Mitomycin

vinblastine

Mitomycin C and vinblastine in anthracycline-resistant metastatic breast cancer: a phase II study. The purpose of this phase II study was to evaluate the clinical efficacy of mitomycin C and vinblastine in patients with anthracycline-resistant metastatic breast cancer. This single-center, non-randomized trial enrolled 39 patients. Eligible patients must have received at least three chemotherapy regimens with epirubicin or CAF and had treatment failure while on chemotherapy or within 6 months of completing therapy. Treatment consisted of mitomycin C at a starting dose of 8 mg/m2 on day 1 and vinblastine (8 mg/m2, days 1 and 28). The regimen was repeated every 6 weeks with a 20% dose escalation of both drugs after the first cycle in the absence of grade III hematologic or other toxicity. On an intent-to-treat basis, 38 patients were eligible for assessment; 9 (23.7%, 95% confidence interval 1.92-2.45%) achieved a partial response and 13 (34.2%) had stable disease. The median time to disease progression was 6.21+/-4.26 months (range, 1-15; 95% confidence interval, 4.81-7.61), and the median survival was 10.76+/-7.6 (range, 1-29; 95% confidence interval 8.0-13.1%). Responsive patients had a significantly better survival than those with stable and progressive disease. Treatment was well tolerated. Anemia and neutropenia (grade I-III) developed in 28.9% and 26.3% of the patients, respectively. One patient with grade III granulocytopenia developed fever and infection that required hospitalization. Moderate neurotoxicity, myalgia, constipation, diarrhea and alopecia were observed. No toxic death occurred. Mitomycin C plus vinblastine is an effective and well-tolerated regimen for anthracycline resistant cancer .


olmesartan

azelnidipine

Synergistic neuroprotective effects of combined treatment with olmesartan plus azelnidipine in stroke-prone spontaneously hypertensive rats.  An angiotensin 2 type 1 receptor blocker , olmesartan , and a calcium channel blocker , azelnidipine , possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects . In the present study, we examined the efficacy of olmesartan and azelnidipine monotherapy (2 mg/kg or 10 mg/kg each) and their combination therapy (1 mg/kg each) on stroke-prone spontaneously hypertensive rats (SHR-SP) in relation to oxidative stress, inflammation, and the neurovascular unit. In comparison with the vehicle group, body weight, regional cerebral blood flow, and motor function were preserved, whereas systolic blood pressure and diastolic blood pressure decreased in the five drug-treatment groups. Spontaneous infarct volume decreased with the low-dose combination of olmesartan plus azelnidipine and with the high-dose olmesartan, with a further decrease in the high-dose azelnidipine group. In addition, these drugs dose-dependently reduced oxidative stresses, proinflammatory molecules, and well-preserved components of the neurovascular unit. The low-dose combination of olmesartan plus azelnidipine showed a better effect than the low-dose olmesartan or azelnidipine monotherapy. The present study shows that the low-dose combination of olmesartan plus azelnidipine demonstrates a greater synergistic benefit than monotherapy with a low-dose of olmesartan or azelnidipine in SHR-SP for preventing spontaneous infarct volume, reducing oxidative stresses and proinflammatory molecules, and imparting neurovascular protection. In addition, a high-dose of olmesartan showed a greater benefit without the lowering of blood pressure, probably because of the antioxidative and anti-inflammatory effects. A high dose of azelnidipine showed the best benefit, probably because of the two effects mentioned above related to the lowering of blood pressure.


methotrexate

cyclophosphamide

prednisone

Combination chemotherapy for advanced breast cancer: response and effect on survival.  Forty patients with metastatic breast cancer who had received no previous cytotoxic therapy were treated with a combination chemotherapy program CMF ( P ) , which included methotrexate , 60 mg/m2 , and 5-fluorouracil , 700 mg/m2 intravenously on the first and eighth days , in addition to cyclophosphamide , 100 mg/m2 , and prednisone , 40 mg/m2 , by mouth daily from the first to the fourteenth day of a 28-day cycle . Only 2 of 25 patients responded to hormonal therapy or endocrine ablation. Twenty-seven of the 40 patients (68%) had a complete response (8 patients) or partial response (19 patients). Lung, soft tissue, and nodal metastases were the most responsive sites. The median survival of 18 months for the responding group. The nonresponders had a median survival of 4 months. The toxicity was primarily hematologic and was especially severe in patients with functional liver impairment due to metastatic disease.


sorafenib

sorafenib

everolimus

Anti-angiogenesis target therapy for advanced osteosarcoma (Review). Osteosarcomas (OS), especially those with metastatic or unresectable disease, have limited treatment options. The greatest advancement in treatments occurred in the 1980s when multi-agent chemotherapy, including doxorubicin, cisplatin, high-dose methotrexate, and, in some regimens, ifosfamide, was demonstrated to improve overall survival compared with surgery alone. However, standard chemotherapeutic options have been limited by poor response rates in patients with relapsed or advanced cases. It has been reported that VEGFR expression correlates with the outcome of patients with osteosarcoma and circulating VEGF level has been associated with the development of lung metastasis. At present , it seems to us that progress has not been made since Grignani reported a phase II cohort trial of sorafenib and sorafenib combined with everolimus for advanced osteosarcoma , which , in a sense , have become a milestone as a second-line therapy for osteosarcoma . Although the recognization of muramyltripepetide phosphatidyl-ethanolamine has made some progress based on its combination with standard chemotherapy, its effect on refractory cases is controversial. Personalized comprehensive molecular profiling of high-risk osteosarcoma up to now has not changed the therapeutic prospect of advanced osteosarcoma significantly. Thus, how far have we moved forward and what therapeutic strategy should we prefer for anti-angiogenesis therapy? This review provides an overview of the most updated anti-angiogenesis therapy in OS and discusses some clinical options in order to maintain or even improve progression-free survival.


succinylcholine

pancuronium

Neuromuscular blockade for critical patients in the emergency department. This retrospective study examines the indications and the effects of 119 doses of succinylcholine or pancuronium given in the emergency department during a 24-month period to patients considered to have immediately life-threatening emergencies. The most common indication for succinylcholine was to accomplish tracheal intubation (20 of 25 patients). Indications for pancuronium included computerized tomography of the head (60 of 94), control of agitation (40 of 94), facilitation of tracheal intubation (20 of 94), control of ventilation (12 of 94), and control of seizure unresponsive to anticonvulsants (4 of 94). Deterioration following succinylcholine occurred in three cases. These included two involving bradycardia and one involving ventricular tachycardia. Major complications following pancuronium included four incidences of ventricular arrhythmias. Intubation failure requiring surgical airway occurred in one patient given succinylcholine, two patients given pancuronium, and one patient who received both succinylcholine and pancuronium. Inadequate documentation of neurological examination prior to blockade was noted in six of 25 succinylcholine and nine of 94 pancuronium cases. Failure to sedate patients who might be aware of paralysis occurred in three of 25 succinylcholine and eight of 94 pancuronium uses . Neuromuscular blocking agents facilitate expeditious management of selected critical patients in the ED. Their prudent use requires anticipation of potential complications, preparation for surgical airway should intubation fail, documentation of physical examination before paralysis, and prior sedation when the patient responds to pain.


amprolium

diclazuril

clopidol

Sensitivity of isolates of Eimeria from turkey flocks to the anticoccidial drugs amprolium, clopidol, diclazuril, and monensin. The sensitivity of field isolates of turkey coccidia from the United States to the anticoccidial drugs amprolium, clopidol, diclazuril, and monensin was investigated. clopidol and diclazuril were the most effective, followed by monensin and amprolium. Thirty-one isolates were classified as resistant to amprolium , 23 resistant to monensin , 10 resistant to diclazuril , and 6 resistant to clopidol . Six isolates were partially resistant to monensin, 10 partially resistant to clopidol, and 11 partially resistant to diclazuril. Four isolates were sensitive to monensin, 12 sensitive to diclazuril, and 17 sensitive to clopidol.


lidocaine

dexamethasone

cystodistention

Electromotive drug administration and hydrodistention for the treatment of interstitial cystitis.  Thirteen patients with interstitial cystitis diagnosed by the NIH criteria were treated with intravesical electromotive administration of lidocaine and dexamethasone followed by cystodistention . After a mean follow-up of 10 (range 3-22) months, 8/13 (62%) of the patients reported complete resolution of bladder symptoms lasting an average 4.5 (range 0.75-17) months. Partial or short-term improvement of bladder symptoms was observed in three patients, while two patients reported aggravation of pain for several days after therapy. A significant increase in bladder capacity, to an average 166% of the pretreatment capacity, was observed in all patients. Whenever symptoms recurred after initially effective therapy, retreatments were performed with equal efficacy in 11 patients. This promising new therapeutic approach, performed on an outpatient basis, may become first-line treatment for patients with interstitial cystitis.


niacin

colesevelam hydrochloride

ezetimibe

simvastatin

Lipoprotein-associated phospholipase A2 mass is significantly reduced in dyslipidemic patients treated with lifestyle modification and combination lipid-modifying drug therapy. Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) mass is a novel inflammatory biomarker. In human blood, Lp-PLA(2) is predominately associated with low-density lipoprotein (LDL). This study examines the ability of lifestyle modification (diet and exercise) and combination lipid therapy to reduce Lp-PLA(2) levels while also determining the relationship between changes in LDL cholesterol and Lp-PLA(2). Thirty dyslipidemic patients who received lifestyle intervention and combination lipid therapy for an average of 6 months were included in these analyses (mean age, 60.9 years); 40% had stable angiographically established coronary artery disease, 40% had the metabolic syndrome, and 70% were men. Drug therapy included omega-3 fish oil , extended-release niacin , colesevelam hydrochloride , and a fixed combination of 10-mg ezetimibe and 40-mg simvastatin . The study revealed a 33% reduction in mean Lp-PLA(2) values (baseline 224.9+/-47.5 vs posttreatment 149.5+/-35.5 ng/mL; P<.001). Significant changes in mean LDL cholesterol from baseline (127.9+/-49.3 vs posttreatment 65.2+/-32.1 mg/dL; P<.001) were also observed. However, regression analysis revealed only a weak positive relationship between changes in LDL cholesterol and Lp-PLA(2) mass (R(2)=0.29; P<.01). Thus, Lp-PLA(2) mass is significantly reduced with lifestyle and combination lipid therapy. Changes in Lp-PLA(2) were only partially explained by the changes observed for LDL cholesterol.


