and 35 had a partial response, with an overall response rate (CR+PR) of 41.7% (95% confidence interval: CI, 32.3-51.5%). The incidences of toxicity (> or =grade 3) were neutropenia 9.1%, anemia 0.9%, anorexia 3.6%, stomatitis 1.8%, nausea/vomiting 1.8%, diarrhea 0.9%, and fatigue 2.7%, however no treatment-related deaths were observed. The median survival time was 872 days (95% CI, 572-1,110 days). There was no difference in response rate or toxicity between the under 65-year-old group and the older group. ### conclusion S-1 was demonstrated to have high efficacy with low gastrointestinal toxicity even in older patients and will be a promising new chemotherapy drug for metastatic breast cancer.


trastuzumab

capecitabine

Pharmacokinetic analysis of capecitabine and cisplatin in combination with trastuzumab in Japanese patients with advanced HER2-positive gastric cancer. To evaluate the pharmacokinetics (PK) of capecitabine and cisplatin, administered in combination with or without trastuzumab, in Japanese patients with HER2-positive advanced gastric cancer (AGC). ### methods Patients eligible for this PK study (study JP19959), which was carried out during treatment Cycle 1 of the ToGA study, received either capecitabine and cisplatin (XP arm) or trastuzumab plus capecitabine and cisplatin (HXP arm). All patients received capecitabine (1,000 mg/m(2) orally, twice daily for 14 days) and cisplatin (80 mg/m(2) intravenous infusion on Day 1). Patients in the HXP arm also received trastuzumab ( 8 mg/kg intravenous infusion on Day 1 ) , concurrently with capecitabine . No further study medication was administered during study JP19959. Serial plasma samples for PK analysis were obtained at intervals before and after the administration of capecitabine and cisplatin on Day 1. ### results Twenty-two patients were enrolled in this PK study: eight in the HXP arm and 14 in the XP arm. All blood samples were available for PK analysis. Co-administration of trastuzumab resulted in no statistically or clinically significant changes in the PK profiles of capecitabine or its metabolites, or of cisplatin (total or unbound platinum). ### conclusions Variability in the AUC(last) and C (max) values for the capecitabine was consistent with the known PK profile of capecitabine and fell within established limits. Concurrent trastuzumab therapy is unlikely to alter the PK or safety profile of capecitabine or cisplatin in Japanese patients with HER2-positive AGC.


lapatinib

capecitabine

Chemotherapy and biological treatment options in breast cancer patients with brain metastasis: an update. Breast cancer (BC) is the second most common cause of CNS metastasis. Ten to 20% of all, and 38% of human epidermal growth factor-2(+), metastatic BC patients experience brain metastasis (BM). Prolonged survival with better control of systemic disease and limited penetration of drugs to CNS increased the probability of CNS metastasis as a sanctuary site of relapse. Treatment of CNS disease has become an important component of overall disease control and quality of life. ### Areas Covered Current standard therapy for BM is whole-brain radiotherapy, surgery, stereotactic body radiation therapy for selected cases, corticosteroids and systemic chemotherapy. Little progress has been made in chemotherapy for the treatment of BM in patients with BC. Nevertheless, new treatment choices have emerged. In this review, we aimed to update current and future treatment options in systemic treatment for BM of BC. ### Expert Opinion Cornerstone local treatment options for BM of BC are radiotherapy and surgery in selected cases. Efficacy of cytotoxic chemotherapeutics is limited. Among targeted therapies , lapatinib has activity in systemic treatment of BM particularly when used in combination with capecitabine . Novel agents are currently investigated.


leflunomide

adalimumab

Treatment with either leflunomide or adalimumab reduces anaemia in patients with rheumatoid arthritis. Rheumatoid arthritis is a chronic disease of the joints, which causes joint pain and disability. Anaemia is a frequent extra-articular manifestation in rheumatoid arthritis, affecting 30-70% of the patients; presenting a negative impact on patient´s quality of life. Some of the drugs used in rheumatoid arthritis treatment improve anaemia; but little is known on the beneficial effects of the anti-rheumatic leflunomide or the anti-TNFα adalimumab, in this parameter. We investigated the incidence of anaemia in rheumatoid arthritis patients treated or not with leflunomide or adalimumab. We also assessed whether anaemia correlates with disease activity. Anaemia was present in patients who had just been diagnosed with rheumatoid arthritis and had never taken disease modifying agents or biologicals ( non-specific therapy group ) , but not in those taking either leflunomide or adalimumab . The erythrocyte sedimentation rate was increased in patients with non-specific therapy in comparison with those taking either leflunomide or adalimumab. Anaemia correlated with increased erythrocyte sedimentation rate. We suggest that leflunomide and adalimumab may be useful in treating anaemia in patients with rheumatoid arthritis.


doxycycline

azithromycin

In vitro effectiveness of azithromycin against doxycycline-resistant and -susceptible strains of Rickettsia tsutsugamushi, etiologic agent of scrub typhus. In an effort to find a potential alternative treatment for scrub typhus, we evaluated the effectiveness of the standard drug doxycycline and the new macrolide azithromycin against a doxycycline-susceptible strain (Karp) and a doxycycline-resistant strain (AFSC-4) of Rickettsia tsutsugamushi. The antibiotics were tested in an in vitro assay system in which infected mouse fibroblast cells (L929) were incubated for 3 days in various concentrations of the drugs. Rickettsial growth was evaluated by direct visual counts of rickettsiae in Giemsastained cells or by flow cytometry. Initial tests were conducted at the concentration of each antibiotic considered to be the upper breakpoint for susceptibility (16 micrograms/ml for doxycycline and 8 micrograms/ml for azithromycin). Growth of both Karp and AFSC-4 was strongly inhibited with both antibiotics , as measured by visual counts , although the percentage of cells infected with AFSC-4 in the presence of doxycycline was three times greater than the percentage of cells infected with Karp but was only 60 % as great as the percentage of cells infected with Karp in the presence of azithromycin . Flow cytometry confirmed that rickettsial growth occurred in the absence of antibiotics, but it failed to detect it in the presence of high concentrations of either drug. Visual counts of rickettsial growth at lower concentrations of the antibiotics (0.25 to 0.0078 microgram/ml) showed that the Karp strain was 16 times more susceptible that the AFSC-4 strain to doxycycline. azithromycin was much more effective than doxycycline against AFSC-4, inhibiting rickettsial growth at 0.0156 microgram/ml to levels below that achieved by 0.25 microgram of doxycycline per ml. azithromycin was also more effective than doxycycline against the Karp strain, causing greater reductions in the number of rickettsiae per cell at lower concentrations. If in vivo testing confirms the in vitro effectiveness of azithromycin, it may prove to be the drug of choice for the treatment of scrub typhus in children and pregnant women, who should not take doxycycline, and in patients with refractory disease from locations where doxycycline-resistant strains of R. tsutsugamushi have been found. When tested in an in vitro assay system, azithromycin was more effective than doxycycline against doxycycline-susceptible and -resistant strains of R. tsutsugamushi.


