phenytoin

gabapentin

Calcium Imaging of Neuronal Activity in Drosophila Can Identify Anticonvulsive Compounds. Although there are now a number of antiepileptic drugs (AEDs) available, approximately one-third of epilepsy patients respond poorly to drug intervention. The reasons for this are complex, but are probably reflective of the increasing number of identified mutations that predispose individuals to this disease. Thus, there is a clear requirement for the development of novel treatments to address this unmet clinical need. The existence of gene mutations that mimic a seizure-like behaviour in the fruit fly, Drosophila melanogaster, offers the possibility to exploit the powerful genetics of this insect to identify novel cellular targets to facilitate design of more effective AEDs. In this study we use neuronal expression of GCaMP, a potent calcium reporter, to image neuronal activity using a non-invasive and rapid method. Expression in motoneurons in the isolated CNS of third instar larvae shows waves of calcium-activity that pass between segments of the ventral nerve cord. Time between calcium peaks, in the same neurons, between adjacent segments usually show a temporal separation of greater than 200 ms. Exposure to proconvulsants (picrotoxin or 4-aminopyridine) reduces separation to below 200 ms showing increased synchrony of activity across adjacent segments. Increased synchrony, characteristic of epilepsy, is similarly observed in genetic seizure mutants: bangsenseless1 (bss1) and paralyticK1270T (paraK1270T). Exposure of bss1 to clinically-used antiepileptic drugs ( phenytoin or gabapentin ) significantly reduces synchrony . In this study we use the measure of synchronicity to evaluate the effectiveness of known and novel anticonvulsive compounds (antipain, isethionate, etopiside rapamycin and dipyramidole) to reduce seizure-like CNS activity. We further show that such compounds also reduce the Drosophila voltage-gated persistent Na+ current (INaP) in an identified motoneuron (aCC). Our combined assays provide a rapid and reliable method to screen unknown compounds for potential to function as anticonvulsants.


amphotericin

flucytosine

fluconazole

Effects of preventive, early, and late antifungal chemotherapy with fluconazole in different granulocytopenic models of experimental disseminated candidiasis. To investigate the potential use of fluconazole for prevention and treatment of disseminated candidiasis in granulocytopenic patients, its in vivo antifungal activity was studied in three models of disseminated candidiasis in persistently granulocytopenic rabbits: acute, subacute, and chronic disseminated candidiasis. fluconazole was compared with the combination of amphotericin B and flucytosine for preventive, early, and late treatment of disseminated candidiasis, depending on the model. fluconazole was most effective when used for preventive or early treatment of acute and subacute disseminated candidiasis. When compared with the combination of amphotericin B plus flucytosine , fluconazole was similarly effective in early treatment of acute and subacute disseminated candidiasis . When treatment was delayed 6 days after established infection, fluconazole was less active in clearing tissues in comparison with its activity in preventive and early treatment. The combination of amphotericin B plus flucytosine, however, was significantly more active than fluconazole in treatment of chronic disseminated candidiasis in all tissues. In summary, fluconazole was most effective against disseminated candidiasis in persistently granulocytopenic rabbits when used for prevention or early treatment.


rubidazone

cytosine arabinoside

vincristine

prednisone

Treatment of patients over 50 years of age with acute myelogenous leukemia with a combination of rubidazone and cytosine arabinoside , vincristine , and prednisone ( ROAP ) . We administered a combination of rubidazone, cytosine arabinoside, vincristine, and prednisone (ROAP) to 91 patients with acute myelogenous leukemia who were 50 yr of age or older. These patients had been identified in previous studies to be a group with a relatively poor prognosis. One-third of the patients had an antecedent hematologic disorder prior to treatment. Forty patients (48%) obtained a complete hematologic and clinical remission. A history of an antecedent hematologic disorder, male sex, and absence of Auer rods were adverse factors for achieving remission in this older population. More than half of the patients achieved remission in one course. The major cause of failure to obtain a remission was death due to infection, 40% of which were caused by fungi. Resistance to chemotherapy, although uncommon, was noted more frequently in patients with an antecedent hematologic disorder. Univariate and multivariate prognostic factor analysis was used to compare these patients with a historical control group treated with a program in which adriamycin was used instead of rubidazone (AdOAP). No significant difference in remission rate was detected. Cyclocytidine was used as a maintenance agent in this study, and while the median remission duration was only 37 wk, 30% of patients are expected to be in remission for 2 yr. Chemotherapy programs combining an anthracycline with cytosine arabinoside, given to older patients in similar fasion to younger patients will achieve remissions in one-half of a group of older patients. These remissions are of comparable quality to those of younger patients. Mathematical models derived from analysis of prognostic factors are of use in identifying patients likely to fail these programs who are in need of innovative approaches to treatment.


docetaxel

pemetrexed

erlotinib

Chemotherapy of advanced non-small cell lung cancer. Patients with advanced NSCLC receive palliative chemotherapy with platinum-based doublets. Cisplatin-based doublets are preferred in patients with good performance status, whereas carboplatin-based protocols are preferred in patients with impaired organ functions (kidney, heart). Customized chemotherapy appears promising but still remains experimental. Improvements of the outcome of first-line chemotherapy have been achieved by the addition of cetuximab in patients with EGFR-positive NSCLC and of bevacizumab in selected patients with non-squamous cell NSCLC. The optimal combination of chemotherapy with targeted therapies remains a challenge. Maintenance therapy and early second-line chemotherapy might improve outcome but are not yet considered as standard treatments. Patients progressing after first-line chemotherapy are treated with docetaxel , pemetrexed or erlotinib . Finally, the efficacy of new anticancer treatments should be assessed by several clinical endpoints with overall survival remaining the most important endpoint in patients with advanced NSCLC.


methotrexate

5-aminosalicylic acid

azathioprine

Effective treatment of mouse experimental colitis by alpha 2 integrin antibody: comparison with alpha 4 antibody and conventional therapy.  To compare the therapeutic effect of α(2 ) and α(4 ) integrin-blocking antibodies to conventional inflammatory bowel disease drugs methotrexate , 5-aminosalicylic acid and azathioprine in the dextran sulphate sodium mouse colitis model . ### methods Colitis was induced in balb/c mice with 2.5-3.0% dextran sulphate sodium. Treatment was given daily for 7 days after the onset of colitis, by rectal installation. Clinical signs of disease were assessed daily using a disease activity index. After 19 days, all animals were killed and colon samples collected for histological grading and mRNA/protein analysis. All treatment groups were compared with an untreated control group and a treatment group receiving dextran sulphate sodium alone to monitor the potential degree of clinical remission. ### results Treatment with anti-α(2) antibodies and methotrexate reduced the body weight loss. At the end of treatment, anti-α(2) antibodies reduced rectal bleeding, while methotrexate reduced the disease activity index score. Histological evaluation showed that anti-α(2) antibodies, methotrexate, 5-aminosalicylic acid and azathioprine treatment reduced the acute inflammation; methotrexate was the only treatment with effect on the crypt score. Compared with the dextran sulphate sodium alone group, the methotrexate group showed down-regulation of IL-1β at the mRNA level, while the anti-α(2) antibody group displayed decreased protein expression of iNOS and IL-1β. ### conclusions Specific blocking of extravascular trafficking of leucocytes with α(2)-antibodies could be a new beneficial drug target in inflammatory bowel disease.


gemcitabine

paclitaxel

paclitaxel

gemcitabine

Combination of gemcitabine antagonizes antitumor activity of paclitaxel through prevention of mitotic arrest and apoptosis. paclitaxel, the first member of taxanes, is one of the most active chemotherapeutic agents developed in the last decade for the treatment of advanced breast cancer and many other types of solid tumors. The promising clinical activity of paclitaxel has also promoted considerable interest in combining this drug with other anti-tumor agents. In this study, we assessed the cytotoxic interaction between paclitaxel and gemcitabine administered at various schedules to human breast and ovarian cancer cells. Through a series of in vitro assays including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, DNA fragmentation, and flow cytometric analyses, we found that gemcitabine could significantly antagonize the cytotoxic effects of paclitaxel when tumor cells were exposed to the two drugs simultaneously or exposed to gemcitabine before paclitaxel. However, there was little antagonistic interaction observed when paclitaxel was administered before gemcitabine. Further analyses demonstrated that gemcitabine could significantly interfere with the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death unless paclitaxel is administered before gemcitabine . In addition, biochemical examinations revealed that pretreatment or cotreatment of gemcitabine inhibited paclitaxel-induced IkappaBalpha degradation and bcl-2 phosphorylation that are believed to play critical roles in the signal pathways leading to apoptotic cell death. These results indicate that the interaction between paclitaxel and gemcitabine is highly schedule dependent. Exposure of tumor cells to gemcitabine before paclitaxel or two drugs simultaneously could result in pronounced antagonism. The optimal schedule for this combination might be sequential exposure to paclitaxel followed by gemcitabine.


phenytoin

carbamazepine

Treatment of infantile spasms. To summarize and evaluate the literature regarding the clinical features, epidemiology, etiology, pathophysiology, and treatment of infantile spasms. ### Data Sources A literature search of articles from January 1966 to July 1993 using MEDLINE, EM-Base, and Current Concepts/Life Sciences, as well as bibliographies of relevant articles. ### Study Selection All identified original and review publications regarding the clinical features, epidemiology, etiology, pathophysiology, and treatment of infantile spasms were reviewed. Emphasis was placed on original studies published since 1975. ### Data Extraction Data from published research were extracted and evaluated according to study design, sample size, dosing regimen, outcome measures, and treatment efficacy and safety. ### Data Synthesis Infantile spasms constitute a rare epileptic syndrome with a poor long-term prognosis for normal intellectual development. The spasms are characterized by a brief symmetric contraction of the muscles of the neck, trunk, and/or extremities, often occurring in a series of 2 to more than 100 spasms during a single episode. The disorder is age-specific, with the peak onset of symptoms occurring between 2 and 8 months of age. Spasms of no identifiable cause in infants with normal development prior to the onset of infantile spasms are classified as cryptogenic or idiopathic, whereas those with an identifiable cause are classified as symptomatic. Long-term prognosis is best in cryptogenic cases, with 30-70 percent attaining normal intellect compared with 5-19 percent in symptomatic cases. The etiology and pathophysiology are not well understood. Recent theory postulates that infantile spasms may be caused by an excess of corticotropin-releasing hormone activity during infancy. The suspected association between the whole-cell pertussis vaccine and infantile spasms is coincidental. Few well-designed, prospective, controlled clinical trials for the treatment of infantile spasms have been conducted. ### conclusions Standard anticonvulsants such as phenytoin , the barbiturates , carbamazepine , and the succinimides have been ineffective . Of the anticonvulsants, only the benzodiazepines, valproic acid, and vigabatrin have shown efficacy in reducing spasm frequency and severity. Hormonal therapy with adrenocorticotropic hormone (ACTH) and/or prednisone has been the most frequently studied treatment modality and appears to be the most effective. Hormonal therapy achieves complete spasm control in 50-75 percent of infants within four weeks of initiation. Opinions differ regarding the relative efficacy between ACTH and prednisone, the need for early initiation of hormonal treatment, and the benefits of high dosages of ACTH (> 40 units/d). No treatment has been shown conclusively to improve the long-term intellectual development of these infants. Neurosurgery may be the treatment of choice in select cases when a localized central nervous system abnormality can be demonstrated. Well-designed, blind, prospective clinical trials are needed to answer definitively many lingering questions regarding the treatment of infantile spasms.