irinotecan

folinic acid

fluorouracil

fluorouracil

bevacizumab

Pharmacokinetics, safety, and efficacy of FOLFIRI plus bevacizumab in Japanese colorectal cancer patients with UGT1A1 gene polymorphisms. Previous reports of the influence of UGT1A1 gene polymorphisms on the pharmacokinetics of irinotecan metabolism have not assessed Asian patients treated with FOLFIRI plus bevacizumab for advanced and recurrent colorectal cancer. Twenty-one Japanese colorectal cancer patients received intravenous FOLFIRI ( bolus irinotecan , folinic acid , and fluorouracil followed by 46-hour fluorouracil infusion ) followed by bevacizumab ( 5 mg/kg ) in Cycle 1 . In Cycle 2, patients received bevacizumab followed by FOLFIRI. The regimen was in 2-week cycles. The area under-the-curves ratio (AUC0-last) (Cycle 2/Cycle 1) was determined from plasma concentrations of irinotecan and metabolites (SN-38, SN-38G). Safety, efficacy, and drug-drug interactions were analyzed. Median observation period was 7.8 months; median number of cycles 15. Drug-drug interactions were evaluated in eight patients without irinotecan dose reduction. Mean AUC0-last ratios (with/without bevacizumab) of irinotecan, SN-38, and SN-38G were 0.959, 0.927, and 0.931 respectively. Response rate was 65%; median progression-free survival 16.4 months. Response occurred in four patients with, and nine without, UGT1A1 polymorphism. No significant differences occurred between efficacy, safety, or polymorphism status. This cohort showed no differences in safety or efficacy compared to previous reports. bevacizumab did not affect the pharmacokinetics of irinotecan and its metabolites, irrespective of UGT1A1 polymorphism status.


vinorelbine

carboplatin

Phase I/II trial of vinorelbine and divided-dose carboplatin in advanced non-small cell lung cancer. vinorelbine administered in a doublet with cisplatin has become a standard treatment in patients with advanced non-small cell lung cancer (NSCLC). However, carboplatin appears to provide comparable efficacy with a better nonhematologic safety profile than cisplatin. Herein we report the results of a phase I/II trial of weekly vinorelbine and divided-dose carboplatin in patients with stage IIIB/IV NSCLC, Eastern Cooperative Oncology Group performance status < or = 2, and adequate bone marrow. Patients received vinorelbine starting at 20 mg/m(2 ) ( to 25 mg/m(2 ) ) and carboplatin area under the curve ( AUC ) 2.5 in divided-doses , both given on Days 1 and 8 every 21-day cycle for up to 6 cycles or until disease progression . Dose-limiting toxicity was defined for Cycles 1 and 2. Tumor response and toxicity were assessed using standard criteria. Twenty-one patients with a mean age of 67 years (range, 43-79) and stage IIIB/IV (8/13) disease were enrolled. All but 1 patient were chemotherapy-nai;ve; the majority (n = 20) had good performance status (< or = 1). Seventy-nine courses (median, 4) were administered. The vinorelbine/carboplatin doublet was well tolerated, with 7 courses interrupted or delayed because of toxicity. Toxicities were generally mild and evenly divided between hematologic (i.e., neutropenia) and nonhematologic (i.e., fatigue). No growth factor support was required for hematologic toxicity. There was only one case of grade 2 alopecia, and no cases of > or = grade 2 neurotoxicity. There were 5 (24%) partial responses, and 9 (43%) patients had stable disease. Weekly vinorelbine 25 mg/m(2) and divided-dose carboplatin AUC 2.5 is a well tolerated regimen with activity in advanced NSCLC patients. Further evaluation of this regimen in combination with novel targeted biologic therapy is warranted.


Dexamethasone

paclitaxel

Efficacy of paclitaxel/dexamethasone intra-tumoral delivery in treating orthotopic mouse breast cancer. The effect of topical co-administration of promoter drugs with paclitaxel to increase anti-tumor effects of paclitaxel was investigated. Mice with orthotopic 4T1-Luc breast cancer received single intra-tumoral injection of a polymeric formulation with paclitaxel and a specific promoter drug. Several promoter drugs were evaluated, including: dexamethasone, losartan, nicotinamide, Azone, and oleic acid. Dexamethasone exhibited the highest effect on paclitaxel anti-tumor activity , in a dose-dependent fashion . However, this effect was accompanied by systemic effects of dexamethasone, and inability to prevent tumor metastasis to the lungs. Topical co-administration of promoter drugs with anti-cancer agents can enhance their anti-tumor effects. Further investigations are needed to identify the most efficient combinations of promoter and anti-cancer drugs, and their suitability for the clinical management of the breast cancer disease.


palbociclib

ribociclib

abemaciclib

[Cell cycle inhibitors in endocrine receptor positive breast cancer]. Dysregulation of cellular cycle is a key component of carcinogenesis and its targeting represents an interesting approach. Recently, the development of selective inhibitors of the cycle targeting the cyclin-dependent kinases (CDK) 4 and 6 revived interest in this therapeutic class after the failure of pan-inhibitors. palbociclib, ribociclib, and abemaciclib are the 3 drugs with the most advanced development. They demonstrated preclinical activity in luminal breast cancer models and are under clinical evaluation. The first available studies demonstrate the value of these compounds with an improved prognosis of metastatic patients in combination with endocrine therapy ( palbociclib , ribociclib ) or in monotherapy ( abemaciclib ) . The results of ongoing studies will clarify the role of these agents in our new strategies and the individualisation of biomarkers will help to define patients who benefit most from this approach.


Flunarizine

diltiazem

Augmented behavioral response and enhanced synaptosomal calcium transport induced by repeated cocaine administration are decreased by calcium channel blockers. Recent studies suggest that calcium influx via L-type calcium channels is necessary for psychostimulant-induced behavioral sensitization. In addition, chronic amphetamine upregulates subtype Cav1.2-containing L-type calcium channels. In the present studies, we assessed the effect of calcium channel blockers (CCBs) on cocaine-induced behavioral sensitization and determined whether the functional activity of L-type calcium channels is altered after repeated cocaine administration. Rats were administered daily intraperitoneal injections of either flunarizine (40 mg/kg), diltiazem (40 mg/kg) or cocaine (20 mg/kg) and the combination of the CCBs and cocaine for 30 days. Motor activities were monitored on Day 1, and every 6th day during the 30-day treatment period. Daily cocaine administration produced increased locomotor activity. Maximal augmentation of behavioral response to repeated cocaine administration was observed on Day 18. Flunarizine pretreatment abolished the augmented behavioral response to repeated cocaine administration while diltiazem was less effective . Measurement of tissue monoamine levels on Day 18 revealed cocaine-induced increases in DA and 5-HT in the nucleus accumbens. By contrast to behavioral response, diltiazem was more effective in attenuating increases in monoamine levels than flunarizine. Cocaine administration for 18 days produced increases in calcium uptake in synaptosomes prepared from the nucleus accumbens and frontal cortex. Increases in calcium uptake were abolished by flunarizine and diltiazem pretreatment. Taken together, the augmented cocaine-induced behavioral response on Day 18 may be due to increased calcium uptake in the nucleus accumbens leading to increased dopamine (DA) and serotonin (5-HT) release. flunarizine and diltiazem attenuated the behavioral response by decreasing calcium uptake and decreasing neurochemical release.


amphotericin

itraconazole

itraconazole

itraconazole

The concentration-dependent nature of in vitro amphotericin B-itraconazole interaction against Aspergillus fumigatus: isobolographic and response surface analysis of complex pharmacodynamic interactions. The interaction between polyenes and azoles is not well understood. We therefore explored the in vitro combination of amphotericin B with itraconazole against 14 clinical Aspergillus fumigatus isolates ( 9 itraconazole susceptible and 5 itraconazole resistant ) with a colorimetric broth microdilution checkerboard technique using two drug interaction models able to explore complicated patterns of interactions : the response surface analysis of Bliss independence and the isobolographic analysis of Loewe additivity zero interaction theories . Synergy was found at combinations with low concentrations of amphotericin B (<0.125 mg/L), whereas antagonism was found at combinations with higher concentrations of amphotericin B. For itraconazole-resistant isolates, synergistic interactions were observed at high concentrations of itraconazole (>0.5 mg/L). Synergy was more frequently observed for the itraconazole-resistant isolates than for the itraconazole-susceptible isolates.


inotuzumab

ozogamicin

rituximab

HDT-aSCT

A phase 2 study of inotuzumab ozogamicin and rituximab, followed by autologous stem cell transplant in patients with relapsed/refractory diffuse large B-cell lymphoma.  This study evaluated the safety and efficacy of inotuzumab ozogamicin ( INO ) , a targeted humanized anti-CD22 antibody conjugated to calicheamicin , plus rituximab ( R-INO ) every 3 weeks , up to six cycles , followed by high dose therapy and autologous stem cell transplant ( HDT-aSCT ) in patients with high-risk relapsed/refractory diffuse large B-cell lymphoma ( DLBCL ) . The primary endpoint was overall response (OR) rate after three cycles of R-INO. Sixty-three patients were enrolled. Common grade 3/4 adverse events during R-INO treatment were thrombocytopenia, lymphopenia and neutropenia. OR rate after three cycles of R-INO was 28.6% (95% confidence interval: 17.9-41.4). Eighteen patients underwent HDT-aSCT; 2-year progression-free survival (PFS) for these patients was 61.1%. Serious infections and hepatic toxicity following aSCT occurred in 33% and 22%, respectively. One- and 2-year PFS rates for all enrolled patients were 28.9% and 25.3%, respectively (median, 3.0 months). R-INO had lower than expected activity as a salvage regimen for transplant eligible patients with DLBCL.


methylprednisolone

mycophenolate

immunoglobulin

Severe Ocular Myositis After Ipilimumab Treatment for Melanoma: A Report of 2 Cases. ipilimumab binds and blocks cytotoxic T-lymphocyte-associated antigen-4, causing enhanced T-cell reaction, antitumor response, and significant improvement of the overall survival of patients with metastatic melanoma. Patients treated with ipilimumab can develop immune-related adverse effects, primarily dermatitis, colitis, hepatitis, and hypophysitis. Although, in phase I-III studies, 64.2% of all patients suffered from immune-related adverse effects, ocular adverse effects occurred in 1.3% only. In the cases reported below, 2 patients with metastatic melanoma developed severe ocular myositis after treatment with ipilimumab. These are the first 2 reports of successful treatment of this condition by use of a combination of methylprednisolone and mycophenolate mofetil , and , in 1 of the cases , additional medication with intravenous immunoglobulin .


moclobemide

mianserin

The management of depression. The place of the new antidepressants. Part 1. General overview.  The introduction of the selective serotonin reuptake inhibitors , moclobemide and mianserin has been a major advance in the treatment of depression , and is already leading to major shifts in the pattern of antidepressants prescribing . These antidepressants are safe, well tolerated and effective, and in conjunction with older agents such as the tricyclics, provide the clinician with a broad range of treatments for this common and disabling disorder. This two-part review will focus on the management of depression in general practice.


epinephrine

clonidine

Overnight clonidine suppression test in the diagnosis and exclusion of pheochromocytoma. In a prospective study designed to differentiate pheochromocytoma from other forms of hypertension, urinary catecholamines were measured after sleep and clonidine administration in 12 patients with pheochromocytoma, 19 hypertensive patients in whom pheochromocytoma was suspected but later excluded, and 31 hypertensive patients in whom pheochromocytoma was never suspected. The test correctly identified all 12 patients in whom pheochromocytoma was present. Four of these had equivocal plasma levels of both norepinephrine and epinephrine , suggesting that overnight clonidine suppression may be of particular value when tumor secretion is intermittent or low . When pheochromocytoma was not present, urinary norepinephrine and epinephrine levels were suppressed below 60 and 20 nmol/mmol creatinine, respectively, after sleep and clonidine, the two in combination giving better suppression than sleep alone. Since urinary catecholamines can be determined relatively easily by high-pressure liquid chromatography with electrochemical detection, this test may be more widely applicable than suppression tests based on plasma measurements.