dexmedetomidine

propofol

Interpatient variability in dexmedetomidine response: a survey of the literature. Fifty-five thousand patients are cared for in the intensive care unit (ICU) daily with sedation utilized to reduce anxiety and agitation while optimizing comfort. The Society of Critical Care Medicine ( SCCM ) released updated guidelines for management of pain , agitation , and delirium in the ICU and recommended nonbenzodiazepines , such as dexmedetomidine and propofol , as first line sedation agents . Dexmedetomidine, an alpha-2 agonist, offers many benefits yet its use is mired by the inability to consistently achieve sedation goals. Three hypotheses including patient traits/characteristics, pharmacokinetics in critically ill patients, and clinically relevant genetic polymorphisms that could affect dexmedetomidine response are presented. Studies in patient traits have yielded conflicting results regarding the role of race yet suggest that dexmedetomidine may produce more consistent results in less critically ill patients and with home antidepressant use. Pharmacokinetics of critically ill patients are reported as similar to healthy individuals yet wide, unexplained interpatient variability in dexmedetomidine serum levels exist. Genetic polymorphisms in both metabolism and receptor response have been evaluated in few studies, and the results remain inconclusive. To fully understand the role of dexmedetomidine, it is vital to further evaluate what prompts such marked interpatient variability in critically ill patients.


azithromycin

gentamicin

In vitro assessment of dual drug combinations to inhibit growth of Neisseria gonorrhoeae. The development of resistance to first-line antimicrobial therapies has led to recommendations for combination therapies for the treatment of gonorrhea infection. Recent studies have shown the success of combination therapies in treating patients, but few have reported on the in vitro activities of these drug combinations. An in vitro assessment of azithromycin in combination with gentamicin demonstrated inhibition of growth and suggests that clinical trials may be warranted to assess the utility of this combination in treating gonorrhea infections .


ciprofloxacin

metronidazole

Prescription pattern in the department of surgery in a tribal district hospital of andhra pradesh, India. Usually, surgical management cannot be completed without the use of antimicrobial and analgesic drugs. Irrational prescription may lead to severe postoperative complications. ### aim The objective of this study was to evaluate the prescription trend in the surgery department of a tribal district hospital so as to determine the extent of rational use of medicines. ### Materials And Methods It was a retrospective study in which 50 cases were selected randomly. Case records were analyzed for prescription trend. Data was analyzed using Microsoft Office Excel 2007 and values were presented descriptively. ### results Most of the cases were between the age group of 21 and 40 years, 18 cases (36%). Commonest cause of hospitalization was renal calculi (10 (20%)) followed by acute abdomen and abscess (6, (12%)). Total of 255 numbers of drugs were used with an average of 5.1 drugs per patient. Most preferred route was intravenous route (174 drugs, 68.2%). Antimicrobial was the most common (97 (38.0%)) group of drugs followed by analgesic/antipyretics (50 (19.6%)). Among antimicrobials , ciprofloxacin ( 22 ( 22.7 % ) ) was the most common drug followed by metronidazole ( 21 ( 18.5 % ) ) . All the cases were managed by empirical treatment. Two different antimicrobials were prescribed to 20 (40%) of cases. Dosage of 83 (32.6%) drugs was inappropriate while frequency was inappropriate in 26 (10.2%) cases. ### conclusion Urgent steps like specific guidelines, training, and monitoring of drugs use are needed to correct some irrational approaches.


rituximab

fludarabine

mitoxantrone

rituximab

Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response. Treatment of follicular lymphoma with rituximab is currently recommended at a dose of 375 mg/m(2). We aimed to provide a rationale for optimal dosing and scheduling of this anti-CD20 antibody based on pharmacokinetics. ### Design And Methods Clinical efficacy of immunochemotherapy with rituximab , fludarabine and mitoxantrone followed by 2-monthly rituximab maintenance was evaluated in 29 patients with previously untreated follicular lymphoma in a prospective phase II trial ( AGMT-NHL9 ) . Pharmacokinetic analysis was assessed in 17 patients. ### results Induction treatment resulted in high clinical response rates (complete remission 66%; ORR 100%). Significantly higher complete remission rates were observed in female patients (86 vs. 47%; Odds Ratio 6.8, 95% CI: 1.12; 41.82; P=0.05). rituximab pharmacokinetic analysis showed a high variability ranging over almost 1 order of magnitude at maintenance cycle 1 (area under the curve 1,540-12,025 g/L*days). Median area under the curve was lower in men (81%) and in patients with initial bone marrow infiltration (76%). Higher rituximab serum concentrations before next therapy (C(trough)) were associated with female sex (P=0.04) as well as with absence of initial bone marrow infiltration (P=0.001). C(trough) correlated with remission quality (complete vs. partial remission; P=0.005) and progression-free survival (P=0.03). A decline in rituximab C(trough) below 25,000 ng/mL was observed 9.5 to 62 months before clinical relapse (P=0.008). ### conclusions The results of this pilot trial suggest that more differentiated dosing schedules based on gender and bone marrow infiltration should be explored for rituximab therapy for lymphoma. This study was registered in ClinicalTrials.gov (Identifier: NCT01560117).


carboplatin

etoposide

Merkel cell carcinoma: A case of palliative upper limb amputation in a patient with refractory in-transit metastases. We report an unusual case of Merkel cell carcinoma in a 70-year-old woman with the rapid development of left upper limb in-transit and hepatic metastases. The patient had a preceding history of left-sided breast cancer. Palliative chemotherapy with carboplatin and etoposide produced a minimal response . The in-transit metastases rapidly progressed and were refractory to chemotherapy and a single fraction of palliative radiotherapy, leading to a marked impact on her quality of life, secondary to sepsis and bleeding. After lengthy discussion, she consented to an above-elbow amputation resulting in a marked improvement in her well-being. In this case, we believe that palliative amputation of the involved arm was justified and beneficial to the patient.


clindamycin

gentamicin

vancomycin

In vitro susceptibilities of ocular Bacillus cereus isolates to clindamycin , gentamicin , and vancomycin alone or in combination . A broth dilution assay was used to determine the in vitro susceptibilities of 10 ocular isolates of Bacillus cereus to clindamycin, gentamicin, and vancomycin both alone and in combination. The checkerboard technique was used to determine fractional inhibitory and bactericidal concentration indices for combinations of clindamycin-gentamicin and vancomycin-gentamicin.