curcumin

doxorubicin

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


Daratumumab

Lenalidomide

Dexamethasone

Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma . lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population. ### methods We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival. ### results At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 10 ### conclusions Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).


doripenem

meropenem

Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: a phase III, prospective, multicenter, randomized, double-blind, noninferiority study. Complicated intra-abdominal infections (cIAIs) require surgical intervention and empiric antibacterial therapy. doripenem, a broad-spectrum carbapenem, provides coverage of key gram-negative and -positive aerobes and anaerobes encountered in cIAI. ### objective This study was designed to compare the efficacy and safety profile of doripenem and meropenem in hospitalized adult patients with cIAI. ### methods In this prospective, multicenter, doubleblind, noninferiority study, hospitalized adults with cIAI were randomly assigned to receive doripenem 500 mg IV q8h or meropenem 1 g IV q8h. After a minimum of 9 doses and adequate clinical improvement (relative to before the start of IV study drug, decreased body temperature and white blood cell count, improved or absent signs and symptoms of cIAI, and return of normal bowel function), patients could be switched to oral amoxicillin/clavulanate. Antibacterial therapy (IV plus subsequent oral) was given for a total of 5 to 14 days. The coprimary efficacy end points were the clinical cure rate (complete resolution or significant improvement of signs or symptoms of the index infection) in patients microbiologically evaluable (>or=1 baseline pathogen isolated from an intra-abdominal culture that was susceptible to both IV study drug therapies) at the test-of-cure (TOC) visit (21-60 days after the completion of study drug therapy) and the clinical cure rate in the microbiological modified intent-to-treat (mMITT) population (a bacterial pathogen identified at baseline, regardless of its susceptibility to the study drug). Noninferiority was concluded if the lower limit of the 2-sided 95 % CI for the difference ( doripenem minus meropenem ) in the proportion of patients classified as clinical cures was > or=-15 % . ### results A total of 476 patients were enrolled. The microbiologically evaluable population (319 patients) was 62.7% male and 67.7% white, with a mean age and weight of 46.7 years and 77.2 kg, respectively. In this population, doripenem and meropenem were associated with clinical cure rates at the TOC visit of 85.9% and 85.3%, respectively. The corresponding treatment difference was 0.6% (95% CI, -7.7% to 9.0%); this difference was not statistically significant. Similarly, in the mMITT population (385 patients), the clinical cure rates were 77.9% and 78.9%, respectively, and the corresponding 1.0% treatment difference was not statistically significant (95% CI, -9.7% to 7.7%). Clinical cure rates were not significantly different between the 2 treatment arms in key subgroups (eg, age, sex, race, baseline Acute Physiology and Chronic Health Evaluation II score, primary infection site). Microbiological eradication rates for common pathogens isolated at study entry were not significantly different between the 2 treatment groups. doripenem was well tolerated in the population studied. In the intent-to-treat population (471 patients), 83.0% and 78.0% of patients experienced >or=1 adverse event (AE) and 13.2% and 14.0% experienced >or=1 serious AE in the doripenem and meropenem treatment arms, respectively. In the doripenem and meropenem treatment arms, AEs resulted in study drug discontinuation in 5.1% and 2.1% of patients and death in 2.1% and 3.0% of patients, respectively. ### conclusions The present study found that doripenem (500 mg q8h) was effective in the treatment of cIAI, was therapeutically noninferior to meropenem (1 g q8h), with a safety profile not significantly different from that of meropenem in this selected population of patients with cIAI.


nivolumab

pembrolizumab

Management of Adverse Events Following Treatment With Anti-Programmed Death-1 Agents. : Immune checkpoint inhibitors have emerged as a mainstay of melanoma therapy and are playing an increasingly important role in the treatment of other tumor types. The clinical benefit afforded by these treatments can be accompanied by a unique spectrum of adverse events, called immune-related adverse events (irAEs), which reflect the drug's immune-based mechanism of action. IrAEs typically originate in the skin, gastrointestinal tract, liver, and endocrine system, although other organ systems may also be affected. This article provides an overview of irAEs associated with anti-programmed death-1 (anti-PD-1) antibodies (nivolumab and pembrolizumab) as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 inhibition (ipilimumab), followed by a discussion of irAEs of special clinical interest based on the potential for morbidity, frequent steroid use, and inpatient admission. We review clinical trial data and provide recommendations on how to manage irAEs associated with anti-PD-1 agents based on clinical experience and established management guidelines. We further illustrate the practical considerations of managing irAEs by presenting three cases of immune-related toxicity in melanoma patients treated with nivolumab or pembrolizumab . A better understanding of the identification and management of irAEs will help inform health care providers about the risks associated with anti-PD-1 treatment, to ensure the safe and appropriate use of these important new treatments. ### Implications For Practice Immune checkpoint inhibitors have demonstrated significant clinical benefit in advanced melanoma and other tumor types. These treatments are associated with immune-related adverse events (irAEs), which most commonly affect the skin and gastrointestinal tract, and, to a lesser extent, the liver, endocrine system, and other organs. This review focuses on the management of irAEs after treatment with anti-programmed death-1 (anti-PD-1) antibodies (nivolumab or pembrolizumab) as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 inhibition (ipilimumab) in patients with advanced melanoma. A better understanding of the management of irAEs will help ensure the safe and appropriate use of anti-PD-1 agents in melanoma and other tumor types.


carboplatin

paclitaxel

lonafarnib

Randomized phase II trial of carboplatin and paclitaxel with or without lonafarnib in first-line treatment of epithelial ovarian cancer stage IIB-IV . This study evaluates whether a molecular targeted therapy with the farnesyltransferase inhibitor lonafarnib added to standard chemotherapy in first-line treatment of advanced ovarian cancer (OC) could improve progression-free (PFS) and overall survival (OS). ### Patients And Methods We performed a prospective randomized phase II study to compare standard therapy carboplatin (C; AUC 5) and paclitaxel (T; 175 mg/m(2)) in primary advanced OC with or without lonafarnib (L). lonafarnib was given in a dose of 100mg orally twice a day during chemotherapy and was increased afterwards to 200mg up to six months as a maintenance therapy. ### results 105 patients were recruited (53 patients were randomized to receive LTC, 52 to TC). Hematologic toxicity was similar in both arms. Grade 3 and 4 non-hematological toxicity, occurred significantly more often with LTC (23% versus 4%, p=0.005) and was associated with a higher dropout rate. PFS and OS were not significantly different among both arms. The LTC arm showed inferiority in the stratum with residual tumor of more than 1cm: median PFS was 11.5 months (95% CI: 7.4-14.2) compared with 16.4 (95% CI: 10.3-40.4) for TC (p=0.0141; HR=0.36 (95% CI: 0.15-0.84)) with median OS 20.6 months (95% CI: 13.1-31.0) and 43.4 months (95% CI: 15.7-) for the TC arm (p=0.012; HR=0.32 (95% CI: 0.13-0.8)). ### conclusion The addition of lonafarnib did not improve PFS or OS. Patients with a residual tumor of more than 1cm had significantly shorter PFS and OS. Incorporation of lonafarnib into future studies for primary therapy of OC is not recommended.


oxaprozin

aspirin

aspirin

Effects of oxaprozin alone or in combination with aspirin on hemostasis and plasma protein binding. oxaprozin, a new nonsteroidal antiinflammatory agent, was studied alone and in combination with aspirin for its effects on hemostasis and protein binding in 10 healthy adults. When both oxaprozin and aspirin were given separately for seven days and in combination for five days, both drugs prolonged bleeding time and inhibited collagen- and epinephrine-induced platelet aggregation to a similar degree. The effects of the combination of oxaprozin and aspirin were not additive. The data from the protein binding study showed that oxaprozin was more than 99 per cent bound to plasma proteins. aspirin displaced oxaprozin from its binding sites. As a result, the rate of plasma clearance of oxaprozin significantly increased from 20 to 26 ml/min/kg (P less than 0.05), and the plasma half-life decreased from 45 to 40 hours. Platelet count and the humoral clotting mechanism were not affected by either drug alone or in combination. There was no clinical evidence of bleeding. One subject who received oxaprozin for 12 days and , in addition , aspirin for the last five days developed a rash that subsided after both drugs were discontinued ; one subject treated with aspirin experienced tinnitus . These data suggest that oxaprozin, like aspirin and other nonsteroidal antiinflammatory drugs, should be used with caution when administered to patients who have suffered trauma, who undergo surgery, or who have known defects in hemostasis.


pyrazinamide

levofloxacin

Limited tolerability of levofloxacin and pyrazinamide for multidrug-resistant tuberculosis prophylaxis in a solid organ transplant population.  To determine the long-term tolerability of prophylactic administration of pyrazinamide and levofloxacin in patients possibly exposed to multidrug-resistant tuberculosis ( MDRTB ) after undergoing solid organ transplantation . ### design Retrospective analysis. ### setting Community outpatient clinic. ### patients Forty-eight recipients of solid organ transplants beginning prophylaxis for MDRTB during August 1999 after possible exposure to a single index case of multidrug-resistant Mycobacterium tuberculosis within our community ### intervention Prophylaxis consisted of pyrazinamide 30 mg/kg/day plus levofloxacin 500 mg/day, administered for 1 year. ### Measurements And Main Results Thirteen (27.1%) of the 48 patients completed therapy; 27 (56.3%) discontinued therapy within 4 months due to adverse drug events. Gastrointestinal intolerance was the major adverse event resulting in early discontinuation. ### conclusion Prophylaxis of MDRTB with levofloxacin and pyrazinamide was associated with limited tolerability due to the high frequency of adverse events. While we search for a better tolerated prophylactic regimen, close monitoring for adverse reactions is recommended.


griseofulvin

ketoconazole

Additive effect of the combination of griseofulvin and ketoconazole against Microsporum canis in vitro . The susceptibility of 28 strains of Microsporum canis to griseofulvin, to ketoconazole and to a combination of both antifungal drugs was determined. griseofulvin proved to be more active than ketoconazole. The combination of both antifungal agents was found to exert an additive effect.