ATGAM

tacrolimus

steroids

cyclosporine

Combination therapy with tacrolimus and anti-thymocyte globulin for the treatment of steroid-resistant acute graft-versus-host disease developing during cyclosporine prophylaxis. We report our experience with the combination of anti-thymocyte globulin (ATGAM) and tacrolimus in the treatment of 20 patients with steroid refractory and dependent acute graft-versus-host disease (GVHD) transplanted between August 1996 and February 2000. All patients received cyclosporine-based GVHD prophylaxis. Thirteen patients developed a maximum of grade IV, five grade III and two grade II acute GVHD, with 15 patients being refractory to steroids and five dependent on steroids. Patients were treated with ATGAM (15 mg/kg for 5 d) and tacrolimus (0.025--0.1 mg/kg/d) in addition to continuation of their high-dose steroids and cessation of their cyclosporine. Within 28 d of treatment, we observed eight complete responses (CR), six partial responses (PR) and six with no response. Overall response (CR + PR) was predicted by GVHD severity. Infectious complications occurred in 80% of patients. The median survival was 86.5 d (range, 21--1081 d) with 35% of patients remaining alive. Survival following combination therapy was significantly more likely in men (P < 0.001), skin-only GVHD (P = 0.027), less severe GVHD (P = 0.048), and in responders to tacrolimus and ATGAM (P < 0.001). In conclusion , concurrent introduction of ATGAM and tacrolimus is a promising therapeutic combination for GVHD refractory to steroids and cyclosporine .


pertuzumab

trastuzumab

docetaxel

Absence of pharmacokinetic drug-drug interaction of pertuzumab with trastuzumab and docetaxel. pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel . In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer.


enoxaparin

heparin

Dendrimers as a carrier for pulmonary delivery of enoxaparin, a low-molecular weight heparin.  This study was designed to test the hypothesis that positively charged dendrimers form a complex with enoxaparin , a low-molecular weight heparin ( LMWH ) , and that the resulting drug-dendrimer complex is effective in preventing deep vein thrombosis after pulmonary administration . Fourier Transform Infrared (FTIR) spectroscopy and the azure A assay were used to evaluate interactions between dendrimers and enoxaparin. The efficacy of polyamidoamine (PAMAM) dendrimers in enhancing pulmonary absorption of enoxaparin was studied by administering enoxaparin-dendrimer formulations into the lungs of anesthetized rats and monitoring drug absorption by measuring plasma anti-factor Xa activity. The optimized formulations were evaluated for their efficacy in preventing deep vein thrombosis in a rodent model. The safety of the formulations was tested by studying their effects on mucociliary transport rate (MTR) in a frog palate model and by measuring injury markers in rat bronchoalveolar fluid. The FTIR data and azure A assay revealed ionic interactions between the amino groups of cationic dendrimers and the carboxylic and sulfate groups of enoxaparin. Positively charged dendrimers increased the relative bioavailability of enoxaparin by 40%, while a negatively charged dendrimer had no effect. Formulations containing 1% G2 or 0.5% G3 PAMAM dendrimer plus enoxaparin were as efficacious in preventing deep vein thrombosis in a rat model as subcutaneously administered enoxaparin. The formulations did not adversely affect the MTR or produce extensive damage to the lungs. Positively charged dendrimers are a suitable carrier for pulmonary delivery of enoxaparin. They enhance pulmonary absorption of LMWH probably by reducing negative surface charge density of the drug molecule.


ibuprofen

S-flurbiprofen

salicylic acid

phenylbutazone

β-cyclodextrins

Revealing equilibrium and rate constants of weak and fast noncovalent interactions. Rate and equilibrium constants of weak noncovalent molecular interactions are extremely difficult to measure. Here, we introduced a homogeneous approach called equilibrium capillary electrophoresis of equilibrium mixtures (ECEEM) to determine k(on), k(off), and K(d) of weak (K(d) > 1 μM) and fast kinetics (relaxation time, τ < 0.1 s) in quasi-equilibrium for multiple unlabeled ligands simultaneously in one microreactor. Conceptually, an equilibrium mixture (EM) of a ligand (L), target (T), and a complex (C) is prepared. The mixture is introduced into the beginning of a capillary reactor with aspect ratio >1000 filled with T. Afterward, differential mobility of L, T, and C along the reactor is induced by an electric field. The combination of differential mobility of reactants and their interactions leads to a change of the EM peak shape. This change is a function of rate constants, so the rate and equilibrium constants can be directly determined from the analysis of the EM peak shape (width and symmetry) and propagation pattern along the reactor. We proved experimentally the use of ECEEM for multiplex determination of kinetic parameters describing weak ( 3 mM > K(d ) > 80 μM ) and fast ( 0.25 s ≥ τ ≥ 0.9 ms ) noncovalent interactions between four small molecule drugs ( ibuprofen , S-flurbiprofen , salicylic acid and phenylbutazone ) and α- and β-cyclodextrins . The affinity of the drugs was significantly higher for β-cyclodextrin than α-cyclodextrin and mostly determined by the rate constant of complex formation.


ifosfamide

etoposide

High-dose ifosfamide and etoposide with filgrastim for stem cell mobilization in patients with advanced ovarian cancer. High-dose chemotherapy combined with autologous peripheral blood stem cell transplantation has shown promise as treatment for recurrent or persistent epithelial ovarian cancer. We evaluated the stem cell mobilization regimen of high-dose ifosfamide plus etoposide in 32 patients with epithelial ovarian cancer , who had a positive second-look laparatomy or recurrent disease . ifosfamide was given at 10 g/m2 by continuous i.v. from days 1 to 3. etoposide was given at 150 mg/m2 every 12 h for six doses on days 1-3. filgrastim was given at 10 microg/kg/d s.c. from day 5 until the completion of peripheral blood stem cell harvest. Fourteen of 32 patients had measurable or evaluable disease before mobilization therapy and were assessed for response. In nine (64%) of the 14 patients, treatment response was demonstrated, and these patients received a second cycle of mobilization therapy. The target CD34+ cell dose (>8 x 106 cells/kg) was achieved with a median of one apheresis (range 1-5). A median of 25.1 (range 8.0-122.5) x 106 CD34+ cells/kg body weight was collected. Non-hematologic toxicity was limited to grade 2 renal dysfunction in one patient and grade 2 hepatic dysfunction in three patients. In this patient group, high-dose ifosfamide plus etoposide with filgrastim support was well tolerated, lead to successful stem cell harvest and had antitumor activity.


Esomeprazole

omeprazole

Esomeprazole: a clinical review. The pharmacology, pharmacodynamics, pharmacokinetics, clinical efficacy, and adverse effects of esomeprazole are reviewed. Esomeprazole , a proton-pump inhibitor ( PPI ) , is the S-isomer of omeprazole . esomeprazole has FDA-approved labeling for use in the treatment of symptomatic gastroesophageal reflux disease (GERD), including healing and maintenance of healing of erosive esophagitis and as part of a triple-drug regimen for Helicobocter pylori infection. esomeprazole is structurally similar to other PPIs but is the first PPI to include only the active isomer, which may lead to improved pharmacokinetic and pharmacodynamic characteristics. esomeprazole maintains intragastric pH at a higher level and above 4 for a longer period than other PPIs. Clinical studies have shown that esomeprazole is at least equivalent in safety and efficacy to other drugs in the class. esomeprazole has demonstrated efficacy in the treatment of erosive esophagitis, the maintenance of healing of erosive esophagitis, and the treatment of signs and symptoms of GERD. Effective dosages are 20 or 40 mg orally every day or as needed. esomeprazole magnesium 40 mg once daily in combination with amoxicillin and clarithromycin is effective in eradicating H. pylori infection. The potential for interacting with other drugs is limited and is similar to that of omeprazole. The most common adverse effects are headache, respiratory infection, and abdominal symptoms. esomeprazole has pharmacokinetic properties that may make it more effective than omeprazole in some patients.


vasopressin

oxytocin

A vasopressin and oxytocin containing nucleus in the pig hypothalamus that shows neuronal changes during puberty. A vasopressin and oxytocin containing nucleus is described for the first time in the pig hypothalamus. It is located near the third ventricle, just dorsal to the suprachiasmatic nucleus, and consists of magnocellular neurons, similar to those of the supraoptic nucleus and paraventricular nucleus. Morphometric analysis of neuronal number, size, density, and volume was performed at four different ages: 1 day, 7 weeks, 16 weeks, and 30 weeks postnatally. No sex difference in these parameters was observed. In this period the volume of the nucleus increased gradually from 6.6 x 10(-3) to 54.2 x 10(-3) mm3. One day after birth 1,215 +/- 191 (mean +/- SEM) neurons were present in the vasopressin and oxytocin containing nucleus, followed by a decrease to 771 +/- 80 neurons at 7 weeks and 697 +/- 116 at 16 weeks. Between 16 and 30 weeks (puberty) there was a dramatic increase in neuron number up to 1,765 +/- 214 neurons. This increase in the number of vasopressin and oxytocin containing neurons in the pig hypothalamus is much later in development than has ever been reported so far .


alkylating agents

fludarabine

cladribine

Clinical pharmacokinetics of nucleoside analogues: focus on haematological malignancies. This review establishes the pharmacokinetic characteristics of the major nucleoside analogues with cytotoxic activity. cytarabine, pentostatin, fludarabine, cladribine and gemcitabine are all prodrugs whose plasma pharmacokinetics do not fully reflect their therapeutic activity; after cellular uptake, these compounds undergo phosphorylation by deoxycytidine kinase before their incorporation into DNA results in cell death. cytarabine is principally active in the S phase of the cell cycle and is most toxic to replicating cells, whereas pentostatin, fludarabine and cladribine are incorporated into DNA during the process in which strand breaks are repaired and are therefore cytotoxic to slowly replicating cells (although the action of pentostatin results from its inhibition of adenosine deaminase). gemcitabine is unusual in being highly metabolised in solid tumour cells. The cytotoxic activity of pentostatin, fludarabine and cladribine against the clonal cells of lymphoproliferative disorders is accompanied by damage to normal lymphoid cells, which results in significant and long-lasting immunosuppression. Useful interactions between nucleoside analogues have been defined. Cells that are primed by exposure to fludarabine or cladribine exhibit enhanced accumulation of cytarabine triphosphate (the cytotoxic nucleotide of cytarabine) and an improved therapeutic effect against acute myeloid leukaemia and chronic lymphocytic leukaemia can be achieved by clinical schedules that exploit this effect. Combinations of alkylating agents and fludarabine or cladribine are also synergistic in producing significantly enhanced activity against refractory lymphoid malignancies , but at the cost of increased haematological toxicity . Developments in the clinical administration of gemcitabine are concentrating on efforts to extend the duration of exposure to the drug as a means of counteracting its rapid catabolism in the circulation. Future developments with this group of agents will further explore the use of fludarabine-based combination therapies to produce a transient period of myelosuppression and immunosuppression that is sufficient to permit the engraftment of allogeneic haemopoietic stem cells and also exploit the immunological benefits of graft-versus-tumour reactions. In addition, the clinical spectrum of activity of gemcitabine is also being extended by combining the drug with other active chemotherapeutic agents, such as cisplatin, and by early studies of its role as a radiosensitiser.