etoposide

methylprednisolone

cytarabine

cisplatin

cisplatin

cytosine arabinoside

dexamethasone

Treatment response and overall outcome of patients with relapsed and refractory peripheral T-cell lymphoma compared to diffuse large B-cell lymphoma. The purpose of the study was to assess treatment response and overall outcome in a cohort of patients with relapsed and refractory peripheral T-cell lymphoma and to compare the results with those for patients with diffuse large B-cell lymphoma treated in a similar manner. We retrospectively analyzed data of 40 consecutive adult patients with relapsed and refractory peripheral T-cell lymphoma referred to our institution for consideration of second-line chemotherapy aiming for autologous stem cell transplant between January 1999 and December 2006. A cohort of 126 patients with diffuse large B-cell lymphoma managed similarly served as a comparison group. Most ( ≥ 75 % ) patients received ESHAP ( etoposide , methylprednisolone , cytarabine , cisplatin ) or DHAP ( cisplatin , cytosine arabinoside , dexamethasone ) as salvage chemotherapy . From first relapse/progression, overall survival at 2 years was 54% (95% confidence interval [CI]: 38-76) for the peripheral T-cell lymphoma cohort and 49% (95% CI: 39-60) for the diffuse large B-cell lymphoma cohort (p = 0.098). Overall response rate to salvage chemotherapy was similar between both groups (63% vs. 52%). Post-autologous stem cell transplant, 1-year progression-free survival was 20% (95% CI: 9-48) for patients with peripheral T-cell lymphoma and 47% (95% CI: 36-61) for patients with diffuse large B-cell lymphoma. Two-year overall survival post-autologous stem cell transplant was 43% (95% CI: 26-71) and 54% (95% CI: 43-68), respectively. Patients with relapsed and refractory peripheral T-cell lymphoma and diffuse large B-cell lymphoma showed a similar response to salvage chemotherapy and overall survival. Likely due to imbalances in risk factors at relapse, progression-free survival post-autologous stem cell transplant was inferior in the peripheral T-cell lymphoma group. Strategies aiming to maintain response duration post-autologous stem cell transplant could improve the outcome of patients with peripheral T-cell lymphoma.


cisplatin

cyclophosphamide

doxorubicin

etoposide

Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective Children's Cancer Group study. A prospective Children's Cancer Group study, CCG-3881, has been completed to determine if a more accurate prediction of prognosis by biologic features can identify subgroups of infants with stage IV neuroblastoma (NBL) who require differing intensities of treatment. ### Patients And Methods One hundred thirty-four infants were registered from June 1989 to August 1995, with a median follow-up of 47.1 months (range, 0 to 88 months). The biologic factors examined were tumor MYCN copy number, Shimada histopathologic classification, serum ferritin, and bone marrow immunocytology (sensitivity, one tumor cell per 10(5) bone marrow cells). Patients treated on CCG-3881 ( n = 116 ) received four-drug chemotherapy for 9 months ( cisplatin , cyclophosphamide , doxorubicin , and etoposide ) , with surgery and local radiation to residual disease . After January 1991, all subsequent infants with tumor MYCN amplification (n = 18) were transferred after one cycle of therapy to the high-risk CCG-3891 protocol (open January 1991 to April 1996) for more intensive treatment. ### results The 3-year event-free survival (EFS) and overall survival (mean +/- SD) for the 134 infants were 63% +/- 5% and 71% +/- 5%, respectively. Patients whose tumors were without MYCN amplification had a 93% +/- 4% 3-year EFS, whereas those with amplified MYCN had a 10% +/- 7% 3-year EFS (P <. 0001). Each of the other biologic features studied had prognostic significance in univariate analysis but not after stratifying by MYCN copy number. ### conclusion Infants less than 1 year of age at diagnosis with stage IV NBL have a much improved outcome compared with children >/= 1 year of age. Nonamplified MYCN tumors identify a group of infants with a 93% +/- 4% EFS, whereas amplified MYCN copy number clearly identifies patients who are unlikely to survive despite intensive chemotherapy.


cetuximab

bevacizumab

FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. ### methods In this open-label, randomised, phase 3 trial, we recruited patients aged 18-75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00433927. ### findings Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 ( 62·0 % , 95 % CI 56·2 - 67·5 ) patients in the cetuximab group achieved an objective response compared with 171 ( 58·0 % , 52·1 - 63·7 ) in the bevacizumab group ( odds ratio 1·18 , 95 % CI 0·85 - 1·64 ; p=0·18 ) . Median progression-free survival was 10·0 months (95% CI 8·8-10·8) in the cetuximab group and 10·3 months (9·8-11·3) in the bevacizumab group (hazard ratio [HR] 1·06, 95% CI 0·88-1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0-36·6) in the cetuximab group compared with 25·0 months (22·7-27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62-0·96; p=0·017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 [25%] of 297 patients in the cetuximab group vs 62 [21%] of 295 patients in the bevacizumab group), skin reactions (77 [26%] vs six [2%]), and diarrhoea (34 [11%] vs 40 [14%]). ### interpretation Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. ### funding Merck KGaA.


docetaxel

carboplatin

Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer. There is no proven, effective, standard second-line chemotherapy for castration- and docetaxel-resistant prostate cancer (DRPC). Recent data suggest that carboplatin may be effective in combination with docetaxel in this setting; however, the optimal docetaxel/carboplatin-based regimen is still unclear. ### Aim Of The Study We identified 43 consecutive patients with DRPC treated with carboplatin (AUC5 d1) and docetaxel (35 mg/m(2) d1, 8, 15 q4w i.v.) as a second-line or subsequent salvage chemotherapy until discontinuation of therapy due to disease progression or unacceptable toxicity. ### results Decreased prostate-specific antigen (> or =50% PSA) was observed in 22/43 (51.2%, 95% CI, 35.5, 66.7%) patients, with > or =90% reduction in 12/43 patients (27.9%). At the time of analysis, the median follow-up time for all patients was 10.4 months. Median progression-free survival (PFS) for all patients was 6.5 months (95% CI 4.1, 8.9), and median overall survival (OS) was 15.8 months (95% CI 12.1, 18.5). In PSA responders, PFS was 9.5 (95% CI 8.2, 19.0) months versus 3.3 (95% CI 2.6, 4.0) months in PSA non-responders (P < 0.0001; hazard ratio (HR) 0.108) and OS was 24.4 months (95% CI 19.5, 29.4) versus 7.8 (95% CI 5.2, 10.3) months (P = 0.001; HR 0.232). Established prognostic factors were associated with survival. This regimen was reasonably well tolerated, with leukopenia/neutropenia as the most common reversible grade 3/4 toxicity (41.9/39.5%). ### conclusion These data suggest that weekly docetaxel plus carboplatin may be an important therapeutic second-line treatment option for patients with DRPC .


clonidine

guanfacine

clonidine

guanfacine

Central effects of guanfacine and clonidine during wakefulness and sleep in healthy subjects. 1. Three double-blind studies in young normotensive male volunteers were carried out: a study in ten awake subjects, comparing guanfacine  2.0 and 4.0 mg with clonidie 0.15 and 0.30 mg and placebo; and two polygraphic sleep studies each with six subjects, comparing guanfacine 1.0 and 2.0 mg with placebo, and clonidine 0.15 and 0.30 mg with placebo, respectively. 2. In awake subjects, both drugs reduced systolic blood pressure without significantly altering diastolic blood pressure, pulse rate and objective performance parameters. ' Side-effects ' such as tiredness , decreased inclination to work , and dryness of the mouth were somewhat more frequent after the higher clonidine dose than after both doses of guanfacine , and peaked 2 h after clonidine but only 4 - 6 h after guanfacine . 3. clonidine 0.15 and 0.30 mg given in the evening was followed by a substantial and dose-dependent reduction in rapid eye movement (REM) sleep. guanfacine 1.0 mg did not alter REM sleep and 2.0 mg of guanfacine had less effect than both doses of clonidine in this respect. clonidine's effect on REM sleep began after about 2 h, whereas guanfacine's action on REM sleep began 5 h after the dose. 4. guanfacine and clonidine possess a qualitatively similar pattern of activity with regard to the parameters studied; but the central effects are less pronounced and occur later after guanfacine than after clonidine in equiactive doses.