Aprepitant

ondansetron

temozolomide

ondansetron

Randomized open-label phase II trial of 5-day aprepitant plus ondansetron compared to ondansetron alone in the prevention of chemotherapy-induced nausea-vomiting (CINV) in glioma patients receiving adjuvant temozolomide. CINV remains a distressing side effect experienced by glioma patients receiving multi-day temozolomide therapy, in spite of guideline-based antiemetic therapy with selective serotonin-receptor-antagonists. Antiemetic research with aprepitant has routinely excluded glioma patients. In this randomized open-label phase II study, use of a nonstandard 5-day regimen of aprepitant for glioma patients was investigated. ### methods One hundred thirty-six glioma patients receiving their first cycle of adjuvant temozolomide (150-200 mg/m ### results Patients were 61% male, 97% white, 48% with KPS > 90%, 60% non-smokers, mean age 54, 92% with low alcohol use, and 46% with a CINV history. The CC was 58.6% (Arm-A) and 54.5% (Arm-B). Acute-complete response (CR) rates, defined as CC on day 1 in Arm-A and -B, were 97.1% and 87.9%, respectively (p = 0.056). Treatment-related toxicities were mild or moderate in severity. ### conclusions Aprepitant plus ondansetron may increase acute-CR , may have benefit regarding CINV 's effect on QoL , and is safe for 5-day temozolomide compared to ondansetron . This study provides no evidence that aprepitant increases CC rate over ondansetron alone.


lenalidomide

daratumumab

Daratumumab-mediated lysis of primary multiple myeloma cells is enhanced in combination with the human anti-KIR antibody IPH2102 and lenalidomide. Despite recent treatment improvements, multiple myeloma remains an incurable disease. Since antibody-dependent cell-mediated cytotoxicity is an important effector mechanism of daratumumab, we explored the possibility of improving daratumumab-mediated cell-mediated cytotoxicity by blocking natural killer cell inhibitory receptors with the human monoclonal anti-KIR antibody IPH2102, next to activation of natural killer cells with the immune modulatory drug lenalidomide. In 4-hour antibody-dependent cell-mediated cytotoxicity assays, IPH2102 did not induce lysis of multiple myeloma cell lines, but it did significantly augment daratumumab-induced myeloma cell lysis. Also in an ex vivo setting, IPH2102 synergistically improved daratumumab-dependent lysis of primary myeloma cells in bone marrow mononuclear cells (n=21), especially in patients carrying the FcγRIIIa-158F allele or the FcγRIIa-131R allele, who bind IgG1 with lower affinity than patients carrying the FcγRIIIa-158V allele or the FcγRIIa-131H allele. Finally , a further synergistically improved myeloma cell lysis with the daratumumab-IPH2102 combination was observed by adding lenalidomide , which suggests that more effective treatment strategies can be designed for multiple myeloma by combining daratumumab with agents that independently modulate natural killer cell function .


doxorubicin

docetaxel

A phase-II study of liposomal doxorubicin and docetaxel in patients with advanced pancreatic cancer.  Both liposomal doxorubicin ( LD ) and docetaxel ( D ) have a broad range of activity against solid tumors , including advanced pancreatic cancer ( APC ) , as single agents , while their combination has produced encouraging response rates in the treatment of several malignancies . We have conducted a Phase-II study in order to evaluate the tolerance and efficacy of their combination as front-line treatment in patients with APC. ### Patients And Methods Twenty-one chemotherapy-naïve patients with unresectable, locally-advanced or metastatic pancreatic cancer were enrolled. These included 16 males and 5 females with median age 66 years (range 57-80). Performance status (PS) was 0 (n = 10 pts), 1 (n = 7 pts) and 2 (n = 4 pts). D (80 mg/m2), and LD (30 mg/m2) were administered on day 1, every 3 weeks. RhG-CSF s.c. was given to all patients. At the time of analysis, all included patients were evaluated for toxicity and for response. ### results A total of 92 cycles were administered (4.38 cycles/patient). Partial response was achieved in 6 patients, with a median duration of response of 3 months. Stable disease was observed in 7 patients and progressive disease in 8 patients. The median duration of survival was 10 months (95% CI, 6-14 months) and the actuarial 1-year survival rate was 33.33%. With regard to toxicity, grades 3,4 neutropenia occurred in 8 (38%) patients and grades 3,4 thrombocytopenia in 4 (19%) patients. Non-hematological toxicity was recorded in 15 (71%) patients: grades 3,4 diarrhea (3 pts, 14%), hypersensitivity reactions (3 pt, 14%), grade 2 neurotoxicity (6 pts, 29%) and palmar-plantar erythrodysesthesia (9 pts, 43%). ### conclusion The doxorubicin and docetaxel combination was well-tolerated by these poor prognosis patients. Although both drugs have a marginal activity in pancreatic cancer, most patients experienced significant clinical improvement, with acceptable toxicity.


ranitidine

lansoprazole

Triple therapy with ranitidine or lansoprazole in the treatment of Helicobacter pylori-associated duodenal ulcer . The aim of this study was to verify the efficacy--in the cure of duodenal ulcer associated H. pylori infection--of ranitidine 300 mg taken late in the evening or lansoprazole 30 mg taken before breakfast, coupled with clarithromycin and metronidazole. ### methods Eighty patients with endoscopically proven active duodenal ulcer were randomized to take ranitidine or lansoprazole for 4-8 wk, together with clarithromycin 250 mg b.i.d. and metronidazole 500 mg b.id. for the first 2 wk. Endoscopic controls, as well as histological and urease tests for H. pylori, were performed at entry and after 4 and 8 wk. ### results According to intent-to-treat analysis, ulcers were healed after 4 wk in 36/40 patients (90%) with ranitidine and in 38/40 (95%) with lansoprazole. After 8 wk, the healing percentage with ranitidine and lansoprazole was 97% (39/40) and 95% (38/40), respectively. H. pylori was eradicated in 85% of the patients taking ranitidine and in 90% of those taking lanzoprazole. Side effects were reported in 25% of the patients in both groups. ### conclusions Our results confirm that the combination of ranitidine, clarithromycin, and metronidazole can be considered an alternative to proton pump inhibitors in terms of clinical efficacy and economy.


cimetidine

L-carnitine

A study on the effect of cimetidine and L-carnitine on myoglobinuric acute kidney injury in male rats . Myoglobinuric acute renal failure is the most important life threatening complication of rhabdomyolysis. Iron, free radicals, nitric oxide and cytochrome p450 are involved in the pathogenesis of mARF. The aim of this study is to compare the effect of cimetidine, l-carnitine and both agents together on mARF in rats. Forty rats were divided into 5 groups; group I: control rats, group II: myoglobinuric ARF rats, group III: mARF rats received l-carnitine (200mg/kg, i.p.), group IV: mARF rats received cimetidine (150mg/kg i.p.) and group V: mARF rats received both agents together. 48h after glycerol injection, systolic blood pressure was measured. Urine and blood samples were collected to evaluate urine volume, GFR, BUN, creatinine, K, Na, serum creatine kinase, NO and glutathione levels. Kidney specimens were taken to investigate renal cytochrome p450 and for histological examinations. cimetidine treatment significantly decreased creatinine, BUN, K, Na, SBP and creatine kinase and increased GFR and urine volume compared to group II. l-carnitine exerted similar changes except for the effect on K and GFR. NO was significantly decreased, while renal glutathione and cytochrome p450 were significantly increased in groups treated with l-carnitine or cimetidine as compared to group II. Combined treatment further improved renal functions, creatine kinase, oxidative stress parameters and SBP as compared to each therapy alone. The histological changes confirmed the biochemical findings. cimetidine and l-carnitine have protective effects - almost equally - against mARF. Using both agents together, minimises the renal injury.


crenolanib

quizartinib

sorafenib

Genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways mediating sorafenib resistance in acute myeloid leukemia. Drug resistance impedes the long-term effect of targeted therapies in acute myeloid leukemia (AML), necessitating the identification of mechanisms underlying resistance. Approximately 25% of AML patients carry FLT3 mutations and develop post-treatment insensitivity to FLT3 inhibitors, including sorafenib. Using a genome-wide CRISPR screen, we identified LZTR1, NF1, TSC1 or TSC2, negative regulators of the MAPK and MTOR pathways, as mediators of sorafenib resistance. Analyses of ex vivo drug sensitivity assays in FLT3-ITD AML patient samples revealed lower expression of LZTR1, NF1, and TSC2 correlated with sorafenib sensitivity. Importantly , MAPK and/or MTOR complex1 ( MTORC1 ) activity were upregulated in AML cells made resistant to several FLT3 inhibitors , including crenolanib , quizartinib , or sorafenib . These cells were sensitive to MEK inhibitors, and the combination of FLT3 and MEK inhibitors showed enhanced efficacy, suggesting its effectiveness in AML patients with FLT3 mutations and those with resistance to FLT3 inhibitors.