trazodone

amitriptyline

ethanol

placebo

Evaluation of possible interactions between ethanol and trazodone or amitriptyline.  The pharmacodynamic effects of single doses of trazodone ( 100 mg ) , amitriptyline ( 50 mg ) or placebo either alone or with ethanol ( 0.5 ml/kg ) were investigated in 6 healthy volunteers in a double-blind crossover study . Plasma concentrations of the drugs and ethanol were also measured. Pharmacodynamic tests were critical flicker fusion frequency threshold (CFF), choice reaction time (CRT), manual dexterity, a digit span test and visual analogue scales. Blood ethanol concentrations were not influenced by the co-administration of either antidepressant. tmax for trazodone was prolonged by ethanol but the other pharmacokinetic parameters for trazodone and amitriptyline were not influenced by ethanol. trazodone and amitriptyline caused the expected profound depressant effects on CFF, CRT, manual dexterity and on the rating scales for drowsiness, 'clearheadedness', aggression and disinhibition. Ethanol alone impaired manual dexterity, increased drowsiness, reduced 'clearheadedness' and also tended to reduce feelings of aggression. In combination with either trazodone or amitriptyline, ethanol caused little additional effect except in the case of manual dexterity, which was further impaired. This result may reflect the profound effects of the antidepressants alone and does not suggest that it is safe for patients receiving antidepressant medication to take ethanolic drinks.


irinotecan

bevacizumab

Portal Vein Thrombosis in Metastatic Colorectal Cancer During FOLFIRI-bevacizumab Chemotherapy Successfully Treated with Apixaban. Portal vein thrombosis (PVT) while using an angiogenesis inhibitor is relatively rare. A 70-year-old Asian man was diagnosed with PVT two months after initiating 5-fluorouracil/leucovorin , irinotecan , and bevacizumab therapy for rectal cancer with liver metastases . Because the metastases were small and shrinking, we suspected that the thrombosis might have been caused by bevacizumab-containing chemotherapy. We stopped bevacizumab and started apixaban, a direct oral anticoagulant (DOAC). Eight months later, the complete dissolution of the thrombus and recanalization of the portal vein were attained. Our case suggests that PVT can occur during bevacizumab-containing chemotherapy, and DOAC therapy might be beneficial for treating PVT in patients with cancer.


imatinib

irinotecan

Imatinib‑induced apoptosis of gastric cancer cells is mediated by endoplasmic reticulum stress. imatinib is a powerful tyrosine kinase inhibitor that specifically targets BCR‑ABL, c‑KIT, and PDGFR kinases, and is used in the treatment of chronic myelogenous leukemia, gastrointestinal stromal tumors, and other types of cancers. However, the possible anticancer effects of imatinib in gastric cancer have not yet been explored. The present study evaluated the in vitro effects of imatinib on gastric cancer cells and determined the molecular mechanism underlying these effects. We determined that imatinib induced mitochondria‑mediated apoptosis of gastric cancer cells by involving endoplasmic reticulum (ER) stress‑associated activation of c‑Jun NH2‑terminal kinase (JNK). We also found that imatinib suppressed cell proliferation in a time‑ and dose‑dependent manner. Cell cycle analysis revealed that imatinib‑treated AGS cells were arrested in the G2/M phase of the cell cycle. Moreover, imatinib‑treated cells exhibited increased levels of phosphorylated JNK, and of the transcription factor C/EBP homologous protein, an ER stress‑associated apoptotic molecule. Results of cell viability assays revealed that treatment with a combination of imatinib and chemotherapy agents irinotecan or 5‑Fu synergistically inhibited cell growth , compared with treatment with any of these drugs alone . These data indicated that imatinib exerted cytotoxic effects on gastric cancer cells by inducing apoptosis mediated by reactive oxygen species generation and ER stress‑associated JNK activation. Furthermore, we revealed that imatinib induced the apoptosis of gastric cancer cells by inhibiting platelet‑derived growth factor receptor signaling. Collectively, our results strongly support the use of imatinib in the treatment of treating gastric cancer.


ifosfamide

cyclophosphamide

Ifosfamide in the treatment of high-grade recurrent non-Hodgkin's lymphomas. We report the results of two phase II trials of ifosfamide in very high risk patients with either partially responsive or recurrent non-Hodgkin's lymphomas. In the first study, in which patients were extremely heavily pretreated (50 per cent had received a very intensive salvage regimen containing very high dose cyclophosphamide), there were two complete responses, two partial responses and one objective (minimal) response among 14 patients treated. Toxicity was acceptable even in this end-stage patient group. We concluded that ifosfamide is an active agent even in patients with tumours resistant to cyclophosphamide . The second trial was a pilot study in 13 patients of a regimen incorporating VP16, ifosfamide/mesna, and high dose ara-C (VIPA). There were four complete responses, five partial responses and two objective responses. Two patients died in complete remission from toxic complications, while a third, with a stably regressed mediastinal mass died after completion of the protocol. While very toxic, we considered that this regimen was highly effective, and have since incorporated a slightly less intensive combination of the same drugs into the primary therapy of high risk patients. Since the primary toxicity of the VIPA combination was myelosuppression, the use of a modified protocol incorporating colony stimulating factors to ameliorate the side-effects and possibly increase dose rate is worthy of further exploration in patients with recurrent B cell tumours.


fluoropyrimidine

oxaliplatin

irinotecan

Options for Second-Line Treatment in Metastatic Colorectal Cancer. Colorectal cancer (CRC) remains a major public health problem in the United States and worldwide. The majority of patients who have CRC eventually present with metastatic disease. The overall therapeutic goals for most patients with metastatic CRC (mCRC) are to control the disease, prolong life span, and maximize quality of life. Therefore, the ratio of efficacy to toxicity is one of the most important factors in choosing among treatment options and sequencing regimens. In addition, the choice of first-line systemic therapy will affect the options for second-line treatment. Several newer cytotoxic agents for the treatment of mCRC have been approved during the past 2 decades by the US Food and Drug Administration (FDA), including irinotecan, oxaliplatin, and capecitabine. The combination of a fluoropyrimidine ( 5-fluorouracil or capecitabine ) with either oxaliplatin or irinotecan has been widely accepted as standard cytotoxic chemotherapy for either the first- or second-line treatment of mCRC . The FDA has approved several pathway-targeting agents for the treatment of mCRC; these include agents that target the vascular endothelial growth factor receptor pathway (bevacizumab, ziv-aflibercept, and ramucirumab) and those that target the epidermal growth factor receptor pathway (cetuximab and panitumumab). Here, we review the current clinical options for the second-line treatment of mCRC and the rationales for their use.


etoposide

vincristine

etoposide

A national survey of the chemotherapy regimens used to treat small cell lung cancer (SCLC) in the United Kingdom. Many chemotherapy regimens are used for treating SCLC in the United Kingdom, but it is not known, in any detail, which regimens are used, by which specialists, for which types of patient. We conducted a survey among all medical and clinical oncologists, respiratory physicians and general physicians with respiratory interest in the United Kingdom to find out. The questionnaire asked for the number of SCLC patients treated annually; how many were given chemotherapy; the drugs, doses and schedules chosen according to prognostic group (as defined by the clinician); and the reasons for choice of regimen. 1214 questionnaires were sent out, and responses were received from 1070 (88%) clinicians; 266 (25%) of these treated SCLC with chemotherapy. Of 4674 patients given chemotherapy annually, 36% were given it by clinical oncologists, 30% by medical oncologists, 27% by respiratory physicians, and 7% by general physicians. In all, 34 regimens were reported with 151 different combinations of dose and schedule. In 2311 good prognosis patients, 23 regimens were used, the commonest being ACE (doxorubicin, cyclophosphamide, etoposide), ICbE (ifosfamide, carboplatin, etoposide), CAV (cyclophosphamide, doxorubicin, vincristine), CbE (carboplatin, etoposide), and PE (cisplatin, etoposide). In 1517 poor prognosis patients , 21 regimens were used , the commonest being CAV , EV ( etoposide , vincristine ) , CbE , CAV alternating with PE , and oral etoposide . 452 patients were treated regardless of prognosis and for 219 no prognostic criteria were specified. The remaining 175 were given second-line chemotherapy or were given regimens chosen to avoid toxicity or because of intercurrent disease or other reasons. The main reasons affecting choice of regimen were routine local practice, patients' convenience, quality of life considerations, trial results and cost. The results show wide variation in routine practice and will be useful in reporting and planning clinical trials and in deciding on local treatment policies.


nivolumab

ipilimumab

cabozantinib

Treatment Decisions for Metastatic Clear Cell Renal Cell Carcinoma in Older Patients: The Role of TKIs and Immune Checkpoint Inhibitors. Given the underrepresentation of older patients in registration trials for metastatic renal cell carcinoma (mRCC), data to support the use of any particular systemic therapy over others, based on age, is limited. This is further complicated by clinical trials not commonly reporting adverse events by age. Thus, recommendations on treatment of older patients with mRCC are generally extrapolated from data on younger patients enrolled in these trials, which may not be ideal as many older patients are frail, have age-related organ dysfunction, or have multiple medical co-morbidities. In the last decade, the treatment landscape for mRCC has drastically changed with the approval of more than ten targeted therapies, as well as immune checkpoint inhibitors. Thus, treatment selection and sequencing of treatments can be especially challenging for clinicians. We begin this review by analyzing the available efficacy and toxicity data of these treatments in younger and older patients. We also discuss a network meta-analysis that compares the efficacy of these agents in older patients with mRCC. Utilizing this data , we suggest that nivolumab plus ipilimumab and cabozantinib may be favored for first-line treatment of specific populations of older patients . For salvage treatment, we suggest that cabozantinib may be the preferred agent for older patients.