bortezomib

docetaxel

Bortezomib plus docetaxel in advanced non-small cell lung cancer and other solid tumors: a phase I California Cancer Consortium trial. This phase I study was performed to determine the dose-limiting toxicity and maximum tolerated dose (MTD) of docetaxel in combination with bortezomib in patients with advanced non-small cell lung cancer (NSCLC) or other solid tumors. ### methods Patients were enrolled in cohorts of three over six dose levels. Each treatment cycle was 3 weeks long and consisted of one docetaxel infusion (day 1) and four bortezomib injections (days 1, 4, 8, and 11). Dose escalation and MTD determination were based on the occurrence of dose-limiting toxicities in cycle 1 only. ### results A total of 36 patients were enrolled, 26 of whom had NSCLC. All patients received at least one dose of study drug at one of five dose levels. The MTD of the combined regimen was determined to be 1.0/75 mg/m bortezomib/docetaxel. The combination was generally well tolerated. Toxicities were manageable, and no additive toxicities were observed. The most common adverse events were fatigue (67% of patients), nausea (50%), diarrhea (39%), and neutropenia (39%). Two patients with NSCLC achieved a partial response, and seven (19%) patients achieved stable disease (including six patients with NSCLC). ### conclusion The combination of bortezomib and docetaxel was feasible and well tolerated in patients with advanced NSCLC or other solid tumors. The recommended phase II dose is bortezomib 1.0 mg/m on days 1 , 4 , 8 , and 11 plus docetaxel 75 mg/m on day 1 , cycled every 21 days . Therapeutic doses of docetaxel and bortezomib are achievable for this combination.


formoterol

formoterol

formoterol

budesonide

Bronchodilation of formoterol administered with budesonide: device and formulation effects. Previous single-dose crossover studies have established therapeutic equivalence of formoterol when administered at the same nominal dose via a dry powder inhaler (DPI) or pressurized hydrofluoroalkane (HFA) metered-dose inhaler (pMDI). Demonstration of equivalent bronchodilation for formoterol administered as formoterol DPI or combined with budesonide in one pMDI (budesonide/formoterol pMDI) would indicate that the greater clinical efficacy of the budesonide/formoterol pMDI combination is due to the budesonide contribution and not to differences in formoterol formulation or delivery device. ### objective To determine whether the formoterol-related bronchodilatory effects of formoterol DPI and budesonide/formoterol pMDI are similar, despite formoterol formulation and delivery device differences. ### methods This was a multicenter, open-label, five-period crossover study conducted in 201 adult patients with stable asthma. The study included a screening visit, a 7- to 14-day run-in period, during which patients were treated with budesonide pMDI (80 microg per inhalation, two inhalations twice daily), and a randomized treatment period that included five single-day treatment periods, during which patients received single-dose crossover treatments, each of which was separated by a 3- to 14-day washout period. Patients were randomized to five of seven single-dose treatments (one, two, or four inhalations of budesonide/formoterol pMDI 80/4.5 microg; four inhalations of budesonide pMDI 80 microg plus one, two, or four inhalations of formoterol DPI 4.5 microg; or four inhalations of budesonide pMDI 80 microg alone). At clinic visits, the budesonide pMDI dose was coordinated with the budesonide dose delivered via the budesonide/formoterol pMDI such that all patients received a 320-microg dose of budesonide. The primary variable was average forced expiratory volume in 1 s (FEV1) from the area under the curve divided by time from 12-h serial spirometry. ### results Average 12-h FEV1 values were similar, regardless of delivery device, among treatments with the same nominal formoterol doses and dose-ordered within each device; mean FEV1 values were significantly higher for treatments containing formoterol versus budesonide alone. The formoterol dose potency ratio for budesonide/formoterol pMDI:formoterol DPI (0.97; 95% confidence interval, 0.73-1.27) demonstrated clinical equivalence in bronchodilation at the same formoterol dose. ### conclusion Budesonide/formoterol pMDI affords equivalent formoterol-related bronchodilatory effects versus formoterol DPI at formoterol doses of 4.5 , 9 , and 18 microg , indicating that practitioners can expect and patients will experience similar bronchodilation from the same dose of formoterol whether it is delivered as monotherapy via a DPI or as combination therapy with budesonide via one pMDI .


cetuximab

panitumumab

Novel approaches to treatment of advanced colorectal cancer with anti-EGFR monoclonal antibodies. The standard treatment of metastatic colorectal cancer (mCRC) is combination of 5- fluorouracil/folinic acid with irinotecan or oxaliplatin-based chemotherapy. Epidermal growth factor receptor (EGFR) is overexpressed in 70%-80% of colorectal cancers (CRC). EGFR overexpression is known to be involved in carcinogenic processes, such as cell proliferation, apoptosis, angiogenesis and metastasis. Monoclonal antibodies targeting EGFR have shown antitumor activity and improved the efficacy of chemotherapy. cetuximab is a chimeric immunoglobulin (Ig) G1 anti-EGFR monoclonal antibody (MoAb). Several clinical studies have shown cetuximab, either as a single agent or in combination with irinotecan, having promising efficacy in patients with metastatic CRC. cetuximab with 5-fluorouracil/LV (leucovorin) plus irinotecan or oxaliplatin-based chemotherapy has shown higher response rate and longer time to progression as first-line treatment of mCRC. Currently, there are no data showing that addition of cetuximab would prolong overall survival in randomized studies. panitumumab, a fully human IgG2 monoclonal antibody, has also shown antitumor activity against EGFR-expressing mCRC with less allergic reaction. Anti-EGFR MoAbs are well tolerated and have limited overlapping toxicities in combination with other cytotoxic drugs. The most common side effect of anti-EGFR MoAb is an acneform skin rash, which is a surrogate marker of efficacy of treatment with MoAbs. In this review , we will discuss the use of anti-EGFR MoAbs in the treatment of mCRC , with focus on cetuximab and panitumumab .


doxorubicin

bleomycin

vinblastine

dacarbazine

Ototoxicity associated with vinblastine. To describe a patient with ototoxicity associated with vinblastine chemotherapy. ### Case Summary A 29-year-old white man with recurrent Hodgkin 's disease received doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ) chemotherapy once every two weeks for 12 cycles . He reported tinnitus after each treatment, with an onset of about six hours and a duration of seven to 10 days. This interfered with reading, watching television, and general concentration. Symptoms returned to baseline prior to the beginning of each subsequent cycle. Audiograms performed before and after several cycles showed mild sensorineural hearing loss in the high-decibel range, but no loss of speech recognition. ### discussion No reported cases of ototoxicity or tinnitus from ABVD were found. All concomitant medications were eliminated as possible causes either due to lack of temporal association with the symptoms or no reports of ototoxicity in the literature. vincristine, a more commonly used vinca alkaloid very similar to vinblastine, was noted to have caused several cases of sensorineural hearing loss. ### conclusions This case suggests that vinblastine may cause ototoxicity.