varenicline

nicotine

Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit: a randomized placebo-controlled trial. nicotine replacement therapy to aid smoking reduction increases the probability of a future quit attempt among smokers not currently planning to quit smoking. We tested whether varenicline , a partial nicotine agonist , would also increase future quit attempts . ### methods This randomized, placebo-controlled trial recruited 218 smokers who were interested in quitting but had no plans to quit in the next month. Participants used varenicline (2 mg/day) or placebo for 2-8 weeks plus received brief counseling on methods to reduce cigarettes/day. The primary measure was the incidence of a quit attempt within 6 months of study entry. Secondary measures were point prevalence abstinence, motivation to stop smoking, and reduction in cigarettes/day. ### results varenicline increased the incidence of a quit attempt more than placebo at the Nebraska site (73% vs. 41%; p < .001) but not at the Vermont site (45% vs. 51%; p = .45). varenicline increased most other measures of quit attempts, motivation and abstinence, independent of site. The beneficial effects of varenicline in quit attempts appeared to be mediated by greater reductions in cigarettes/day, dependence, craving, and cigarette satisfaction. varenicline had a greater effect on quit attempts in less-dependent smokers, in minority smokers, and in those who had less prior cessation or reduction activity. Adverse events were minimal. ### conclusions varenicline increased quit attempts in smokers who are not currently trying to quit at one of the two study sites and improved most all secondary outcomes independent of site. This appeared to be due to decreasing cigarettes/day and level of dependence.


pioglitazone

sulfasalazine

Comparative evaluation of different doses of PPAR-γ agonist alone and in combination with sulfasalazine in experimentally induced inflammatory bowel disease in rats. Inflammatory bowel disease (IBD) is an idiopathic, chronic inflammatory condition, which affects the gastrointestinal tract and has no curative treatment. The present study aimed to investigate the effect of different doses of pioglitazone alone and in combination with sulfasalazine in TNBS (trinitrobenzenesulfonic acid)-induced inflammatory bowel disease (IBD) in rats. ### methods A total of 36 animals were included in the study. Animals were divided into five groups (n = 6): group I--vehicle (ethanol), group II--TNBS + ethanol, group IIIA--TNBS + pioglitazone (15 mg/kg), group IIIB--TNBS + pioglitazone (30 mg/kg), group IV--TNBS + sulfasalazine (360 mg/kg), group V--TNBS + sulfasalazine (360 mg/kg) + pioglitazone (least effective dose found in group III). Group III was divided into two subgroups, namely IIIA and IIIB, on the basis of different doses of pioglitazone used. After completion of two weeks of treatment, rats were sacrificed under ether anesthesia by cervical dislocation for assessment of intestinal inflammation, histological analysis, myeloperoxidase assay, malondialdehyde assay and TNF-α estimation. ### results All the drug-treated groups showed both gross morphological and microscopic score either 1 or 2. None of them showed score of > 2 on both gross and microscopic morphological examination. Both MDA levels and MPO activity were significantly reduced in the drug-treated groups, with maximum reduction seen in the combination group. TNF-α was reduced in pioglitazone group. It was highly reduced in sulfasalazine group (group V) as compared to TNBS group thereby indicating that pioglitazone is protective in TNBS-induced inflammatory bowel disease. ### conclusion The present study showed reduction in lipid peroxidation, malondialdehyde levels and TNF-α levels in pioglitazone-treated group and hence, there was significant improvement in gross and microscopic features, too. However , combination of pioglitazone and sulfasalazine has shown greater efficacy .


zidovudine

zidovudine

stavudine

Phenotypic and genotypic resistance to nucleoside reverse transcriptase inhibitors in HIV-1 clinical isolates. To assess phenotypic and genotypic cross-resistance to nucleoside reverse transcriptase inhibitors in patients treated with a combination including zidovudine, who were switched to a combination including stavudine. ### methods We analysed 24 clinical HIV-1 isolates from 12 patients before and several months after therapeutic switching. Plasma HIV-1 RNA was measured using quantitative polymerase chain reaction (Roche). Genotypic resistance was measured by sequencing the reverse transcriptase gene from plasma HIV-1 RNA. Phenotypic resistance was measured using a recombinant assay (Virco). ### results Patients were treated with a combination including zidovudine for a mean (+/- SEM) period of 21.8 +/- 3.5 months and had a plasma viral load of 4.1 +/- 0.2 log HIV-1 RNA copies/mL (time 1). After a mean period of 19.3 +/- 1.6 months following the therapeutic change, the plasma viral load was 3.6 +/- 0.1 log copies/mL (time 2). At time 1, genotypic resistance to zidovudine was found in all cases (41L: four cases; 41L, 215Y: five cases; 41L, 210W, 215Y: two cases; K70R: one case) with a mean 6.6 +/- 1.6-fold increase in the median inhibitory concentration (IC50) to zidovudine and 1.7 +/- 0.4-fold to stavudine. At time 2 , genotypic resistance to zidovudine was found in 11 out of 12 cases ( 41L : two cases ; 41L , 215Y : six cases ; 41L , 210W , 215Y : two cases ; M41L , D67N , L210W , T215Y : one case ) with a mean 18.9 + /- 8.8-fold increase in the IC50 to zidovudine and 1.4 + /- 0.4-fold to stavudine ### conclusions In this clinical series of patients with suboptimal control of plasma HIV-1 RNA using a combination including zidovudine, the presence of zidovudine-related mutations was associated with a decreased phenotypic sensitivity to this drug. Despite persistent HIV-1 replication, switching to stavudine was associated with a further decrease in phenotypic sensitivity to zidovudine but not to stavudine after 19 months. These data suggest that stavudine remains a possible option in zidovudine-experienced patients.


Sorafenib

Oxaliplatin

Leucovorin

Phase II Study of Sorafenib Combined with Concurrent Hepatic Arterial Infusion of Oxaliplatin , 5-Fluorouracil and Leucovorin for Unresectable Hepatocellular Carcinoma with Major Portal Vein Thrombosis . sorafenib is recommended for the first-line treatment of advanced hepatocellular carcinoma (HCC). However, the median progression-free survival (PFS) of patients with HCC and major portal vein tumor thrombosis treated with sorafenib monotherapy is no more than 3 months. A prospective single-arm phase II study was conducted to determine whether adding hepatic arterial infusion chemotherapy of oxaliplatin, 5-fluorouracil and leucovorin to sorafenib could improve on these results. ### methods Thirty five patients were treated with sorafenib 400 mg orally twice a day, oxaliplatin 85 mg/m ### results The 3-, 6-, and 12-month PFS rates were 82.9, 51.4, and 22.9%, respectively. The median PFS and overall survival was 6.7 and 13.2 months, respectively. The objective response rate was 40%, and the disease control rate was 77.1% by RECIST criteria. Five (14.3%) patients achieved conversion to complete resection after the study treatment, and one of them experienced a pathological complete response. Treatment-related deaths did not occur. Grade 3-4 toxicities consisted of increases in aspartate aminotransferase (31.4%), hand-foot syndrome (17.1%), thrombocytopenia (14.3%), and neutropenia (8.6%). ### conclusions The combination treatment met the pre-specified end point of a 3-month progression free survival rate exceeding 65% and was clinical tolerable. The merits of this approach need to be established with a phase III trial. Clinical trial number http://ClinicalTrials.gov (No. NCT02981498).


levodopa

betaine

levodopa

betaine

levodopa

benserazide

levodopa

betaine-benserazide

Betaine protects cerebellum from oxidative stress following levodopa and benserazide administration in rats. The aim of the present study was to evaluate antioxidant and methyl donor effects of betaine in cerebellum following levodopa and benserazide administration in rats. ### Materials And Methods Sprague-Dawley male rats were treated with levodopa ( LD ) , betaine ( Bet ) , levodopa plus betaine ( LD/Bet ) , levodopa plus benserazide ( LD/Ben ) , levodopa plus betaine-benserazide ( LD/Bet-Ben ) , and the controls with vehicle for 10 consecutive days , orally . ### results Treatment of rats with LD and benserazide significantly increased total homocysteine in plasma of the LD/Ben group when compared to the other groups. Lipid peroxidation of cerebellum increased significantly in LD-treated rats when compared to the other groups. In contrast, glutathione peroxidase activity and glutathione content in cerebellum were significantly higher in the betaine-treated rats when compared to the LD and LD/Ben groups. Serum dopamine concentration increased significantly in LD-treated rats in comparison with the LD/Ben group. LD/Bet-treated rats also demonstrated significantly higher dopamine levels when compared to the LD/Ben group. ### conclusion We observed valuable effects of Bet in combination with LD and benserazide, which routinely were used for Parkinson's disease (PD) treatment, in experimentally-induced oxidative stress and hyperhomocysteinemia in rats. Therefore, it seems that Bet is a vital and promising agent regarding PD for future clinical trials in humans.


Cixutumumab

temsirolimus

A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer. The mammalian target of rapamycin (mTOR) plays a critical role in promoting tumor cell growth and is frequently activated in breast cancer. In preclinical studies, the antitumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated in part by Insulin-like growth factor type 1 receptor (IGF-1R). We designed a phase I trial to determine the maximum-tolerated dose ( MTD ) and pharmacodynamic effects of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer refractory to standard therapies . A 3 + 3 Phase I design was chosen. Temsirolimus and cixutumumab were administered intravenously on days 1, 8, 15, and 22 of a 4-week cycle. Of the 26 patients enrolled, four did not complete cycle 1 because of disease progression (n = 3) or comorbid condition (n = 1) and were replaced. The MTD was determined from the remaining 22 patients, aged 34-72 (median 48) years. Most patients (86 %) had estrogen receptor positive cancer. The median number of prior chemotherapy regimens for metastatic disease was 3. The MTD was determined to be cixutumumab 4 mg/kg and temsirolimus 15 mg weekly. Dose-limiting toxicities (DLTs) included mucositis, neutropenia, and thrombocytopenia. Other adverse events included grade 1/2 fatigue, anemia, and hyperglycemia. No objective responses were observed, but four patients experienced stable disease that lasted for at least 4 months. Compared with baseline, there was a significant increase in the serum levels of IGF-1 (p < 0.001) and IGFBP-3 (p = 0.019) on day 2. Compared with day 2, there were significant increases in the serum levels of IGF-1 (p < 0.001), IGF-2 (p = 0.001), and IGFBP-3 (p = 0.019) on day 8. A phase II study in women with metastatic breast cancer is ongoing.