piperacillin

netilmicin

Piperacillin-resistant Escherichia coli bacteraemia: relation to empiric therapy and clinical outcome. Escherichia coli is a leading cause of bacteraemia. The aim of this study was to evaluate all E. coli positive blood cultures collected during a 4-y period in a haematological department using piperacillin plus netilmicin for empiric treatment of febrile episodes . We measured the incidence of piperacillin-resistant E. coli bacteraemia among haematological and non-haematological patients, described the importance of previous antibiotic treatment for resistance development in E. coli and evaluated the impact of piperacillin resistance on the clinical outcome of E. coli bacteraemia. 114 episodes of E. coli bacteraemia in 104 patients were recorded and 98 episodes in 88 patients (42 males and 46 females) with a median age of 64 y (range 19-85 y) were evaluated. In 81.6% of the episodes the patients had a haematological disorder, dominated by acute leukaemia (41.3%), chronic leukaemia (16.3%) and lymphoma (10%). The proportion of piperacillin-resistant E. coli was higher among haematological patients than non-haematological patients (25% vs 0%, p=0.02) and resistance was associated with piperacillin therapy during the previous month (p=0.05). No difference in clinical outcome was found between haematological patients infected with piperacillin-susceptible or -resistant E. coli (intensive care 12% vs 15%; mortality 22% vs 25%).


docetaxel

docetaxel

thalidomide

A randomized phase II trial of docetaxel (taxotere) plus thalidomide in androgen-independent prostate cancer. New therapeutic alternatives are needed to improve outcomes in patients with androgen-independent prostate cancer (AIPC). For several years, researchers at the National Cancer Institute have been interested in elucidating the importance of angiogenesis in the pathogenesis of prostate cancer and in identifying inhibitors of this process. thalidomide has been shown to inhibit the ability of tumors to recruit new blood vessels. In a recent phase II trial of thalidomide in AIPC, 28% of patients achieved a prostate-specific antigen (PSA) decrease of >40%. The taxane docetaxel also produces PSA and measurable disease responses when used as monotherapy or as a component of combination chemotherapy for AIPC. Thus, based on the single-agent activity of thalidomide and docetaxel, we initiated a randomized phase II study of weekly docetaxel with or without thalidomide, 200 mg at bedtime, in patients with chemotherapy-naive metastatic AIPC. docetaxel, 30 mg/m(2) intravenously, was administered every 7 days for 3 weeks, followed by a 1-week rest period. Both regimens have been well tolerated among the first 59 treated patients, with a near absence of grade (3/4) myelosuppression. Fatigue, hyperglycemia, and pulmonary toxicity were seen in both groups. Thrombotic events have been seen in the combination arm. Thirty-five percent ( 6 of 17 ) of the patients receiving docetaxel alone and 53 % ( 19 of 36 ) of those receiving docetaxel and thalidomide have had a PSA decrease of at least 50 % . Combining a cytotoxic agent with an angiogenesis inhibitor is a promising area of investigation for prostate cancer management.


nicotine

bupropion

varenicline

Smoking cessation intervention: an evidence-based approach. Cigarette smoking represents the most important source of preventable morbidity and premature mortality worldwide. Approximately 100 million deaths were caused by tobacco use in the 20th century. There are >1 billion smokers worldwide, and globally the use of tobacco products is increasing, with the epidemic shifting to the developing world. Tobacco dependence is a chronic condition that often requires repeated intervention for success. Just informing a patient about health risks, although necessary, is usually not sufficient for a decision to change. Smokers should be provided with counseling when attempting to quit. Pharmacologic smoking cessation aids are recommended for all smokers who are trying to quit, unless contraindicated. Evidence-based guidelines recommend nicotine replacement therapy , bupropion SR , and varenicline as effective alternatives for smoking cessation therapy , especially when combined with behavioral interventions . Combination pharmacotherapy is indicated for highly nicotine-dependent smokers, patients who have failed with monotherapy, and patients with breakthrough cravings. An additional form of nicotine replacement therapy or an addition of a non-nicotine replacement therapy oral medication (bupropion or varenicline) may be helpful. The rate of successful smoking cessation at 1 year is 3% to 5% when the patient simply tries to stop, 7% to 16% if the smoker undergoes behavioral intervention, and up to 24% when receiving pharmacological treatment and behavioral support.


methotrexate

cyclosporin

Methotrexate vs Cyclosporin A as a single agent for graft-versus-host disease prophylaxis in pediatric patients with hematological malignancies undergoing allogeneic bone marrow transplantation from HLA-identical siblings: a single-center analysis in Japan.  The efficacy of methotrexate ( MTX ) as a single graft-versus-host disease ( GVHD ) prophylaxis agent was compared to that of cyclosporin A ( CSA ) in 62 pediatric patients ( median age : 8 years ) with hematological malignancies who had undergone bone marrow transplantation ( BMT ) from HLA-identical sibling donors at National Kyushu Cancer Center since 1977 . In all, 30 patients received MTX by intravenous bolus injection, with a dose of 15 mg/m(2) on day +1, followed by 10 mg/m(2) on days +3, +6, and +11, and then once a week until day +100. A total of 32 patients were treated with CSA, which was given intravenously in the early stages and orally thereafter until day +100, and then gradually tapered and stopped 6 months after BMT. There were no differences between the groups in terms of rates of hematopoietic recovery after BMT. The probabilities of acute GVHD (grades II-IV) and chronic GVHD were 29.6 vs 40.6% (P=0.294) and 19 vs 20% (MTX vs CSA), respectively. Relapse rates and event-free survival were identical. These results suggest that MTX and CSA were equally effective when given after BMT in Japanese pediatric patients with hematological malignancies. Since MTX was given over a shorter time than CSA, it might be more practical in the management of such patients.


trametinib

cobimetinib

Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas. The Ras-Raf-MEK-ERK (Map kinase) cellular pathway is a highly conserved eukaryotic signaling module that transduces extracellular signals from growth factors and cytokines into intracellular regulatory events that are involved in cell growth and proliferation or the contrary pathway of cell differentiation. Dysregulation of this pathway occurs in more than one-third of all malignancies, a process that has fostered the development of targeted Map kinase pathway inhibitors. Cutaneous melanomas, which arise from skin melanocytes, are the most aggressive form of skin cancer. Mutations that activate the Map kinase pathway occur in more than 90% of these melanomas. This has led to the development of the combination of dabrafenib and trametinib or vemurafenib and cobimetanib for the treatment of BRAF V600E mutant melanomas. dabrafenib and vemurafenib target V600E/K BRAF mutants while trametinib and cobimetanib target MEK1/2. The latter two agents bind to MEK1/2 at a site that is adjacent to, but separate from, the ATP-binding site and are therefore classified as type III allosteric protein kinase inhibitors. These agents form a hydrogen bond with a conserved β3-lysine and they make numerous hydrophobic contacts with residues within the αC-helix, the β5 strand, and within the activation segment, regions of the protein kinase domain that exhibit greater diversity than those found within the ATP-binding site. One advantage of such allosteric inhibitors is that they do not have to compete with millimolar concentrations of cellular ATP, which most FDA-approved small molecule competitive inhibitors such as imatinib must do. Owing to the wide spread activation of this pathway in numerous neoplasms , trametinib and cobimetinib are being studied in combination with other targeted and cytotoxic drugs in a variety of clinical situations . Except for BRAF and NRAS mutations, there are no other biomarkers correlated with treatment responses following MEK1/2 inhibition and the discovery of such biomarkers would represent an important therapeutic breakthrough.


ampicillin

tetracycline

streptomycin

chloramphenicol

Identification and Characterization of the microbial communities found in electronic industrial effluent and their potential for bioremediation. Microbial communities are dynamic systems that develop depending on the ecological niche in which they survive. Electronic industry effluent, rich in heavy metals and salts is one such ecosystem where diverse heavy metal resistant microbes exist. Taxonomic identification of this microbial community would be interesting as no information on the microbial diversity from electronic industry effluent is available till date. Our paper attempts to characterize the microbial inhabitants of this niche. Culture dependent microbiological methods were used to establish and identify various microbial species from the effluent. Culture independent methods of identification involving biochemical tests and molecular biology based methods like 16 S- r DNA sequencing and lipid analyses (FAME analysis) were also carried out to confirm the identity of isolated species. Our study, first of its kind revealed the presence of a diverse group of resistant aerobic microbes and disclosed a total of ten bacterial and two fungal isolates. All these isolates were found to survive in presence of heavy metals like cadmium , lead and zinc and were resistant to antibiotics like ampicillin , tetracycline , streptomycin , penicillin and chloramphenicol as indicated by their Minimum Inhibitory Concentrations ( MIC ) . Such resistant isolates harbor possibilities of metal adaptive/selective pathways which render them as economically beneficial bio-sorbent alternatives in bioremediation of heavy metals.


bortezomib

pemetrexed

cisplatin

Analysis of Gene Expression in 3D Spheroids Highlights a Survival Role for ASS1 in Mesothelioma. To investigate the underlying causes of chemoresistance in malignant pleural mesothelioma, we have studied mesothelioma cell lines as 3D spheroids, which acquire increased chemoresistance compared to 2D monolayers. We asked whether the gene expression of 3D spheroids would reveal mechanisms of resistance. To address this, we measured gene expression of three mesothelioma cell lines, M28, REN and VAMT, grown as 2D monolayers and 3D spheroids. A total of 209 genes were differentially expressed in common by the three cell lines in 3D (138 upregulated and 71 downregulated), although a clear resistance pathway was not apparent. We then compared the list of 3D genes with two publicly available datasets of gene expression of 56 pleural mesotheliomas compared to normal tissues. Interestingly, only three genes were increased in both 3D spheroids and human tumors: argininosuccinate synthase 1 (ASS1), annexin A4 (ANXA4) and major vault protein (MVP); of these, ASS1 was the only consistently upregulated of the three genes by qRT-PCR. To measure ASS1 protein expression, we stained 2 sets of tissue microarrays (TMA): one with 88 pleural mesothelioma samples and the other with additional 88 pleural mesotheliomas paired with matched normal tissues. Of the 176 tumors represented on the two TMAs, ASS1 was expressed in 87 (50%; staining greater than 1 up to 3+). For the paired samples, ASS1 expression in mesothelioma was significantly greater than in the normal tissues. Reduction of ASS1 expression by siRNA significantly sensitized mesothelioma spheroids to the pro-apoptotic effects of bortezomib and of cisplatin plus pemetrexed . Although mesothelioma is considered by many to be an ASS1-deficient tumor, our results show that ASS1 is elevated at the mRNA and protein levels in mesothelioma 3D spheroids and in human pleural mesotheliomas. We also have uncovered a survival role for ASS1, which may be amenable to targeting to undermine mesothelioma multicellular resistance.