venetoclax

rituximab

The combination of venetoclax and rituximab for the treatment of patients with recurrent chronic lymphocytic leukemia. In patients with recurrent chronic lymphocytic leukemia (CLL), treatment with targeted agents such as Bruton tyrosine kinase inhibitors and the Bcl-2 inhibitor venetoclax is rapidly replacing chemo-immunotherapy regimens. venetoclax has demonstrated efficacy as monotherapy in patients with previously treated CLL and has been evaluated in combination with the anti-CD20 monoclonal antibody rituximab. ### Areas Covered This review focuses on the activity and toxicity of the time-limited combination of venetoclax plus rituximab for the treatment of relapsed or refractory CLL , presenting clinical trial results and data from correlative studies , with the aim of highlighting the strengths of this treatment approach and discuss weaknesses and possible areas of improvement . Data from PubMed indexed papers as well as from abstracts presented at major international conferences are included. ### Expert Opinion Deep responses with venetoclax-based regimens have been shown to allow time-limited treatment and prolonged remission off-therapy in patients with CLL. The clinical benefit of venetoclax and rituximab over chemo-immunotherapy has been demonstrated in recurrent CLL. Potential advantages of time-limited treatment approaches include avoidance of long-term toxicities, high drug costs, and the selection of resistant subclones.


buserelin

flutamide

Advanced male breast cancer treatment with the LH-RH analogue buserelin alone or in combination with the antiandrogen flutamide . Ten men with advanced breast cancer were evaluated for response to treatment with the luteinizing hormone-releasing hormone (LH-RH) analogue, buserelin, alone or in combination with the antiandrogen, flutamide. One of five patients receiving buserelin as a single agent had a partial remission lasting 12 months, and with the addition of flutamide, this lasted over 24 additional months. Three patients had stable disease with a median duration of 6 months (range, two to 14). One patient had progressive disease. Of five patients receiving the combination of buserelin and flutamide from the beginning of therapy, four patients had a partial remission with a median duration of over 15 months (range, over five to 16). One patient's disease remained stable for 12 months. Major side effects were hot flushes, loss of libido, and impotence. buserelin initiates a castration-like endocrine response and has potential in the treatment of men with disseminated breast cancer when used either alone or in combination with flutamide.


piroxicam

naproxen

A double-blind multicentre trial of piroxicam and naproxen in osteoarthritis . A multicentre, double-blind study of unprecedented size was conducted to compare the safety and efficacy of piroxicam and naproxen in the treatment of osteoarthritis. The study comprised 2,035 patients and a treatment period of 12 weeks. The dosage was 20 mg piroxicam and 750 mg naproxen daily with the option to reduce to 10 and 500 mg, respectively, at week 4 or 8. No major difference between the drugs was observed with regard to overall incidence of adverse events. The frequency of serious adverse events was about 1% for both drugs. A statistically significant decline of adverse events with age was found in both sexes. piroxicam was significantly superior to naproxen for pain at rest and pain on movement at 12 weeks and degree of restriction in daily activity at 4 weeks. A significantly increasing beneficial effect was observed with both drugs between 4 and 12 weeks of treatment. The comparable safety observed for the two drugs is in contrast to perceptions based on spontaneous reports to official monitoring systems.


cyproterone acetate

raloxifene

Effects of estradiol , cyproterone acetate , tibolone and raloxifene on uterus and aorta atherosclerosis in oophorectomized cholesterol-fed rabbits . Different hormonal replacement regimens are used for treating climacteric complaints; however, not all of them have the same clinical profile. Cardiovascular disease (CVD) is a major health problem and tibolone, raloxifene, estradiol (alone or with cyproterone acetate) have been added to cholesterol-fed rabbits to study atherosclerosis. ### methods A total of 48 cholesterol-fed New Zealand white rabbits were studied for 4 months. Forty rabbits underwent bilateral ovariectomy and the other eight were sham operated (group S). The ovariectomized rabbits were allocated to five groups of eight animals each receiving tibolone (Group T, 6 mg/day), raloxifene (R, 35 mg/day), estradiol valerate (E, 3 mg/day), estradiol valerate plus cyproterone acetate (EC, 3+0.5 mg/day, respectively), and no treatment for the control group (C). The sham group received no treatment too. ### results After 4 months the percentage of the extent of atherosclerosis in the aorta was 30.4% in C group, 24.5% in S group, 10.2% in T group, 30.3% in R group, 17.9% in E group and 28.1% in EC group (P<0.05 T vs. C, R, EC). The aortic cholesterol content compared with aortic weight was 8.55 microg/mg in C group, 11.97 microg/mg in S group, 1.86 microg/mg in T group, 3.82 microg/mg in R group, 2.86 microg/mg in E group and 5.24 microg/mg in EC group (P<0.05 T vs. EC, C, S; R vs. C, S; E vs. C, S). Uterine weights in grams were: 1.89 (C group), 2.24 (S), 7.38 (T), 1.94 (R), 9.92 (E), and 5.94 (EC); P<0.05 (C, S, R, vs. T, E, EC; T vs. E; EC vs. T, E). ### conclusion Our study showed a decrease in the extent of aortic atherosclerosis in oophorectomized cholesterol-fed rabbits treated with tibolone or estradiol, and a decrease in aortic cholesterol content in rabbits treated with tibolone, raloxifene and estradiol. However, rabbits treated with tibolone showed an increased uterine weight, which is contrary to that observed in humans.


propranolol

carvedilol

Efficacy of carvedilol versus propranolol versus variceal band ligation for primary prevention of variceal bleeding. Band ligation and propranolol are the current therapies for primary prevention of variceal bleeding. carvedilol is a rising nonselective beta-blocker used for reducing portal pressure with favorable outcome. The aim of this study to assess the efficacy of carvedilol, propranolol, and band ligation for primary prevention of variceal bleeding based on the effect of each regimen on progression of Child score and portal hypertensive gastropathy after 1 year. ### methods The study included 264 cirrhotic patients with medium/large-sized varices who were candidates for primary prophylaxis of variceal bleeding. Patients were randomly divided into three groups : group I : band ligation ; group II : propranolol ; group III : carvedilol . ### results Group I showed higher success rate of 75 %, followed by group III with 70.2 % and group II with 65.2 %. Risk of bleeding was comparable between the three groups, with group II carrying the highest rate of complications (34.7 %) followed by group III (14.2 %) and finally group I (5.7 %). After 1 year of follow-up, Child score did not improve in any of the studied groups, while portal hypertensive gastropathy significantly increased in group I but decreased in groups II and III. ### conclusions Band ligation is the best treatment option for primary prevention of variceal bleeding with minimal complications. carvedilol is a good pharmaceutical alternative medicine to propranolol with lesser side-effects. Progress of liver disease as represented by Child score is not affected by any of the primary variceal prophylactic regimens, although medical treatment reduces portal hypertensive gastropathy. Choice of treatment depends on patient will, compliance with treatment, and endoscopist competence.