amphotericin

itraconazole

itraconazole

amphotericin

Systemic histoplasmosis: a 15-year retrospective institutional review of 111 patients. To our knowledge, an institutional review of systemic histoplasmosis has not been conducted in the United States since the major outbreaks in Indianapolis in 1978-4982. We conducted a retrospective review of all patients with systemic histoplasmosis diagnosed at Mayo Clinic over a 15-year period. The case definitions employed were based on an international consensus statement by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC/IFICG) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG). One hundred eleven patients with systemic histoplasmosis were identified between January 1, 1991, and December 31, 2005. Of these, 78 patients had disseminated histoplasmosis and 55 patients had Histoplasma capsulatum fungemia. The mean age of patients was 55 years, 66% were male, and 98% were white. Fifty-nine percent of patients were immunocompromised. Fever was the most frequently reported symptom (63%), followed by respiratory complaints (43%) and weight loss (37%). The peripheral white blood cell count was <3000 cells/mm in 28%, hemoglobin was <10 g/dL in 29%, and platelet count was <150,000 cells/mm in 41% of patients. Liver enzymes were elevated (alanine aminotransferase >60 U/L in 39%, aspartate aminotransferase >60 U/L in 27%), alkaline phosphatase was >200 U/L in 55%, and albumin was <3.5 g/dL in 70%. Serologic and histopathologic examinations were each positive in 75% of cases, Histoplasma urine antigen screening was positive in 80%, and H. capsulatum was culture positive in 84%. Forty-seven percent of patients were sequentially treated with an amphotericin B-containing product followed by itraconazole , 31 % received itraconazole alone , and 7 % received an amphotericin B-containing product only . Another 13% of patients did not receive antifungal treatment, and the remaining 2% did not have treatment data available. Sixty percent of patients required hospitalization, and in hospital mortality was 6% with a median survival time of 61 days. The relapse rate was 9%, with a median relapse-free survival of 857 days. Systemic histoplasmosis should be suspected in patients who have lived in endemic areas with fever, bone marrow suppression, and elevated hepatic enzymes, particularly if they are immunocompromised. Evaluation including a combination of Histoplasma serologic screening, urine antigen assay, and fungal culture will secure the diagnosis in most cases.


pemetrexed

oxaliplatin

bevacizumab

Pemetrexed, oxaliplatin and bevacizumab as first-line treatment in patients with stage IV non-small cell lung cancer. oxaliplatin has less haematological toxicity than cisplatin and carboplatin. The combination of pemetrexed, oxaliplatin and bevacizumab appeared well tolerated and active as second- or third-line treatment in a previous phase II study. Its role as first-line therapy remains to define. ### Patients And Methods From August 2008 to May 2011 , consecutive chemo-naïve patients with stage IV non-squamous non-small cell lung cancer ( NSCLC ) received pemetrexed 500mg/m(2 ) , oxaliplatin 100mg/m(2 ) and bevacizumab 7.5mg/kg every 3 weeks for 6 cycles , in the outpatient setting . Maintenance therapy including pemetrexed and bevacizumab was given to patients with non-progressive disease. The primary evaluation criterion was safety. Secondary evaluation criteria were response rate, progression-free survival (PFS) and overall survival (OS). ### results Thirty-eight patients (50% males, median age: 55 years, range 38-76) received a total of 199 cycles (median per patient: 6, range 2-6), plus 98 cycles of maintenance therapy. Twenty patients (52.6%) had a PS of 2, and 6 (15.8%) had brain metastases. The most frequent toxicities were hypertension (all grades: 42.1%) and peripheral neuropathy (grade 2-3: 21.1%). Haematological toxicities included grade 4 neutropenia, grade 3 anaemia and thrombopenia (5.3% each). Neither febrile neutropenia nor arterial thrombo-embolic event occurred. The objective response rate was 55.3% (95%CI: 39.5-71.1). The median PFS and OS were 6.2 (95%CI: 5.4-9.0) and 14.6 (95%CI: 9.8-19.5) months, respectively. ### conclusions In this single centre experience, the combination of pemetrexed, oxaliplatin and bevacizumab was well tolerated and had promising activity as first-line therapy in unselected patients with stage IV non-squamous NSCLC.


sulfadiazine

chlorhexidine

Decreased bacterial adherence and biofilm formation on chlorhexidine and silver sulfadiazine-impregnated central venous catheters implanted in swine.  To determine if antiseptic central venous catheters impregnated with silver sulfadiazine and chlorhexidine ( antiseptic ) reduce bacterial adherence and biofilm formation without producing local or systemic toxicity . ### design Prospective, randomized, controlled trial. ### setting Experimental laboratory in a university teaching hospital. ### subjects Ten outbred New Hampshire pigs. ### interventions Nonimpregnated (control) and antiseptic-impregnated catheters were inserted intravascularly into swine for 7 days. After explantation, the catheters were assessed for bacterial adherence and biofilm formation, and the surrounding tissue was assessed for signs of toxicity. Before retrieval, systemic concentrations of antimicrobials were determined. ### Measurements And Main Results Sequential roll plate and centrifuging were used to detect moderately and tightly adherent bacteria on the outer and luminal surfaces of the catheter. The presence of biofilm was detected by scanning electron microscopy. Tissues surrounding the catheters were examined histopathologically; systemic concentrations of chlorhexidine, sulfadiazine, and silver were determined by atomic absorption and high-performance liquid chromatography. As compared with the controls, antiseptic catheters had significantly (p < .01) fewer moderately and tightly adherent bacteria on outer and luminal surfaces, and fewer adherent bacteria when outer surfaces alone were examined (p < .01). Scanning electron microscopy showed bacterial biofilm and adherence on the control catheters but not on the antiseptic catheters. There were no abnormal histopathologic changes associated with the test catheter, and serum concentrations of the antibacterial agents were shown to be within nontoxic ranges. ### conclusion The antiseptic-impregnated catheters prevented bacterial adherence and biofilm formation and produced no local or systemic toxicity.


stavudine

zidovudine

The prevalence of lipodystrophy in an ambulant HIV-infected population: it all depends on the definition. This study's objective was to determine the prevalence of body shape changes and metabolic abnormalities in an ambulant population with HIV infection. Three different definitions of lipodystrophy were used to assess these changes. Patients' anthropometric measures and dual-energy X-ray absorptiometry (DEXA) scans were compared in order to estimate fat distribution in this population. We sought to evaluate potential predictors for lipodystrophy according to each of the three definitions. ### methods We performed a cross-sectional study in the outpatient clinic of a tertiary referral hospital in Melbourne, Australia. We enrolled a total of 167 HIV-infected ambulatory patients over 3 months in mid-1998. Data on 159 males, 149 of whom were receiving triple combination antiretroviral therapy, were evaluated. Anthropometric measures, clinical examination, self-report of body shape changes, biochemical measures and DEXA scan were used to assess lipodystrophy and risk factors for cardiovascular disease. Patients described body shape changes in the face, trunk, arms and legs. Laboratory parameters measured included fasting triglyceride (TG), cholesterol, high-density lipoproteins (HDL), glucose, insulin, CD4 cell count and plasma HIV RNA. Current and past antiretroviral therapies were ascertained. ### results According to one proposed Australian national definition of lipodystrophy (LDNC), the prevalence of lipodystrophy in this population was 65%. This definition included an objective assessment with major and minor criteria. Patient-defined lipodystrophy (LDP), which involved a subjective assessment of thinning arms and legs and central adiposity, occurred in 19%. Patient-defined lipoatrophy (LAP), which involved a subjective assessment of thinning arms and legs without central adiposity, occurred in 21.3%. No change in body habitus was noted by 37% of the cohort. Hypercholesterolaemia was recorded in 44%, hypertriglyceridaemia in 52% and elevated insulin levels in 23%. Anthropometry was predictive of the per cent total body fat recorded by DEXA scan, but produced consistently lower values. In multivariate analysis , LDP and LAP were significantly associated with stavudine ( d4 T ) use , while LAP was also associated with zidovudine ( ZDV ) treatment . There were no treatment associations with LDNC. Protease inhibitor (PI) exposure was associated with metabolic changes but not patient perceived body shape changes, while d4T and ZDV exposure was associated with increased triglycerides and reduced peripheral fat stores. ### conclusions The prevalence of body shape changes in a single population varied depending on the definition applied. The LDNC definition overestimated body shape abnormalities in comparison with patient perception. LAP was associated with significantly lower fat stores measured by anthropometry and DEXA scan than those identified under the LDNC definition. In contrast to LDNC, LAP was associated with d4T exposure, nucleoside reverse transcriptase inhibitor (NRTI) and ZDV duration of use, but not PI use. Until a consensus definition for lipodystrophy is developed, including agreement on objective measurement and thresholds for abnormality, careful description of the individual components of the syndrome is required to enable cohort comparisons so that predictors of the syndrome can be assessed more accurately and outcome studies made feasible.


vinblastine

vincristine

A new bis-indole, KARs, induces selective M arrest with specific spindle aberration in neuroblastoma cell line SH-SY5Y.  KARs , new semisynthetic antitumor bis-indole derivatives , were found to be inhibitors of tubulin polymerization with lower toxicity than vinblastine or vincristine , used in chemotherapy . Here, we compare the effect of KARs with those of vinblastine and vincristine on cell viability, cell proliferation, and cell cycle in neuroblastoma cell line (SH-SY5Y). At concentrations of the different compounds equivalent in causing 50% of inhibition of cell growth, KARs induced a complete arrest in the G2/M phase, whereas vinblastine and vincristine induced a partial arrest in both G0/G1 and G2/M. Moreover, a combination of KAR-2 and W13 (an anticalmodulin drug) qualitatively caused a similar arrest in both G0/G1 and G2/M than vinblastine. Levels of cyclin A and B1 were higher in KARs-treated cells than in vinblastine- or vincristine-treated cells. Cdc2 activity was much higher in KAR-2 than in vinblastine-treated cells, indicating a stronger mitotic arrest. The effect of KAR2 and vinblastine on microtubules network was analyzed by immunostaining with anti-tubulin antibody. Results indicated that KAR-2-induces the formation of aberrant mitotic spindles, with not apparent effect on interphase microtubules, whereas vinblastine partially destroyed interphase microtubules coexisting with normal and aberrant mitotic spindles.