thalidomide

cyclosporine

Effects of thalidomide, cyclosporine, and diclofenac on skin allograft survival in rabbits. The present study evaluated the effects of thalidomide, cyclosporine, and diclofenac on skin allograft survival in 42 rabbits divided into the following groups (n = 6): group 1, autograft control; group 2, allograft control; group 3, allografts under thalidomide (100 mg/kg/d); group 4, allografts under sodium diclofenac (2 mg/kg/d); group 5, allografts under cyclosporine (10 mg/kg/d); group 6, allografts under cyclosporine (5 mg/kg/d); group 7, allografts under cyclosporine (5 mg/kg/d) plus thalidomide (100 mg/kg/d). The drugs were given via the orogastric tube the day before transplantation and daily during the postoperative period. Total circular skin grafts from the ear were exchanged between California and White New Zealand rabbits. cyclosporine (10 mg/kg/d) increased allograft survival, an effect that was comparable to cyclosporine (5 mg/kg/d) plus thalidomide (100 mg/kg/d). thalidomide and diclofenac given alone had minimally significant effects on the mean survival of skin allografts. The number of eosinophils around the necrotic skin was higher in the diclofenac group. The group receiving cyclosporine combined with thalidomide displayed the lowest number of eosinophils surrounding the allograft. In conclusion , the combination of thalidomide and cyclosporine in subtherapeutic doses may be useful for the treatment of skin allografts .


streptomycin

kanamycin

gentamicin

ampicillin

novobiocin

Envelope composition and antibiotic hypersensitivity of Escherichia coli mutants defective in phosphatidylserine synthetase. Mutants of Escherichia coli K12, defective in phosphatidylserine synthetase (pss), can be isolated as temperature-sensitive, conditional lethals. When cultivated at intermediate temperatures (30 degrees), such mutants contain approximately 3 times more phosphatidylglycerol plus cardiolipin (and less phosphatidylethanolamine) than normal. We now wish to report that , under these conditions , the pss-8 mutant is hypersensitive to certain antibiotics , especially to streptomycin , kanamycin , and gentamicin , although also to ampicillin and novobiocin . At 30 degrees, the membrane protein and fatty acid composition of pss-8 is nearly normal, i.e. identical with an isogenic pss+ organism. Radiochemical labeling and bacteriophage growth studies show that lipopolysaccharide is also unaltered. Therefore, the antibiotic hypersensitivity of pss-8 differs from previously reported hypersensitivities, associated with lipopolysaccharide defects. These results suggest that the polar phospholipid headgroups may play an important role in maintaining the barrier function of the outer gramnegative membrane and that putative inhibitors of the phosphatidylserine synthetase might potentiate the action of numerous antibiotics currently in clinical use.


yohimbine

propranolol

fasudil

yohimbine

propranolol

fasudil

Cold-induced cutaneous vasoconstriction is mediated by Rho kinase in vivo in human skin. Cutaneous vasoconstriction (VC) is the initial thermoregulatory response to cold exposure and can be elicited through either whole body or localized skin cooling. However, the mechanisms governing local cold-induced VC are not well understood. We tested the hypothesis that Rho kinase participates in local cold-induced cutaneous VC. In seven men and women (20-27 yr of age), up to four ventral forearm skin sites were instrumented with intradermal microdialysis fibers for localized drug delivery during cooling. Skin blood flow was monitored at each site with laser-Doppler flowmetry while local skin temperature was decreased and maintained at 24 degrees C for 40 min. Cutaneous vascular conductance (CVC; laser-Doppler flowmetry/mean arterial pressure) was expressed as percent change from 34 degrees C baseline. During the first 5 min of cooling , CVC decreased at control sites ( lactated Ringer solution ) to -45 + /- 6 % ( P < 0.001 ) , increased at adrenoceptor-antagonized sites ( yohimbine + propranolol ) to 15 + /- 14 % ( P = 0.002 ) , and remained unchanged at both Rho kinase-inhibited ( fasudil ) and adrenoceptor-antagonized + Rho kinase-inhibited sites ( yohimbine + propranolol + fasudil ) ( -9 + /- 1 % , P = 0.4 and -6 + /- 2 % , P = 0.4 , respectively ) . During the last 5 min of cooling, CVC further decreased at all sites when compared with baseline values (control, -77 +/- 4%, P < 0.001; adrenoceptor antagonized, -61 +/- 3%, P < 0.001; Rho kinase inhibited, -34 +/- 7%, P < 0.001; and adrenoceptor antagonized + Rho kinase inhibited sites, -35 +/- 3%, P < 0.001). Rho kinase-inhibited and combined treatment sites were significantly attenuated when compared with both adrenoceptor-antagonized (P < 0.01) and control sites (P < 0.0001). Rho kinase mediates both early- and late-phase cold-induced VC, supporting in vitro findings and providing a putative mechanism through which both adrenergic and nonadrenergic cold-induced VC occurs in an in vivo human thermoregulatory model.


nicotine

clozapine

saline

Nicotine and clozapine cross-prime the locus coeruleus noradrenergic system to induce long-lasting potentiation in the rat hippocampus. A priming-challenge schedule of nicotine treatment causes long-lasting potentiation (LLP), a form of synaptic plasticity closely associated with the norepinephrine (NE) neurotransmitter system, at the medial perforant path (MPP)-dentate gyrus (DG) synapse in the rat hippocampus. Previous reports revealed that nicotine activates the locus coeruleus (LC) noradrenergic (NAergic) system and this mechanism may underlie its beta-adrenoceptor sensitive LLP effects. clozapine, an atypical antipsychotic, is also known to activate the LC. Interactions between nicotine and clozapine are of interest because of the prevalence of smoking in patients with schizophrenia and increasing interest in the use of nicotinic receptor ligands as cognitive enhancers. Rats were subchronically primed with nicotine , clozapine or saline . Twenty-one to twenty-eight days later, the effects of the nicotine, clozapine or saline challenge on the evoked field excitatory postsynaptic potentials (fEPSP) at the MPP-DG monosynaptic pathway were recorded as a measure of LLP. We confirmed the hypothesis that a challenge dose of either nicotine or clozapine induces LLP exclusively in nicotine- and clozapine-primed rats, and not in saline-primed rats, thus indicating a cross-priming effect. Moreover, unilateral suppression of LC using lidocaine abolished the LLP induced by nicotine in clozapine-primed rats. Furthermore, systemic treatment with clonidine (an α2 adrenoceptor agonist that reduces NAergic activity via autoreceptors) prior to the challenge doses blocked the nicotine/clozapine-induced LLP in nicotine- and clozapine-primed rats. These findings may add to understanding of the cognitive enhancing effects of nicotine.


cetuximab

irinotecan

The future of anti-EGFR therapy. We report here on the state of our knowledge of the target--namely, the epidermal growth factor (EGF) and its receptor--and the challenges related to the methods of determination of the epidermal growth factor receptor (EGFR) and associated molecular pathways. A critical review of the anti-EGFR therapeutic strategies is also outlined. The chimeric anti- EGFR monoclonal antibody cetuximab has been approved for EGFR-expressing colorectal tumors in patients who progress after irinotecan-based chemotherapy in combination with irinotecan and in squamous cell head and neck carcinomas for patients with locally advanced disease in combination with radiation therapy or after failure of platinum-based chemotherapy in recurrent or metastatic disease ( FDA ) . cetuximab has the potential to provide an improvement of clinical outcome also in other indications and tumor types, particularly when used as first-line therapy combined with standard chemotherapy for metastatic disease or in the adjuvant setting. Possible strategies to improve the effectiveness of anti-EGFR agents are suggested and include (i) the use of predictive tools capable of making a more rational selection of patients; (ii) the development of standardized predictive biomarkers as surrogates for early monitoring of drug efficacy; and (iii) adequate study design, statistical analysis and proper end points of efficacy to be applied in future prospective trials.


irinotecan

oxaliplatin

taxane

cisplatin

Chemotherapy for advanced gastric cancer: slow but further progress. Gastric cancer remains a significant problem in terms of global health, and is the most common cancer in Korea. Surgery is the only potentially curative treatment for localized gastric cancer, but most cases present at an advanced stage. Randomized trials have demonstrated that chemotherapy for advanced gastric cancer improves the quality of life and extends survival, by 4 approximately 6 months, compared with best supportive care alone. Single agents with a proven activity in a first-line setting include 5-fluorouracil (5-FU), doxorubicin, mitomycin C, cisplatin, taxanes (docetaxel and paclitaxel) and oral fluoropyrimidines (capecitabine and TS-1). Based on the results from several large scale randomized trials, FP (5-FU/cisplatin) and ECF (epirubicin/cisplatin/5-FU) combinations are the most widely used regimen against advanced gastric cancer. Phase II studies of the FP and ECF combination reported a 40~51% response rate in previously untreated patients, and this regimen also produced a significantly higher response rate than the FAM (5-FU/doxorubicin/mitomycin) and FAMTX (5-FU/doxorubicin/methotrexate) regimens, respectively. However, significant treatment related-toxicities and discomfort were reported from ECF, which prevents this combination from becoming the standard treatment regimen. While no one combination chemotherapy regimen is accepted as the standard for advanced gastric cancer, FP is currently considered a suitable reference regimen worldwide. New agents , such as taxane , irinotecan and oxaliplatin , combined with old agents , such as cisplatin and 5-FU , are currently under evaluation to further improve treatment outcomes . Also, oral 5-FU prodrugs are replacing the cumbersome 5-FU long-term infusion due to its convenience and superior toxicity profile. However, the low complete response rate and short response duration are still the main obstacles in the chemotherapy for gastric cancer. Only large scale comparative clinical trials will give clues to improve the results of gastric cancer treatments.