naloxone

nicotine

acetylcholine

glutamate-diethylester

Iontophoretically applied dopamine depolarizes and hyperpolarizes the membrane of cat caudate neurons. Dopamine (DA) was applied iontophoretically on intracellularly recorded cat caudate neurons. Ejected approximately 100 micrometers away from the cell soma, it caused slow depolarizations of the membrane while the ongoing firing rate was reduced. This last effect was not due to sodium inactivation. Cortically evoked EPSP-IPSP sequences were inhibited during the depolarizations. The latency of cortically evoked action potentials was consistently increased during DA-ejections. These effects were blocked by fluphenazine, relatively selective blocker of the DA-sensitive adenylate cyclase. Nevertheless , there are serious doubts as to the specificity of these actions of DA as a number of other substances like naloxone , nicotine , acetylcholine or glutamate-diethylester occasionally had very similar effects on membrane potential , firing rate and cortically evoked EPSP-IPSP sequences . If DA was applied nearer to the soma, approximately 50 micrometers away, 70% of the recorded neurons continued to display the slow depolarizations above described, while 30% of the cells now reacted by a hyperpolarization accompanied also by a reduced firing rate. If DA was applied for prolonged periods on such cells, the initial hyperpolarization was followed by the slow depolarization. The observation that during the slow depolarization there is a decrease in firing rate and amplitude of the cortically evoked IPSP is explained by the assumption that the region of the axon hillock is hyperpolarized by DA, and that the slow depolarization is a phenomenon restricted to the distant recording site and possibly to the dendritic region. None of the 74 responsive neurons displayed an increased firing fate when DA was ejected either continuously, i.e. for more than 5 sec, or in short pulses of 50--500 msec.


dihydroartemisinin

artemether

artesunate

Validation of ELISA for quantitation of artemisinin-based antimalarial drugs. The circulation of counterfeit or substandard artemisinins (ARTs) in malaria-endemic areas poses a serious threat to the long-term use of these drugs. Here , we validated an indirect competitive enzyme-linked immunosorbent assay ( icELISA ) for quantification of ARTs and found that 50 % of inhibitory concentrations of dihydroartemisinin , artemether , and artesunate were 8.1 , 207.0 , and 4.7 ng/mL , respectively . We compared the icELISA with high-performance liquid chromatography (HPLC) for quantifying ART and its derivatives in 22 convenience samples of commercial antimalarial drugs. Paired t tests showed a borderline significant difference between the two methods (mean = 0.03, 95% confidence interval [CI] 0.00-0.07, P = 0.074) and the icELISA results were more variable than those of the HPLC analysis (P < 0.001), suggesting that further improvement is needed to enhance the performance of the icELISA. Our results showed that the icELISA has the potential to be improved for quality assurance of ARTs at the point of care in endemic settings.


mitoxantrone

cidofovir

Inhibition of cowpox virus and monkeypox virus infection by mitoxantrone. mitoxantrone, an FDA-approved therapeutic for the treatment of cancer and multiple sclerosis, was previously reported to exhibit antiviral activity against vaccinia virus. To determine whether this activity extends to other orthopoxviruses, mitoxantrone was tested against cowpox and monkeypox. mitoxantrone demonstrated an EC(50) of 0.25 μM against cowpox and 0.8 μM against monkeypox. Intraperitoneal treatment of cowpox virus-challenged C57Bl/6 mice with 0.5 mg/kg mitoxantrone resulted in 25% survival and a significant increase in survival time. In an effort to improve its efficacy , mitoxantrone was tested for synergistic activity with cidofovir . In vitro tests demonstrated significant synergy between the two drugs against cowpox; however, no synergistic effect on animal survival or median time-to-death was seen in intranasally-infected BALB/c mice. Significantly fewer animals survived when treated with a combination of 0.5 mg/kg mitoxantrone and 100 mg/kg cidofovir than with 100 mg/kg cidofovir alone. This is, to our knowledge, the first report of limited anti-orthopoxvirus activity by mitoxantrone in an animal model.


atorvastatin

bezafibrate

Allelic polymorphism -491A/T in apo E gene modulates the lipid-lowering response in combined hyperlipidemia treatment. Combined hyperlipidemia (CHL) is one of the dyslipidemias more frequently found in clinical practice, and lipid-lowering drugs are often necessary in its management. Some genetic loci have been associated with CHL expression, and some studies have shown modulation of drugs efficiency in the treatment of dyslipidemias by genetic polymorphisms. We have investigated whether common polymorphisms and mutations in the apolipoprotein (apo) E, lipoprotein lipase (LPL), and apo CIII genes influence atorvastatin or bezafibrate responses in patients with CHL. ### design One hundred and sixteen subjects participating in the ATOMIX study (atorvastatin in Mixed dyslipidemia) were randomized to treatment with either atorvastatin or bezafibrate. Apolipoprotein E genotype and common -491A/T and -219T/G polymorphisms in the apo E gene promoter region, Sst I polymorphism in the apo CIII gene (3238C/G), and D9N and N291S common mutations in the LPL gene were determined by polymerase chain reaction (PCR) and restriction enzyme digestion. ### results Statistical analysis showed the influence of the -491A/T polymorphism in atorvastatin and bezafibrate treatments. Subjects carrying the -491T allele showed an increased LDL-cholesterol-lowering effect with atorvastatin compared with -491T allele noncarriers (-35% vs. -27%, P = 0.037). Subjects carrying the -491T allele, when on bezafibrate treatment, showed a lower triglyceride reduction compared with -491T allele noncarriers (-23% vs. -39%, P = 0.05). ### conclusions In our study , the -491A/T polymorphism in the apo E gene promoter region modulated the lipid-lowering efficiency of atorvastatin and bezafibrate in CHL patients . Such influence might explain some of the interindividual response variabilities observed for the two drugs, and could help in CHL management.


methotrexate

chloroquine

Efficacy and safety of methotrexate in articular and cutaneous manifestations of systemic lupus erythematosus.  A prospective open-label study comparing the efficacy and safety of methotrexate ( MTX ) and chloroquine ( CQ ) in articular and cutaneous manifestations of systemic lupus erythematosus ( SLE ) . ### methods Consecutive SLE patients were randomly assigned to either 10 mg MTX weekly or 150 mg CQ daily during 24 weeks. Outcome measures were: numbers of swollen and tender joints, duration of morning stiffness, visual analog scale (VAS) for articular pain, physician global assessment index, patient global assessment index, SLE Disease Activity Index (SLEDAI), disappearance of skin rash and erythrocyte sedimentation rate (ESR). ### results Forty-one patients consented to participate, 15 were allocated in the MTX group and 26 in the CQ group. Two patients on MTX dropped out due to side-effects and two in the CQ group, one due to side-effects and one due to inefficacy. Baseline demographic, clinical and laboratory parameters of the two groups were nearly identical. In both groups the clinical and laboratory parameters improved significantly over 24 weeks, except the ESR in the MTX group. The results of the outcome measures at the end of the trial did not differ significantly between the two groups, except morning stiffness (P < 0.05 in favor of the MTX group) and ESR (P < 0.01 in favor of the CQ group). Rise of serum alanine aminotransferase was observed in two cases in the MTX group and in none in the CQ group. ### conclusion Low-dose MTX appears to be as effective as CQ in patients with articular and cutaneous manifestations of SLE, having an acceptable toxicity profile. Results of this prospective study need to be confirmed in a larger study.