Danazol

Anti Thymocyte Globulin

Cyclosporine

Cyclosporine

Danazol

Danazol increases T regulatory cells in patients with aplastic anemia. danazol is an attenuated androgen and is used in the treatment of aplastic anemia (AA) in resource constraint settings. We chose to study the role of CD4+ CD25 ### methods T-regs' percentages of 25 acquired idiopathic AA patients and 25 healthy controls who completed study protocol were analyzed by performing multicolor flowcytometry on peripheral blood samples. ### results More than one-third ( 36 % ) of AA patients in our study received Danazol as monotherapy , whereas less than a third ( 32 % ) each received standard doses of IST with equine Anti Thymocyte Globulin ( ATG ) and Cyclosporine combination , or Cyclosporine and Danazol combination , respectively . Results showed that all AA patients had a significantly lower percentage of T-regs at the time of diagnosis when compared to healthy controls (p < 0.0001), implicating their role in the pathophysiology. On treatment, all 25 patients showed a significant rise in the percentage of T-regs when compared to baseline (p < 0.0001). ### discussion The rise in T-regs' percentage was higher in patients treated with danazol alone when compared to standard IST (ATG with cyclosporine), or cyclosporine with danazol combinations (p = 0.585). ### conclusion We conclude that danazol also leads to increase in T-regs in acquired idiopathic AA.


colchicine

nifedipine

Colchicine biotransformation by human liver microsomes. Identification of CYP3A4 as the major isoform responsible for colchicine demethylation. colchicine disposition involves both active biliary and renal excretion of parent drug, and at least in mammals a substantial fraction undergoes hepatic demethylation prior to excretion. We investigated the biotransformation of [3H]colchicine in a panel of microsomal preparations obtained from sixteen human liver samples. The production rate of the main metabolites of colchicine's 3-demethylcolchicine (3DMC) and 2-demethylcolchicine (2DMC), was linear in relation to incubation time, cytochrome (P450) content, and substrate concentration. Following the incubation of colchicine (5 nM) with microsomes in the presence of an NADPH-generating system for 60 min, 9.8% and 5.5% of the substrate were metabolized to 3DMC and 2DMC, respectively. The formation rate of colchicine metabolites exhibited a marked variation between the different microsomal preparations. The formation rates of both colchicine metabolites were correlated significantly with nifedipine oxidase activity, a marker of CYP3A4 activity (r = 0.96, P < 0.001), but not with the metabolic markers of CYP2A6, CYP2C19, CYP2C9, CYP2D6, and CYP2E1 activities. Chemical inhibition of CYP3A4 by preincubation with gestodene (40 microM) or troleandomycin (40 microM) reduced the formation of 3DMC and 2DMC by 70 and 80%, respectively, whereas quinidine, diethyldithiocarbamate, and sulfaphenazole had no inhibitory effect. Similarly , antibodies raised against CYP3A4 almost completely abolished colchicine demethylation and nifedipine oxidase activity , but preimmune IgG had no effect . In conclusion, colchicine was metabolized to 3DMC and 2DMC by human liver microsomes. The production of colchicine metabolites was mediated by CYP3A4, and its rate varied greatly between microsomal preparations obtained from different liver samples. The coadministration of colchicine with known inhibitors or substrates of CYP3A4 may inhibit colchicine metabolism, resulting in concentration-related toxicity.


paclitaxel

carboplatin

First-line chemotherapy with paclitaxel by three-hour infusion and carboplatin in advanced breast cancer (final report): a phase II study conducted by the Hellenic Cooperative Oncology Group. To evaluate the activity and toxicity of the combination of paclitaxel given by three-hour infusion, and carboplatin as first-line chemotherapy in patients with advanced breast cancer (ABC). ### background paclitaxel is an active agent in ABC. Furthermore , our group has shown that the combination of paclitaxel and carboplatin is effective in anthracycline-resistant ABC . ### Patients And Methods From January 1996 until March 1997, 66 women with ABC were treated with paclitaxel (175 mg/m2) by three-hour infusion followed by carboplatin at an AUC of 6 mg x min/ml every three weeks. The median age of the patients was 56 years (range 28-75). A total of 39 patients had received adjuvant chemotherapy and 22 of them were treated with an anthracycline or mitoxantrone-containing regimen. ### results A total of 324 cycles (median: six) were administered, 273 (85%) of them at full dose. The median number of delivered cycles was six. The median delivered dose intensity (DI) of paclitaxel was 55.1 mg/m2/week (range 30.5-69.3) and the relative DI was 0.95 (range 0.5-1.2). Eight patients (12%, 95% confidence interval (CI): 5%-22%) achieved complete and 28 (42%, 95% CI: 30%-55%) partial responses. Grade 3-4 toxicities included anemia (5%), granulocytopenia (24%), thrombocytopenia, nausea/vomiting and allergic reaction (3% each), myalgias/arthralgias and neurotoxicity (1.5% each). Febrile neutropenia occurred in eight (12%) patients. Alopecia was universal. After a median follow-up of 17.3 (range 0.07-24.5) months, 48 (72%) patients have demonstrated tumor progression and 24 (36%) have died. Median time to progression was 8.6 (range 0.07-23+) months and median survival 20.4 (range 0.07-24.5+) months. ### conclusions The combination of paclitaxel and carboplatin has moderate activity in ABC and can be easily delivered on an outpatient basis with manageable toxicity. This regimen may be useful especially in patients to whom anthracyclines or cisplatin administration is precluded because of other concomitant diseases.


Cyclosporine

resveratrol

Resveratrol ameliorates the cyclosporine-induced vascular and renal impairments: possible impact of the modulation of renin-angiotensin system. cyclosporine, an immunosuppressive drug, exhibits a toxic effect on renal and vascular systems. The present study investigated whether resveratrol treatment alleviates renal and vascular injury induced by cyclosporine. Cyclosporine ( 25 mg/kg per day , s.c . ) was given for 7 days to rats either alone or in combination with resveratrol ( 10 mg/kg per day , i.p . ) . Relaxation and contraction responses of aorta were examined. Serum levels of blood urea nitrogen, creatinine, angiotensin II, and angiotensin 1-7 were measured. Histopathological examinations as well as immunostaining for 4-hydroxynonenal and nitrotyrosine were performed in the kidney. RNA expressions of renin-angiotensin system components were also measured in renal and aortic tissues. cyclosporine decreased the endothelium-dependent relaxation and increased vascular contraction in the aorta. It caused renal tubular degeneration and increased immunostaining for 4-hydroxynonenal, an oxidative stress marker. cyclosporine also caused upregulations of the vasoconstrictive renin-angiotensin system components in renal (angiotensin-converting enzyme) and aortic (angiotensin II type 1 receptor) tissues. resveratrol co-treatment prevented the cyclosporine-related deteriorations. Moreover, it induced the expressions of vasodilatory effective angiotensin-converting enzyme 2 and angiotensin II type 2 receptor in aorta and kidney, respectively. We conclude that resveratrol may be effective in preventing cyclosporine-induced renal tubular degeneration and vascular dysfunction at least in part by modulating the renin-angiotensin system.


bupivacaine

lidocaine

Efficacy of combined treatment with medial branch radiofrequency neurotomy and steroid block in lumbar facet joint arthropathy. To evaluate the long-term efficacy of combined radiofrequency (RF) neurotomy and steroid nerve block in patients with lumbar facet joint arthropathy. ### Materials And Methods Combined RF neurotomy and steroid nerve block was performed in 34 patients with chronic paravertebral low back pain. The diagnosis was confirmed by comparative double diagnostic block of the medial branch with bupivacaine and lidocaine . Under fluoroscopy, RF thermal ablation of the medial branch was performed (at RF needle tip temperature 85°C for 90 seconds), three times for each target nerve. At the end of the procedure, 20 mg of methylprednisolone acetate (sustained-release preparation) was infiltrated on each ablated nerve. Outcome variable was the degree of improvement in pain using visual analog scale (VAS) and numerical rating scale (NRS). Improvement in the quality of life was assessed using the Roland-Morris (RM) questionnaire. The procedure was repeated in cases of unbearable pain (>5 VAS score). ### results Patients had a mean VAS score of 8.6 before the procedure. Thereafter, VAS score was 0.91 immediately after the procedure and 3.0, 2.8, 3.7, and 3.6 at 1 month, 2 months, 6 months, and 1 year. NRS showed pain relief after the procedure of 85%, 65%, 78%, 62%, and 59.5% at the same time points. RM score was 18 before the procedure, 7.6 at 6 months after the procedure, and 8.5 at 1 year after the procedure. No major complication was noted except local pain in all patients and numbness of the back in six patients after the procedure. ### conclusions Combined RF neurotomy and steroid nerve block produced substantial improvement in terms of long-term pain relief and quality of life.


Pemetrexed

bortezomib

Phase I study of two different schedules of bortezomib and pemetrexed in advanced solid tumors with emphasis on non-small cell lung cancer. bortezomib and pemetrexed are approved anticancer agents with non-overlapping mechanisms of action and toxicity. We examined the safety and tolerability of pemetrexed in combination with two different schedules of bortezomib in patients with advanced solid tumors. ### methods Two separate dose-escalating arms (arm A and arm B) were conducted simultaneously. Patients received pemetrexed on day 1 (D1) (500-600 mg/m2 IV) every 21 days. In arm A, bortezomib was given twice weekly (0.7-1.3 mg/m2 on D1, 4, 8, and 11). In arm B, bortezomib was given weekly (1.0-1.6 mg/m2 on D1 and 8). ### results We treated 27 patients on four dose levels in arm A and three dose levels in arm B. Tumor types included lung (n = 16), adenoid cystic carcinoma (n = 2), prostate (n = 2), sarcoma (n = 2), breast (n = 1), thymus (n = 1), head and neck (n = 1), and gastrointestinal(n = 2). Dose-limiting toxicities were seen in arm A only; grade 3 asthenia (n = 2), grade 3 transaminitis and dehydration (n = 1). The most common grade 3/4 toxicity was neutropenia. Of 26 evaluable patients, 2 patients had partial response (1 in arm A and 1 in arm B), 13 had stable disease (7 in arm A and 6 in arm B), and 11 had progression (6 in arm A and 5 in arm B). Of the 16 patients with non-small cell lung cancer, 2 (12.5%) had partial response and 9 had stable disease, for a disease control rate of 68.8%. Recommended phase II dose for arm A is pemetrexed 500 mg/m2 and bortezomib 1.3 mg/m2 twice weekly. For arm B, the recommended dose is pemetrexed 500 mg/m2, bortezomib 1.6 mg/m2 weekly. ### conclusions Pemetrexed with bortezomib is feasible and tolerable at recommended single-agent doses . Based on the observed efficacy, a phase II study in non-small cell lung cancer is warranted.