Gemcitabine

Epirubicin

Non-surgical therapy for patients with advanced non-small cell lung cancer. Advanced non-small cell lung cancer (NSCLC) denotes those of TNM stage III and IV. NSCLC has its specific characteristics in respect of oncological behaviour, molecular biology, sensitivity to chemotherapy (CT) and radiotherapy (RT), and requires different therapeutic strategies in comparison with small cell lung cancer. The therapies include: (1) surgery in combination with new effective drugs is resulted in improved RR from 15% a decade ago to 40-60% today. Cisplatin (C-DDP) is the most attractive drug in the treatment of NSCLC, in lengthening the life-span of Stage IV NSCLC patients and as an indispensable sensitizer in RT. Taxinol , Gemcitabine ( GEM ) , Navelbine ( NVB ) , Edatrexate ( ETX ) , CPT-11 and high dose Epirubicin ( EPI HD ) are recommended as new effective drugs . Response rates recently reported for the combination CT with the drugs mentioned above for NSCLC are from 30-65%, and with 8-42 weeks of MST. Induction or neoadjuvant therapies for advanced NSCLC, with 40-69% of RR, 25-29% of complete resection rate, 8-34% of CR and 17-45% of one year SR are reviewed. Eight random studies comparing MST between CT with C-DDP and best supportive care for NSCLC are statistically significant. (2) RT for Stage III NSCLC with 2 year and 5 year survivals of 20 and 5% respectively. Although such outcome is hardly acceptable, RT sensitizer, modified RT techniques and chemoradiotherapy (CRT) are imperative to improve the effect of RT in advanced NSCLC. Clinical literature suggest that CRT is better than RT, though without marked difference. Further studies and sufficient follow-up are necessary to judge the efficacy in terms of long-term survival and toxic reaction. (3) Biological therapy: gene therapy of NSCLC is still in the experimental and developmental stage. Of biological response modifier (BRM), alpha IFN in 11 cases of NSCLC with RR of 9% and MST of 14 months, IL-2 and LAK cell treatment in 11 cases with RR of 9% and MST of 18 months are reported. Instillation of BRM such as IL-2 or alpha-IFN into the pleura after drainage of cancerous effusion has been reported as the most effective for those whose RR is of 80-90% and the clinical response time is fairly long. Hematological cytokine as a protective adjuvant therapy against CT/RT toxicity makes high dose of CT possible and raises the response and patient tolerance. In multimodality therapy, it plays an important role to reduce post CT infection and septicemia.


enalapril

lovastatin

puromycin

The combination of lovastatin and enalapril in a model of progressive renal disease. puromycin-induced nephrotic syndrome is an animal model of progressive renal disease. Both angiotensin converting enzyme inhibitors and lipid-lowering agents have been used to preserve renal structure and function in this model, although neither completely prevents progression. We tested the hypothesis that the combination of the two agents would be more protective than either alone. Rats were divided into five groups; all were uninephrectomized. Four groups were given puromycin at a dose of 10 mg/100 g body weight (BW) with additional doses of 4 mg/100 g BW given intraperitoneally at 4, 5, and 6 weeks thereafter. One group was given enalapril ( EN ) 50 mg/l dissolved in the drinking water ; the second received lovastatin ( L ) 15 mg/kg given daily by gavage ; the third received both agents ; the fourth was left untreated , and the final group received no puromycin and served as the control group . Eight weeks after the initial dose of puromycin, glomerular filtration rate (GFR), as inulin clearance, and protein excretion were determined and blood was collected for cholesterol and triglycerides. Blood pressure was not different between any of the groups. At the end of the study period, serum cholesterol [mean +/- SD, 252 +/- 185 mg/dl (L), 135 +/- 101 mg/dl (L + EN)] and triglycerides (239 +/- 200, 148 +/- 158 mg/dl) were significantly lower (P < 0.001) in the lovastatin-treated groups than in the untreated puromycin group (535 +/- 255 mg/dl and 579 +/- 561 mg/dl, cholesterol and triglyceride, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)


fosfomycin

vancomycin

teicoplanin

In vitro activity of fosfomycin in combination with vancomycin or teicoplanin against Staphylococcus aureus isolated from device-associated infections unresponsive to glycopeptide therapy. fosfomycin is a molecule that inhibits the early stage of peptidoglycan synthesis and shows a broad-spectrum bactericidal activity against Gram-positive and Gram-negative bacteria. Using the Killing-curve method , we tested the in vitro bactericidal activity of fosfomycin alone or in combination with vancomycin or teicoplanin at a concentration of 8 microg/mL , that is easily achievable in serum at standard dosing regimens , against seven methicillin-resistant Staphylococcus aureus strains , isolated from patients with well documented device-associated infections unresponsive to or relapsing after glycopeptide therapy . MICs of vancomycin ranged from 1 to 4 microg/mL, MICs of teicoplanin from 2 to 8 microg/mL; MICs of fosfomycin were 8 microg/mL for two strains and >128 microg/mL for the remaining strains. The seven strains proved tolerant when tested for vancomycin and teicoplanin used alone at 2x MIC concentration. fosfomycin was bactericidal (reduction of 2 log of the inoculum) only against the two susceptible strains. In all cases both vancomycin and teicoplanin in combination with fosfomycin developed bactericidal synergism already at a concentration of 1x MIC. If these results are confirmed by in vivo experiments, the combination of fosfomycin with glycopeptides might be useful for treating device-associated infections, and in preventing the phenomenon of increasing MICs for glycopeptides.


mitomycin

tamoxifen

UFT

UFT and mitomycin plus tamoxifen for stage II, ER-positive breast cancer. Hokkaido ACETBC Study Group. A trial was designed to examine the combination of UFT and mitomycin (Mutamycin) plus tamoxifen (Nolvadex) as postoperative adjuvant therapy in the treatment of patients with stage II, estrogen receptor (ER)-positive primary breast cancer. mitomycin was administered intravenously at 13 mg/m2 on the day of surgery. Patients judged to be ER-positive were randomly allocated to either group A, which received oral tamoxifen 20 mg/day 14 days after surgery for 2 years, or group B, receiving oral UFT 400 mg/day plus tamoxifen 20 mg/day. A total of 219 patients were enrolled in group A, of which 213 (97.3%) were determined to be eligible; 225 patients enrolled in group B and 223 (99.1%) were eligible. The 5-year survival rates were 93.0% for group A and 95.4% for group B, with no significant difference between groups. The 5-year relapse-free survival rates were 83.1% for group A and 90.7% for group B, a significant advantage (P = .020) for the UFT plus tamoxifen group. Combination therapy with mitomycin , tamoxifen , and UFT proved to be an effective postoperative chemoendocrine therapy for stage II , ER-positive breast cancer .


cyclosporine

methotrexate

mycophenolate

The impact of graft-versus-host disease prophylaxis in reduced-intensity conditioning allogeneic stem cell transplant in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. The impact of the intensity of graft-versus-host-disease immunoprophylaxis on transplantation outcomes in patients undergoing transplantation following reduced-intensity conditioning is unclear. This study addresses this issue in 228 adult patients above 50 years of age with acute myeloid leukemia in first complete remission given peripheral blood stem cells from HLA-identical siblings after fludarabine and 2 days of intravenous busulfan reduced-intensity conditioning. A total of 152 patients received anti-thymocyte globulin, either in combination with cyclosporine A in 86 patients (group 1), or with cyclosporine A and mycophenolate mofetil or short course methotrexate in 66 patients (group 2). The remaining 76 patients did not receive anti-thymocyte globulin but were given cyclosporine A and methotrexate or mycophenolate mofetil ( group 3 ) . Incidences of grade II-IV acute graft-versus-host-disease were comparable in the three groups (16.5%, 29.5% and 19.5% in groups 1, 2 and 3, respectively, P=0.15). In multivariate analysis, the absence of anti-thymocyte globulin was the only factor associated with a higher risk of chronic graft-versus-host-disease (P=0.005), while the use of triple immunosuppression (group 3) was associated with an increased risk of relapse (P=0.003). In comparison to anti-thymocyte globulin and cyclosporine A alone, the other two strategies of graft-versus-host-disease prophylaxis were associated with reduced leukemia-free survival and overall survival (P=0.001 for each parameter), independently of the dose of anti-thymocyte globulin. These data suggest that fine tuning of the intensity of this prophylaxis can affect the outcome of transplantation and that anti-thymocyte globulin and cyclosporine A alone should be the preferred combination with the fludarabine-busulfan reduced-intensity conditioning regimen and sibling donors.


Propranolol

propranolol

lacidipine

The pharmacokinetic and pharmacodynamic interaction between lacidipine and propranolol in healthy volunteers. The pharmacokinetic and pharmacodynamic profiles of lacidipine, a 1,4-dihydropyridine calcium antagonist, and the beta-adrenoceptor blocker propranolol were determined alone and in combination in 24 healthy male volunteers. One group (I) of 12 subjects received a single oral dose of 4 mg lacidipine on two separate occasions, which was taken together with a single oral dose of either 160 mg propranolol or placebo; a second group (II) of 12 subjects received propranolol on two occasions, taken with either lacidipine or placebo. Propranolol significantly decreased the maximum plasma concentration ( Cmax ) and area under the plasma concentration-time curve ( AUC ) of lacidipine ( by 38 % and 42 % , respectively ) whereas lacidipine significantly increased the Cmax and AUC of propranolol ( by 35 % and 26 % , respectively ) ; neither the time to maximum plasma concentration ( tmax ) nor the terminal half-life ( t 1/2 ) were affected . With regard to the pharmacodynamics, in Group I, there was a greater reduction in supine systolic blood pressure (6 mm Hg) and diastolic blood pressure (4 mm Hg) compared to the reduction produced by lacidipine alone, and pulse rate was approximately 5 beats/min less. In Group II, a significantly greater reduction (6 mm Hg) in supine systolic blood pressure compared to the reduction produced by propranolol alone occurred, but there was no marked difference in supine diastolic blood pressure and pulse rate. In conclusion, a modest pharmacokinetic and pharmacodynamic interaction is evident and should be evaluated further in patients with hypertension.


vincristine

doxorubicin

cyclophosphamide

actinomycin

cisplatin

Autologous peripheral blood stem cell transplantation in a patient with relapsed pleuropulmonary blastoma. Pleuropulmonary blastoma (PPB) is a rare and aggressive primary intrathoracic neoplasma of children. The prognosis is extremely poor with frequent metastasis to the brain and bone. We present a 4-year-old girl with a tumor mass in the right hemithorax initially diagnosed as pneumoniae. Tumor resection was performed and the histologic report indicated the diagnosis of PPB. The patient received chemotherapy comprising vincristine , actinomycin D , doxorubicin , cisplatin , and cyclophosphamide . Irradiation was performed with total 45 Gy at the right lower pulmonary lobe. She relapsed 29 months later at the pleura between the right middle and lower pulmonary lobe. Tumor resection and total 45 Gy of irradiation were performed again. High-dose chemotherapy comprising cisplatin, adriamycin, and cyclophosphamide was performed followed by autologous peripheral blood stem cell transplantation (PBSCT). The patient achieved complete hematologic recovery. Thirty-one months after PBSCT, no signs of relapse have been observed. Although it might be that the patient could have been cured with second surgery alone or by the surgery and subsequent chemotherapy, high-dose chemotherapy and PBSCT should be considered for the treatment of relapsed PPB.


nicotine

haloperidol

Nicotine and ethanol enhancements of acoustic startle reflex are mediated in part by dopamine in C57BL/6J mice. nicotine has been shown to have additive as well as antagonistic effects on behavior stimulated by ethanol. Here, we examine the effects of nicotine, ethanol, and the coadministration of each drug on acoustic startle responding in C57BL/6J mice. Mice were tested at a range of decibel levels (80-115 dB, 5 dB increments), with administration of 0.031, 0.062, 0.125, and 0.25 mg/kg nicotine or 0.5, 1.0, 1.5, and 2.0 g/kg ethanol. nicotine and ethanol each caused an increase in the acoustic startle response at the highest and lowest doses tested, respectively. mecamylamine, a nicotinic receptor antagonist, administered in combination with nicotine or ethanol attenuated these increases in acoustic startle responding. nicotine and ethanol, administered together, did not produce greater enhancement of startle than when administered alone. haloperidol (1 mg/kg) was administered in combination with nicotine or ethanol to investigate if dopamine modulated nicotine or ethanol enhancement of acoustic startle. It was found that the increase in acoustic startle responses observed with ethanol or nicotine was attenuated by haloperidol . Thus, ethanol or nicotine may enhance the acoustic startle reflex through a common dopaminergic mechanism.