diltiazem

gemcitabine

Diltiazem potentiates the cytotoxicity of gemcitabine and 5-fluorouracil in PANC-1 human pancreatic cancer cells through inhibition of P-glycoprotein. Pancreatic cancer (PC) is one of the most aggressive tumors with dismal survival and a high death rate due to chemotherapeutic failure. P-glycoprotein (P-gp) plays a pivotal role in PC response to gemcitabine and 5-fluorouracil (5-FU). diltiazem, a calcium channel blocker, is a P-gp inhibitor. In the current study , we investigated the hypothesis that targeting of P-gp by diltiazem can enhance the cytotoxicity of gemcitabine and 5-FU against human pancreatic cancer cells . ### Main Methods The cytotoxic effect of diltiazem, gemcitabine, and 5-FU in single and combined forms against PANC-1 and AsPC-1 cells were assayed by MTT. Flow cytometric analysis was used for the determination of cell cycle, apoptosis, and stemness markers in PC cells. Besides, immunoblotting was used for assessment of Bax, caspase 3, cyclin D1, and P-gp expressions. ### Key Findings diltiazem co-treatment, either with gemcitabine or 5-FU, synergistically reduced cell viability, induced apoptosis, and caused cell cycle arrest. In addition, diltiazem co-treatment decreased the expressions of stem cell markers CD24 and CD44, increased the expressions of Bax and cleaved caspase 3, enhanced DNA fragmentation, and attenuated cyclin D1 and P-gp expressions as compared to cells treated with either gemcitabine or 5-FU alone. ### significance Our findings suggest that diltiazem may be potential neoadjuvant therapy to enhance the response of PC to gemcitabine or 5-FU treatment.


raltegravir

efavirenz

Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. The purpose of this study was to evaluate the safety and efficacy of raltegravir vs efavirenz-based antiretroviral therapy after 96 weeks in treatment-naive patients with HIV-1 infection. ### methods Multicenter, double-blind, randomized study of raltegravir (100, 200, 400, or 600 mg twice a day) vs efavirenz (600 mg every day), both with tenofovir/lamivudine (TDF/3TC), for 48 weeks, after which raltegravir arms were combined and all dosed at 400 mg twice a day. Eligible patients had HIV-1 RNA > or =5000 copies per milliliter and CD4 T cells > or =100 cells per microliter. ### results One hundred ninety-eight patients were randomized and treated; 160 received raltegravir and 38 received efavirenz. At week 96, 84% of patients in both groups achieved HIV-1 RNA <400 copies per milliliter; 83% in the raltegravir group and 84% in the efavirenz group achieved <50 copies per milliliter (noncompleter = failure). Both groups showed similar increases in CD4 T cells (221 vs 232 cells/uL, respectively). An additional 2 patients ( 1 in each group ) met the protocol definition of virologic failure between weeks 48 and 96 ; no known resistance mutations were observed in the raltegravir recipient ; the efavirenz recipient had nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance mutations . Investigator reported drug-related clinical adverse events (AEs) were less frequent with raltegravir (51%) than efavirenz (74%). Drug-related AEs occurring in >10% of patients in either group were nausea in both groups and dizziness and headache in the efavirenz group. Laboratory AEs remained infrequent. raltegravir had no adverse effect on total or low-density lipoprotein cholesterol or on triglycerides. Neuropsychiatric AEs remained less frequent with raltegravir (34%) than efavirenz (58%). There were no drug-related serious AEs in patients receiving raltegravir. ### conclusions In antiretroviral therapy-naive patients, raltegravir with TDF/3TC had potent antiretroviral activity, which was similar to efavirenz/TDF/3TC and was sustained to week 96. raltegravir was generally well tolerated; drug-related AEs were less frequent in patients treated with raltegravir compared with efavirenz.


ifosfamide

etoposide

Experience with ifosfamide combinations (etoposide or DDP) in non-small cell lung cancer.  In all , 171 patients with histologically verified non-small cell lung carcinoma were treated with ifosfamide 2.0 g/m2 on days 1 - 5 in combination with ( 91 patients ) etoposide 120 mg/m2 on day 1 . Therapeutic regimens were repeated after 4 weeks. Supportive treatment with mesna (20% of the ifosfamide doses at 0, 4, and 8 h) was performed. cisplatin treatment was supported by mannitol-induced diuretic hydration. The overall response rate of ifosfamide/etoposide was calculated to be 27%, with 1 complete and 24 partial remissions. The median survival time for all patients was 8.5 months, for responders 14 months (P less than 0.05), for patients with no change 9.5 months, and for patients with tumor progression 4 months. With ifosfamide/cisplatin, there were 4 complete and 21 partial remissions (response rate 35%). The median survival time for all patients was 8.3 months, for responders 11.5 months, and for patients with tumor progression 4 months. Age, sex, and histological tumor type had no significant effect on survival. Patients with better performance stage and limited disease lived significantly longer. The main side-effects of the cisplatin combination were vomiting, bone marrow depression, and neuropathy. The etoposide combination was tolerated better. Urotoxicity was not significant, as a consequence of treatment with mesna. The results show that the combination ifosfamide/etoposide or ifosfamide/cisplatin are effective in the treatment of non-small cell lung cancer, being comparable to other combinations of etoposide/cisplatin and vindesine/cisplatin. Because of the better tolerability, the combination ifosfamide/etoposide is superior to cisplatin combinations.


amodiaquine

primaquine

Mass administration of an antimalarial drug combining 4-aminoquinoline and 8-aminoquinoline in Tanganyika. For the eradication of malaria from hyperendemic regions of tropical Africa it is apparent that use may have to be made of antimalarial drugs, administered individually on a census basis, in addition to measures directed against the mosquito. The suppressive activity of existing compounds among individuals having different degrees of immunity is well established, and trials among large groups of people have been conducted with single drugs and with combination of drugs. In the large-scale trials carried out in Tanganyika and described in this paper , such a combination , containing amodiaquine for schizontocidal effect and primaquine as a gametocytocide , was administered to three distinct population groups of more than 5000 at differing intervals of time , in order to determine the ability of this combination to interfere with transmission in the absence of other malaria control measures . It was found that treatment of 93% of the population at intervals of one or two weeks resulted in a reduction of the malaria indices to a very low level but such success was not obtained when the combination of drugs was administered every four weeks, although in the area concerned population coverage was less satisfactory owing to migration.


bortezomib

lenalidomide

dexamethasone

Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Multiple myeloma accounts for approximately 10% of hematologic malignancies. ### diagnosis The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE) namely CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging (MRI). ### Risk Stratification The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high-risk multiple myeloma. Presence of any two high risk factors is considered double-hit myeloma; three or more high risk factors is triple-hit myeloma. ### Risk Adapted Initial Therapy In transplant eligible patients , induction therapy consists of bortezomib , lenalidomide , dexamethasone ( VRd ) given for approximately 3 - 4 cycles followed by autologous stem cell transplantation ( ASCT ) . In high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd. Selected standard risk patients can get additional cycles of induction, and delay transplant until first relapse. Patients not candidates for transplant are typically treated with VRd for approximately 8-12 cycles followed by lenalidomide; alternatively these patients can be treated with daratumumab, lenalidomide, dexamethasone (DRd). ### Maintenance Therapy After ASCT, standard risk patients need lenalidomide maintenance, while bortezomib-based maintenance is needed for patients with high-risk myeloma. ### Management Of Refractory Disease Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse.