Bevacizumab

bevacizumab

TANIA

Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy ( TANIA ): an open-label , randomised phase 3 trial . Combining bevacizumab with first-line or second-line chemotherapy improves progression-free survival in HER2-negative locally recurrent or metastatic breast cancer. We assessed the efficacy and safety of further bevacizumab therapy in patients with locally recurrent or metastatic breast cancer whose disease had progressed after treatment with bevacizumab plus chemotherapy. ### methods In this open-label, randomised, phase 3 trial, we recruited patients who had HER2-negative locally recurrent or metastatic breast cancer that had progressed after receiving 12 weeks or more of first-line bevacizumab plus chemotherapy from 118 centres in 12 countries. Patients were randomly assigned (1:1) by use of a central interactive voice response system using a block randomisation schedule (block size four) stratified by hormone receptor status, first-line progression-free survival, selected chemotherapy, and lactate dehydrogenase concentration, to receive second-line single-agent chemotherapy either alone or with bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks). Second-line therapy was continued until disease progression, unacceptable toxicity, or consent withdrawal. At progression, patients randomly assigned to chemotherapy alone received third-line chemotherapy without bevacizumab; those randomly assigned to bevacizumab continued bevacizumab with third-line chemotherapy. The primary endpoint was progression-free survival from randomisation to second-line progression or death in the intention-to-treat population. This trial is ongoing, and registered with ClinicalTrials.gov, number NCT01250379. ### findings Between Feb 17, 2011, and April 3, 2013, 494 patients were randomly assigned to treatment (247 in each group). The median duration of follow-up at the time of this prespecified primary progression-free survival analysis was 15·9 months (IQR 9·1-21·7) in the chemotherapy-alone group and 16·1 months (10·6-22·7) in the combination group. Progression-free survival was significantly longer for those patients treated with bevacizumab plus chemotherapy than for those with chemotherapy alone (median: 6·3 months [95% CI 5·4-7·2] vs 4·2 months [3·9-4·7], respectively, stratified hazard ratio [HR] 0·75 [95% CI 0·61-0·93], two-sided stratified log-rank p=0·0068). The most common grade 3 or more adverse events were hypertension (33 [13%] of 245 patients receiving bevacizumab plus chemotherapy vs 17 [7%] of 238 patients receiving chemotherapy alone), neutropenia (29 [12%] vs 20 [8%]), and hand-foot syndrome (27 [11%] vs 25 [11%]). Grade 3 proteinuria occurred in 17 (7%) of 245 patients receiving combination therapy and one (<1%) of 238 patients receiving chemotherapy alone. Serious adverse events were reported in 61 (25%) of 245 patients receiving bevacizumab plus chemotherapy versus 44 (18%) of 238 patients receiving chemotherapy alone. ### interpretation These results suggest that continued VEGF inhibition with further bevacizumab is a valid treatment option for patients with locally recurrent or metastatic HER2-negative breast cancer whose disease was stabilised or responded to first-line bevacizumab with chemotherapy. ### funding F Hoffmann-La Roche.


Goserelin

tamoxifen

cyclophosphamide

doxorubicin

Goserelin ('Zoladex')--offering patients more choice in early breast cancer. The luteinising hormone-releasing hormone analogue goserelin ('Zoladex') suppresses ovarian oestrogen production in pre- and perimenopausal women. goserelin is a biodegradable, sustained-release 3.6 mg depot that is administered by subcutaneous injection every 28 days. Clinical trials in premenopausal women with hormone-sensitive early breast cancer have demonstrated that goserelin alone, or in combination with tamoxifen, is at least as effective as cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. Goserelin plus tamoxifen after cyclophosphamide , doxorubicin and 5-fluorouracil ( CAF ) chemotherapy resulted in improved disease-free survival compared with CAF alone . These trials have also shown that goserelin is well tolerated and is associated with less acute toxicity than cytotoxic chemotherapy. Early improvements in quality of life over the first 3-6 months of goserelin treatment support the use of this agent as an alternative to chemotherapy in this patient population. Patients should be provided with information on the benefits and risks associated with available treatment options so that they can be involved in the decision-making process.


triazolam

cimetidine

Prolonged hypnotic response to triazolam-cimetidine combination in an elderly patient.  An 82-year-old white female developed a 36-hour episode of unresponsiveness/drowsiness after a single dose of triazolam 0.5 mg in combination with cimetidine . This case illustrates the need for careful dose-titration of drug therapy in the elderly, particularly when a drug with the potential to impair drug metabolism is coadministered. cimetidine, when coadministered with triazolam, may increase the intensity and duration of action of single doses of triazolam.


melatonin

irinotecan

The modulatory effect of melatonin on genotoxicity of irinotecan in healthy human lymphocytes and cancer cells. Drug-target interactions can be modified by adding modulatory agents to increase treatment efficacy and clinical outcome. Combination chemotherapy has become increasingly important because drugs acting synergistically can achieve therapeutic effects at substantially lower doses and with a limited spectrum of side effects. irinotecan, known as one of the camptothecin analogs, has shown a broad spectrum of antitumor activity against various malignancies. In this study, we evaluated the effect of melatonin on the genotoxic activity of irinotecan in healthy human lymphocytes and a lung cancer cell line (A549) and a colorectal adenocarcinoma cell line (HT29) in vitro. irinotecan, as a single agent, was shown to induce DNA damage in all types of analyzed cells. The combination of melatonin at concentrations of 50 μM with increasing doses of irinotecan ( 7.5 , 15 , 30 , and 60 μM ) resulted in an increase in the amount of DNA damage in A549 and HT29 cancer cells , but was not effective in inducing DNA damage in healthy human lymphocytes . Analysis of the efficacy of DNA repair, performed after 60 and 120 minutes of postincubation, showed the gradual decrease of DNA percentage in comet tails during repair postincubation in all experimental samples. Our results indicate that melatonin can modulate the genotoxic activity of irinotecan and DNA repair efficacy in human cancer cells in vitro. These findings may be supportive for the optimization of therapeutic efficacy in irinotecan treatment.


cyclophosphamide

filgrastim

Conventional adjuvant chemotherapy versus single-cycle, autograft-supported, high-dose, late-intensification chemotherapy in high-risk breast cancer patients: a randomized trial. Breast cancer patients with four or more positive axillary lymph nodes who are treated with conventional adjuvant therapy have a poor prognosis. In uncontrolled studies, high-dose chemotherapy produced much better results than conventional therapy. We compared the benefits of a single cycle of high-dose chemotherapy and the benefits of conventional chemotherapy in patients with high-risk breast cancer in a prospective, unblinded, randomized trial. ### methods Between February 23, 1995, and June 29, 1999, 605 patients with breast cancer who had four or more positive lymph nodes were randomly assigned to treatment (307 to high-dose therapy and 298 to conventional therapy). The conventional chemotherapy regimen was four cycles of doxorubicin (75 mg/m2) followed by eight cycles of CMF (cyclophosphamide [600 mg/m2], methotrexate [50 mg/m2], and 5-fluorouracil [600 mg/m2]), all given intravenously on day 1 of a 21-day cycle. The high-dose regimen was four cycles of doxorubicin (75 mg/m2), followed by a single cycle of intermediate-dose cyclophosphamide (4000 mg/m2) supported by filgrastim (300 microg/day) for up to 10 days followed by high-dose cyclophosphamide (6000 mg/m2) and thiotepa (800 mg/m2). Peripheral blood progenitor cells were harvested by leukapheresis after treatment with cyclophosphamide and filgrastim and then re-infused after the high-dose cycle . Log-rank tests were used to compare survival rates. All statistical analyses were two-sided. ### results At a median follow-up of 6 years, no statistically significant differences were detected between the arms in 5-year relapse-free survival (high-dose arm = 57%, 95% confidence interval [CI] = 51% to 63%; conventional-dose arm = 54%, 95% CI = 48% to 61% (P =.73) or in 5-year overall survival (high-dose arm = 62%, 95% CI = 56% to 68%; conventional-dose arm = 64%, 95% CI = 57% to 70%) (P =.38). ### conclusion Autograft-supported, high-dose therapy is not superior to conventional chemotherapy in patients with breast cancer who have multiple involved lymph nodes. This conclusion should be viewed in the context of improving the success of conventional chemotherapy.


cisplatin

gemcitabine

carboplatin

Gemcitabine and carboplatin in combination for the treatment of advanced, metastatic, non-small cell lung cancer. The universally accepted first-line treatment for advanced (stage IIIB effusion/IV) non-small-cell lung cancer in patients with a good performance status is a platinum drug in combination with one of gemcitabine, paclitaxel, vinorelbine or docetaxel. Although cisplatin is generally the favoured platinum agent , gemcitabine partnered with carboplatin is convenient to administer and has a favourable toxicity profile . Here, the pharmacology, preclinical and clinical data to support the use of this regimen for the treatment of advanced non-small-cell lung cancer is evaluated.