tacrolimus

ganciclovir

Ganciclovir prophylaxis delays but does not prevent cytomegalovirus infection in renal transplant recipients. Cytomegalovirus (CMV) infection is associated with reduced graft and patient survival among renal transplant recipients. The purpose of this study was to examine the effect of routine prophylaxis with 12 weeks of oral ganciclovir on the incidence of CMV infection in a center that predominantly uses antibody induction together with tacrolimus/mycophenolate mofetil-based maintenance immunosuppressive therapy. The control group consisted of a historical patient cohort transplanted immediately prior to the use of oral ganciclovir prophylaxis. The use of tacrolimus ( 88 % vs 77 % , P=.02 ) and cytolytic therapy ( 81 % vs 46 % , P < .0001 ) was likewise greater among patients who received ganciclovir prophylaxis . CMV infection occurred in 20 (9%) patients in the ganciclovir era and 4 (3%) patients in the preganciclovir era (P=.003). The mean time to CMV infection was longer in patients who received ganciclovir prophylaxis than in patients in the preganciclovir era (23.4 +/- 10.9 weeks vs 9.8 +/- 5.6 weeks, P=.03). We conclude that 12 weeks of ganciclovir prophylaxis delays but does not prevent CMV infection from occurring in renal transplant recipients. These results suggest that with the use of 12 weeks of ganciclovir prophylaxis, vigilance for CMV infection is needed well beyond 24 weeks posttransplant.


gemcitabine

gemcitabine

bevacizumab

cetuximab

First-line treatment for advanced pancreatic cancer. Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011. Pancreatic adenocarcinoma remains a treatment-refractory cancer. Although pancreatic adenocarcinoma is only the 10th most common cause of new cancer in the United States, it is the fourth most common cause of cancer-related death. Most cases are not suitable for resection and a majority is metastatic at presentation. gemcitabine, with or without erlotinib, has been the standard chemotherapy in this setting but the benefit is only modest. Because gemcitabine has been considered a standard treatment for advanced pancreatic cancer for the past decade , several randomized trials have tested the combination of gemcitabine plus a second agent , including platinum based agents , topoisomerase inhibitors , taxanes , bevacizumab and cetuximab , as biologically " targeted " agents . At large this approach has not been successful and novel strategies are clearly needed. In this article, the authors summarizes the data from the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, including: Abstract #175 (review of survival data in a large cohort); Abstract #286 (rapid change in prescriber patterns after the suggestion of benefit of a new regimen, FOLFIRINOX); Abstracts #238, #277, #304, and #315 (phase II trials looking at combinations that utilized EGFR blockade); Abstracts #221, #266, and #284 (phase I/II trials including VEGF blockade, anticoagulation, and traditional Chinese medicines).


Gemcitabine

leucovorin

oxaliplatin

irinotecan

Immunotherapy updates in pancreatic cancer: are we there yet? Pancreatic cancer is a lethal disease and remains one of the most resistant cancers to traditional therapies. Historically, chemotherapy or radiotherapy did not provide meaningful survival benefit in advanced pancreatic cancer. Gemcitabine and recently FOLFIRINOX ( 5-flourouracil , leucovorin , oxaliplatin and irinotecan ) have provided some limited survival advantage in advanced pancreatic cancer . Targeted agents in combination with gemcitabine had not shown significant improvement in the survival. Current therapies for pancreatic cancer have their limitations; thus, we are in dire need of newer treatment options. Immunotherapy in pancreatic cancer works by recruiting and activating T cells that recognize tumor-specific antigens which is a different mechanism compared with chemotherapy and radiotherapy. Preclinical models have shown that immunotherapy and targeted therapies like vascular endothelial growth factor and epidermal growth factor inhibitors work synergistically. Hence, new immunotherapy and targeted therapies represent a viable option for pancreatic cancer. In this article, we review the vaccine therapy for pancreatic cancer.


ampicillin

chloramphenicol

ampicillin

penicillin

penicillin

[Bactericidal action of chloramphenicol and synergism with beta-lactam antibiotics]. Excellent clinical results were observed with the combination therapy of chloramphenicol with beta-lactam-antibiotics in the treatment of purulent meningitis. This came as a surprise as bacteriostatic antibiotics like chloramphenicol are commonly thought to antagonize the bactericidal action of penicillin or ampicillin. We reevaluated the mode of action of chloramphenicol against the three most common meningeal pathogens after the newborn period. chloramphenicol was found to be bactericidal against H. influenzae, Streptococcus pneumoniae and Neisseria meningitidis at clinically achievable levels in the CSF. In addition chloramphenicol showed synergistic action with ampicillin against H. influenzae which can possess clinical relevance particularly with the high inoculum of 10(7) organisms/ml which is frequently seen in bacterial meningitis. No synergism was found against Pneumococci and Meningococci but also no antagonism of the lower MIC and MBC values seen with ampicillin and penicillin G. The combination of chloramphenicol with either penicillin or ampicillin constitutes a clinically successful therapeutic regimen which is now also proven by in vitro investigations .


nifedipine

hydralazine

Treatment of acute severe hypertension: current and newer agents. Approximately 72 million people in the US experience hypertension. Worldwide, hypertension may affect as many as 1 billion people and be responsible for approximately 7.1 million deaths per year. It is estimated that approximately 1% of patients with hypertension will, at some point, develop a hypertensive crisis. Hypertensive crises are further defined as either hypertensive emergencies or urgencies, depending on the degree of blood pressure elevation and presence of end-organ damage. Immediate reduction in blood pressure is required only in patients with acute end-organ damage (i.e. hypertensive emergency) and requires treatment with a titratable, short-acting, intravenous antihypertensive agent, while severe hypertension without acute end-organ damage (i.e. hypertensive urgency) is usually treated with oral antihypertensive agents. The primary goal of intervention in a hypertensive crisis is to safely reduce blood pressure. The appropriate therapeutic approach of each patient will depend on their clinical presentation. Patients with hypertensive emergencies are best treated in an intensive care unit with titratable, intravenous, hypotensive agents. Rapid-acting intravenous antihypertensive agents are available, including labetalol, esmolol, fenoldopam, nicardipine and sodium nitroprusside. Newer agents, such as clevidipine and fenoldopam, may hold considerable advantages to other available agents in the management of hypertensive crises. Sodium nitroprusside is an extremely toxic drug and its use in the treatment of hypertensive emergencies should be avoided. Similarly , nifedipine , nitroglycerin and hydralazine should not to be considered first-line therapies in the management of hypertensive crises because these agents are associated with significant toxicities and/or adverse effects .


Bendamustine

rituximab

Bendamustine in chronic lymphocytic leukemia and refractory lymphoma. bendamustine is a water-soluble, bifunctional chemotherapeutic agent with characteristics of both an alkylator and a purine analog. bendamustine combined with rituximab in vitro shows synergistic effects against various leukemia and lymphoma cell lines. Clinical trials supporting these results show that bendamustine plus rituximab is highly effective in relapsed and refractory patients with indolent lymphoma. The results have been found in rituximab-naive, rituximab-pretreated, and rituximab-refractory patients with excellent response rates and toxicity profiles. Bendamustine is effective both with rituximab and as a monotherapy in rituximab-refractory patients . Interim results from a phase III, randomized trial comparing bendamustine and rituximab to a standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab regimen suggest that combination bendamustine and rituximab may provide a viable alternative for treatment of many indolent lymphomas.


gefitinib

topotecan

mitoxantrone

topotecan

Gefitinib ("Iressa", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance. gefitinib ("Iressa", ZD1839) is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor, and the single agent is clinically effective in non-small cell lung cancer. Although gefitinib combined with various cytotoxic agents has been reported to enhance cytotoxicity in vitro and in mouse models, the mechanism remains undetermined. Here, to explore the mechanism with topoisomerase I inhibitors, we focused on the efflux pump of the breast cancer resistance protein (BCRP/ABCG2), and then examined whether gefitinib restored drug sensitivity in multidrug-resistant cancer cells overexpressing BCRP. We used PC-6 human small cell lung cancer cells and multidrug-resistant PC-6/SN2-5H cells selected with SN-38 of the active metabolite of irinotecan, and BCRP-overexpressing MCF-7/MX cells selected with mitoxantrone and BCRP cDNA transfectant MCF-7/clone 8 cells. Drug sensitivity against anticancer drugs was determined by tetrazolium dye assay, and intracellular topotecan accumulation by FACScan. The topotecan transport study was done using the plasma membrane vesicles of PC-6/SN2-5H cells. The resistant PC-6/SN2-5H cells overexpressed BCRP but not epidermal growth factor receptor mRNA. Ten micromoles of gefitinib reversed topotecan , SN-38 , and mitoxantrone resistance , and increased the intracellular topotecan accumulation in the resistant cells but not in the parental cells . Furthermore, gefitinib inhibited the topotecan transport into the vesicles, and the K(i) value was 1.01 +/- 0.09 micromol/L in the Dixon plot analysis, indicating direct inhibition of BCRP by gefitinib. However, gefitinib was not transported into the vesicles with the high-performance liquid chromatography method. These results indicate that gefitinib reverses BCRP-mediated drug resistance by direct inhibition other than competitive inhibition as a BCRP substrate. Combination of gefitinib and topoisomerase I inhibitors could be clinically effective in cancers expressing BCRP.


vincristine

cyclophosphamide

methotrexate

adriamycin

prednisolone

The effects of multiple combination chemotherapy with vincristine , cyclophosphamide ( Endoxan ) , methotrexate , 5-fluorouracil , adriamycin and prednisolone ( VEMFAH ) for advanced breast cancer . Thirty-eight patients with advanced breast cancer were treated with the 'VEMFAH' multiple-drug combination chemotherapy, consisting of vincristine (V), cyclophosphamide (Endoxan; E), methotrexate (M), 5-fluorouracil (F), adriamycin (A), and prednisolone (H). Disease response was evaluated by the UICC criteria. Among the 35 evaluable cases, 4 complete responses (CR), 23 partial responses (PR), 2 cases of no change (NC), and 6 of progressive disease (PD) were observed. The response rate (CR + PR) was 77.1%. The median duration of response was 52 weeks (8-192 weeks) or 12 months. In 32 patients who received more than two courses of therapy the 50% survival time of responders was 27.0 months, which was significantly longer than the 10.3 months of nonresponders (P less than 0.05). Except for 2 patients who developed myocardial damage, the therapy was never terminated because of side effects. Cumulative cardiotoxicity was not apparent in this study. This multiple-drug combination chemotherapy with 'VEMFAH' is concluded to be an effective treatment for advanced and disseminated breast cancer.