Genistein

docetaxel

bicalutamide

Genistein combined polysaccharide enhances activity of docetaxel , bicalutamide and Src kinase inhibition in androgen-dependent and independent prostate cancer cell lines . To determine the benefit of genistein combined polysaccharide (GCP) in combination with the androgen receptor antagonist bicalutamide, the antimicrotubule taxane docetaxel, and the Src kinase inhibitor pp2 as part of a treatment regimen for advanced prostate cancer (CaP). ### Materials And Methods The growth inhibitory and apoptotic effects of GCP in combination with bicalutamide, docetaxel and pp2 were evaluated in both the androgen-dependent LNCaP line, and three androgen-independent lines: CWR22Rv1, PC-3, and LNCaP-R273H. The LNCaP-R273H model is an LNCaP variant expressing a p53(GOF) allele; like CWR22Rv1 and PC-3, it is able to grow in a minimal androgen environment. The effects of GCP treatment in combination with the aforementioned drugs were measured using an MTT assay, Western blotting, flow cytometric analysis, and caspase activation assay. Altered schedules of drug administration were explored using combinations of GCP and docetaxel. ### results GCP potentiated the activity of docetaxel in all four cell lines, resulting in growth inhibition and increased apoptosis. The combination of GCP and bicalutamide had enhanced activity in both the LNCaP and LNCaP-R273H lines, which may better represent patient tumour cells after progression to androgen independence. Administration of docetaxel followed by GCP resulted in a synergistic interaction in LNCaP cells, with increased apoptosis. By contrast, GCP administered first showed subadditivity, probably resulting from GCP-mediated induction of G1 arrest interfering with docetaxel activity. ### conclusion These data suggest that GCP, an isoflavone-enriched compound with minimal side-effects and far superior intestinal absorption rate of genistein, has significant clinical potential in combination with docetaxel, bicalutamide or targeted agents for the treatment of advanced CaP.


bosentan

sildenafil

[Efficacy of combination therapy with bosentan and sildenafil for refractory pulmonary arterial hypertension associated with fibrotic lung in systemic sclerosis]. A 54-year-old woman with a 20-year history of Raynaud phenomenon was admitted to our hospital complaining of progressive dyspnea on exertion since 5 years previously. Interstitial lung disease was diagnosed, accompanied by pulmonary arterial hypertension (PAH) associated with systemic sclerosis. After oxygen therapy and treatment with sildenafil, her clinical condition and PAH gradually improved. However, she was readmitted due to deterioration of Raynaud phenomenon and progressive dyspnea in March 2009. Right heart catheterization findings demonstrated that her mean pulmonary arterial pressure (PAP) was elevated, at 48 mmHg. bosentan was therefore added to an increased dose of sildenafil. Consequently, her dyspnea, 6-min walking distance, serum brain natriuretic peptide level, and PAP improved. Combination therapy with bosentan and sildenafil was effective for this case of refractory PAH associated with fibrotic lung in systemic sclerosis .


infliximab

etanercept

Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Two tumor necrosis factor alpha (TNFalpha) antagonists were recently licensed in the US. infliximab was licensed in 1998 for the treatment of Crohn's disease (CD), and since 1999, it has been licensed in combination with methotrexate for treatment of rheumatoid arthritis (RA). etanercept was licensed in 1998 for treatment of RA and, more recently, for juvenile RA and psoriatic arthritis. Because of potential immunosuppression related to use of anti-TNFalpha agents, we sought to identify postlicensure cases of opportunistic infection, including histoplasmosis, in patients treated with these products. ### methods The US Food and Drug Administration's (FDA) passive surveillance database for monitoring postlicensure adverse events was reviewed to identify all reports received through July 2001 of histoplasmosis in patients treated with either infliximab or etanercept. ### results Ten cases of Histoplasma capsulatum (HC) infection were reported: 9 associated with infliximab and 1 associated with etanercept. In patients treated with infliximab, manifestations of histoplasmosis occurred within 1 week to 6 months after the first dose and typically included fever, malaise, cough, dyspnea, and interstitial pneumonitis. Of the 10 patients with histoplasmosis, 9 required treatment in an intensive care unit, and 1 died. All patients had received concomitant immunosuppressive medications in addition to infliximab or etanercept , and all resided in HC-endemic regions . ### conclusion Postlicensure surveillance suggests that acute life-threatening histoplasmosis may complicate immunotherapy with TNFalpha antagonists, particularly infliximab. Histoplasmosis should be considered early in the evaluation of patients who reside in HC-endemic areas in whom infectious complications develop during treatment with infliximab or etanercept.


vincristine

etoposide

carboplatin

Postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin for the treatment of high-risk retinoblastoma.  Analysis of 52 eyes with high-risk retinoblastoma managed with postenucleation adjuvant chemotherapy using vincristine sulfate , etoposide phosphate , and carboplatin showed no evidence of systemic metastasis in any case during a mean ( range ) follow-up of 66 ( 12 - 202 ) months . ### purpose To determine the efficacy of postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin in the prevention of metastasis for patients with high-risk retinoblastoma. ### methods Retrospective, nonrandomized, interventional case series of 52 eyes in 51 patients with high-risk retinoblastoma consisting of tumor invasion into the anterior segment, posterior uvea 3 mm or greater, postlaminar optic nerve, or any combination of posterior uvea and optic nerve involvement. ### results Of 51 consecutive patients with high-risk retinoblastoma, there were 30 males (59%) and 21 females (41%), with a median age of 28 months at diagnosis. All 52 eyes were classified as group E. The main histopathologic risk factors included anterior segment invasion (7 [13%]), isolated massive posterior uveal invasion of 3 mm or greater (6 [12%]), isolated postlaminar optic nerve invasion (15 [29%]), or any posterior uveal invasion with any optic nerve involvement (24 [46%]). There was additional invasion into the sclera (3 [6%]) and extrascleral structures, including the orbit (1 [2%]). A single histopathologic high-risk factor was present in 32 eyes (62%), whereas 20 eyes (38%) manifested 2 or more high-risk characteristics. Based on previously published series, untreated high-risk retinoblastoma carries at least a 24% risk for metastatic disease. In the present series, using vincristine, etoposide, and carboplatin in all cases, there was no metastasis during a mean follow-up of 66 months (median [range], 55 [12-202] months). ### conclusions Retinoblastoma with invasion into the postlaminar optic nerve and/or posterior uvea is at high risk for metastasis and death. In this study, postenucleation chemotherapy using vincristine, etoposide, and carboplatin was effective in preventing metastasis in every case (100%).