epirubicin

paclitaxel

Phase II study of paclitaxel and epirubicin as first-line therapy in patients with metastatic breast cancer. paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane used in routine clinical practice, has aroused considerable interest for its high single-agent activity against breast cancer and for its novel mechanism of action. epirubicin, the 4' epimer of doxorubicin, is another agent with a high activity against breast cancer and is known for its lower rate of toxic side effects, especially toxic cardiac events, compared with its mother compound. The combination of paclitaxel and doxorubicin yielded response rates between 63% and 93% in phase I/II studies. In these studies, however, the investigators reported severe cardiac toxic events. The rationale for the current study was therefore to evaluate the combination of paclitaxel/epirubicin, focusing mainly on cardiac toxicity. In two groups, 85 patients with metastatic breast cancer entered the study. Approximately 20% of the patients had primary metastatic breast cancer with large tumors at the primary site. Half of the patients had received adjuvant chemotherapy. Study medication in group A consisted of epirubicin 60 mg/m2 given intravenously over 1 hour, followed by paclitaxel 175 mg/m2 administered as a 3-hour intravenous infusion after premedication with steroids, antihistamines, and H2-blockers. In group B , epirubicin 90 mg/m2 was combined with paclitaxel 175 mg/m2 , given in the same manner as in group A. Dose escalation to 225 mg/m2 paclitaxel was planned in both groups. The main toxicity in both groups was neutropenia (73% World Health Organization grade 3/4 in group A and 93% in group B). Other hematologic side effects were rare. No febrile neutropenia was reported in group A, but two episodes occurred in group B. Peripheral neuropathy, arthralgia, and myalgia were mild (only World Health Organization grades 1 and 2). Alopecia was universal. In group A, the paclitaxel dose could be escalated to 200 mg/m2 in 15 patients and to 225 mg/m2 in seven patients. Dose reduction due to severe neutropenia was necessary in 11 patients. No cardiac events were reported in group A. In group B, the paclitaxel dose could be escalated to 200 mg/m2 in only one patient, and no patient reached 225 mg/m2. Three patients needed a dose reduction. In this group, one patient had a greater than 10% decrease in the left ventricular ejection fraction with no clinical signs. In group A, 43 patients were evaluable for response; in group B, 25 patients were evaluable. Thirteen patients were out of protocol with only bone metastasis, and two patients had more than one prior chemotherapy for metastatic disease. The response rate was identical in both groups, with five complete remissions and 24 partial remissions in group A and three complete responses and 14 partial remissions in group B. The duration of response was 8.2 months in both groups. The median cumulative epirubicin dose was 420 mg/m2 in group A and 630 mg/m2 in group B. The combination of paclitaxel 175 mg/m2 and epirubicin 60 or 90 mg/m2 can be administered safely to patients with metastatic breast cancer. Although response was not the primary end point of this trial, the response data are nonetheless encouraging and suggest that further evaluation of this combination-line treatment of metastatic breast cancer is warranted.


ceritinib

nivolumab

Ceritinib plus Nivolumab in Patients with Advanced ALK-Rearranged Non-Small Cell Lung Cancer: Results of an Open-Label, Multicenter, Phase 1B Study. Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients . ### methods In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal. ### results In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9-99.6) in the 450-mg cohort and 60% (95% CI: 26.2-87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7-84.3) in the 450-mg cohort and 25% (95% CI: 5.5-57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1-87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0-58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported. ### conclusion ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.


somatostatin

decitabine

trichostatin

somatostatin

Incubation with somatostatin , 5-aza decitabine and trichostatin up-regulates somatostatin receptor expression in prostate cancer cells . somatostatin (SMS), binds to its specific receptors (SSTRs) and transduces growth inhibitory, anti-secretory and apoptotic signals. Several human cancers express SSTRs, including prostate cancer, and therefore SMS is of interest for anti-cancer therapy. DNA methylation and histone modifications are involved in normal cell development, gene imprinting and human carcinogenesis. Reversing DNA methylation is an attractive therapeutic possibility, since epigenetic modifications change gene expression without changing the gene function. DNA methylation inhibitors such as 5-aza-2'-deoxycytidine (5'-aza, decitabine) have been used to treat several types of haematological malignancies. Histone deacetylase inhibitors such as trichostatin (TSA), are a new class of 'targeted anti-cancer agents'. TSA and decitabine can induce growth arrest, apoptosis or terminal differentiation in a variety of solid and haematological cancers in advanced disease patients. In the present study, the LNCaP cell line (prostate cancer) was incubated with SMS or Somadex (an SMS polymer conjugate) for three days, 1 nM per day, and the untreated cells were the negative control. For DNA demethylation, cells were grown in the presence of 2.5 microM 5-aza for 120 h, and re-fed with 5-aza-containing fresh medium at day 3. The total incubation time with 5-aza was 120 h. TSA at 1.0 microM was added into the cultured cells for 24 h. The combined treatment of 5-aza and TSA was performed by incubating the cells with 5-aza for 120 h followed by a 24-h exposure to TSA. Using cDNA obtained from these cell lines, the difference in the expression level of SSTR mRNA transcripts before and after 5-aza and TSA treatments was analyzed by RT-PCR. An increased induction of mRNA expression of the five SSTR subtypes was observed in the LNCaP cells when incubated with SMS/Somadex (dose-dependent). The inhibition of DNA methylation and histone acetylation resulted in the up-regulation of SSTR5 mRNA expression. The results demonstrate a positive feedback loop between SMS and its receptors. This regulation pathway may enhance the anti-tumor activity of somatostatin. To benefit from this effect in a clinical setting, the dose, dose frequency and pan affinity of the SMS derivative are important factors. The epigenetic manipulation with DNA methylation or histone deacetylase inhibitors, combined with SMS, may offer a novel alternative for the treatment of advanced prostate cancer.


famotidine

diphenhydramine

Famotidine in the treatment of acute urticaria. Recent studies suggest that histamine H2-receptor antagonists may be useful in the treatment of urticaria. This study was conducted to determine whether famotidine , a H2 antagonist , is effective in the treatment of acute urticaria and compare its effect with that of the H1 antagonist diphenhydramine . In this prospective, double-blind, controlled trial, 25 patients with urticaria of less than 72 h duration were randomized to receive a single dose of either famotidine 20 mg i.m. or diphenhydramine 50 mg i.m. Prior to treatment and 30 min after treatment, patients rated pruritus and sedation using visual analogue scales, while physicians evaluated intensity of urticaria and percentage of body surface area involved by urticaria. famotidine was found to reduce pruritus associated with acute urticaria, intensity of urticaria, and body surface area affected by urticaria without causing sedation. famotidine was comparable to diphenhydramine in efficacy; however, there was a (nonsignificant) trend for diphenhydramine to be more effective than famotidine in the treatment of pruritus, and for famotidine to be more effective in the reduction of surface area of involvement. It is concluded that famotidine merits further investigation as a potential medication for treatment of urticaria.


clonazepam

chlordiazepoxide

Effect of combined treatment of diphenylhydantoin with clonazepam and chlordiazepoxide on the threshold for maximal electroconvulsions in mice. The anticonvulsant effect of either clonazepam (0.2-6.4 mg/kg) or chlordiazepoxide (2.5-40 mg/kg) alone or in combination with diphenylhydantoin (4-16 mg/kg) was studied against electroconvulsions in mice. All drugs were injected intraperitoneally, diphenylhydantoin - 75 min and the benzodiazepines - 60 min before the test. Adding either clonazepam or chlordiazepoxide (in doses moderately increasing the convulsive threshold) was more effective than doubling the dose of diphenylhydantoin. Both the interaction between benzodiazepines and diphenylhydantoin at the level of the receptor for picrotoxin-barbiturates and benzodiazepine-induced potentiation of specific diphenylhydantoin binding are likely to contribute to the observed phenomenon. On the other hand , a diphenylhydantoin-induced increase in the total number of specific benzodiazepine binding sites seems of minor importance since clonazepam ( with a high affinity for these sites ) and chlordiazepoxide ( with a low affinity ) were equipotent in the enhancement of the combined treatment efficacy .


Letrozole

Alpelisib

A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive , Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer ( NEO-ORB ) . Addition of alpelisib to fulvestrant significantly extended progression-free survival in ### results In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade ≥3 adverse events (≥5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculo-papular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the ### conclusions In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR


bromocriptine

pyridoxine

Aromatic amino Acid decarboxylase deficiency not responding to pyridoxine and bromocriptine therapy: case report and review of response to treatment. Aromatic L-amino acid decarboxylase (AADC) deficiency (MIM #608643) is an autosomal recessive inborn error of monoamines. It is caused by a mutation in the DDC gene that leads to a deficiency in the AADC enzyme. The clinical features of this condition include a combination of dopamine, noradrenaline, and serotonin deficiencies, and a patient may present with hypotonia, oculogyric crises, sweating, hypersalivation, autonomic dysfunction, and progressive encephalopathy with severe developmental delay. We report the case of an 8-month-old boy who presented with the abovementioned symptoms and who was diagnosed with AADC deficiency based on clinical, biochemical, and molecular investigations. Treatment with bromocriptine and pyridoxine showed no improvement . These data support the findings observed among previously reported cohorts that showed poor response of this disease to current regimens. Alternative therapies are needed to ameliorate the clinical complications associated with this disorder.


trimethoprim

sulfamethoxazole

Bactericidal activity of trimethoprim alone and in combination with sulfamethoxazole on susceptible and resistant Escherichia coli K-12 . The combined effects of trimethoprim and sulfamethoxazole on the viability of Escherichia coli K-12 and resistant strains possessing resistance plasmids were examined in minimal medium. When methionine, glycine, and adenine were present, sulfamethoxazole could enhance trimethoprim activity against E. coli K-12 so that the combination was bactericidal. However, this enhancement occurred over a narrow range of trimethoprim concentrations (0.04 to 0.2 mg liter-1) and only when the sulfamethoxazole concentration was more than 10 times that of trimethoprim. Under certain conditions, sulfamethoxazole enhanced trimethoprim bactericidal activity against E. coli K-12 carrying plasmid R1 at concentrations of sulfamethoxazole far below those required to inhibit the organism, but there was no such enhancement with the same host containing the SSu plasmid. Similar differences were found with strains possessing trimethoprim resistance plasmids R483 and R751. sulfamethoxazole can promote a bactericidal response with trimethoprim in E. coli K-12 and some of its resistant derivatives, but only under a narrow range of concentrations.


chloroquine

proguanil

mefloquine

Current status and replies to frequently posed questions on atovaquone plus proguanil (Malarone) for the prevention of malaria. Each year at least 30 000 Western travellers acquire malaria and approximately 1-4% of those who acquire Plasmodium falciparum malaria will die as a result of infection. Almost all cases and fatalities are preventable with the use of measures to reduce mosquito bites and appropriate chemoprophylaxis for those at high risk of infection. There are currently a limited number of licensed drugs available to prevent malaria in travellers. New effective and well tolerated agents are urgently needed because of increasing resistance to antimalarials such as chloroquine and proguanil , and real and perceived intolerance to standard drugs such as mefloquine . A newly licensed antimalarial (atovaquone plus proguanil; Malarone) compares favourably with other drug options, although some prescribers may be unfamiliar with the specific advantages and disadvantages of this antimalarial. This article reviews recent clinical experience and randomised controlled trial data in order to address frequently asked questions about this new combination drug.