Alternative Drug Therapies Research Articles

Panitumumab-Conjugated Pt-Drug Nanomedicine for Enhanced Efficacy of Combination Targeted Chemotherapy against Colorectal Cancer.

Targeted combination chemotherapy (TCT) has recently been used to increase the induction of tumor cell death. In particular, the combination of Panitumumab and the platinum (Pt)-derived chemotherapeutic drug Oxaliplatin is clinically effective against KRAS and BRAF wild-type colorectal cancer (CRC) cells that overexpress epidermal growth factor receptors, and significantly greater efficacy is observed than with either drug alone. However, low accumulation of Pt drug in tumor sites prevents achievement of ideal efficacy. To develop an alternative drug therapy that achieves the ideal efficacy of TCT, the novel nanomedicine NANOPt-Pan using self-assembled dichloro(1,2-diaminocyclohexane)Pt(II)-modified Panitumumab is generated. Treatments with NANOPt-Pan lead to significant accumulation of Pt drug and Panitumumab in tumors, reflecting enhanced permeability and retention effect, active targeting, and sustained circulation of the Pt drug in the blood. In addition, NANOPt-Pan has excellent in vivo anti-CRC efficacy. These data indicate that NANOPt-Pan has high potential as a candidate nanomedicine for CRC.

The Incidence of hypotension with continuous infusion atracurium compared to cisatracurium in the Intensive Care Unit.

Background:A drug shortage of cisatracurium led to use of atracurium as an alternative neuromuscular blocker (NMB). Cisatracurium may be preferred due to less histamine release and potentially less hypotension. The study purpose is to compare the incidence of hypotension with continuous infusion atracurium to continuous infusion cisatracurium in ICU patients.Materials and Methods:This retrospective cohort analysis reviewed 119 ICU patients who received either continuous infusion atracurium (56) or cisatracurium (63). The primary outcome was the incidence of hypotension (mean arterial pressure <60mmHg). Secondary outcomes included: incidence of blood pressure decrease of >20% from baseline, time to first hypotensive episode, treatment for hypotension during NMB use, hospital mortality, ICU and hospital length of stay (LOS), duration of mechanical ventilation (MV), and NMB duration.Results:Hypotension occurred in 64.3% of atracurium patients and 58.7% of cisatracurium patients (P = 0.58), with 60.7% experiencing >20% drop in blood pressure in atracurium group and 54.0% in cisatracurium (P = 0.58). Median time to first hypotensive episode was 9.4[Interquartile range 1.17-19.7] hours atracurium and 4.4[1.5-13.9] hours cisatracurium (P = 0.36). There were no differences between atracurium and cisatracurium groups respectively for median ICU LOS (10.5 days and 12.4 days, P = 0.34), hospital LOS (14.0 days and 17.7 days, P = 0.37), MV duration (9.3 days and 10.5 days, P = 0.43), infusion duration (34.5 hours and 25 hours P = 0.27), or hospital mortality (62.5% and 53.9%, P = 0.336). Hypotension treatment was similar between groups.Conclusions:The incidence of hypotension was similar between atracurium and cisatracurium. Critical drug shortages may provide an opportunity to study alternative drug therapy.

Synergistic antibacterial effect of apigenin with β-lactam antibiotics and modulation of bacterial resistance by a possible membrane effect against methicillin resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) infections are easily spread among infected patients, where resistance has dramatically increased resulted in serious health issues. Therefore, there is a need to develop alternative natural or combination drug therapies. Apigenin (AP) is a natural poly phenolic flavonoid has been found to possess many beneficial biological actions. The aim of this study was to investigate the anti-MRSA efficacy and synergistic effect of apigenin (AP) and in combination with ampicillin (AM) and ceftriaxone (CEF). The antibacterial activity of apigenin was assessed by the broth macro dilution, checkerboard micro dilution method and time-kill assay. The mode of action was studied by outer and inner membrane permeabilisation assays, scanning electron microscopy and transmission electron microscopy. The minimum inhibitory concentration (MIC) of apigenin against gram positive and gram negative strain ranged from 32.5 to 62.5µg/ml. In checkerboard method apigenin markedly reduced the MIC of the antibiotics ampicillin 800 µg/ml shifted to 107 µg/ml (AM+AP) and ceftriaxone 58 µg/ml shifted to 2.6 µg/ml (CEF+AP) against MRSA. The synergistic activity of ampicillin and ceftriaxone plus apigenin combinations with FIC indices (CI) between 0.18-0.47. The modulation of methicillin-resistance by apigenin significantly enhanced the activities of ampicillin and ceftriaxone. The result of time-kill assays of the two drug combinations AM +AP and CEF+AP against MRSA showed significant inhibitory effect and reduced the colony count by approximately 99% after 8 h The results for outer membrane (OM) and inner membrane (IM) permeabilization showed that ampicillin and ceftriaxone in combination with apigenin damaged MRSA cytoplasmic membrane and caused subsequent leakage of intracellular constituents. Electron microscopy clearly showed that the above said combination also caused marked morphological damage of cell wall, cell shape and plasma membrane of this strain. From these results, it can be concluded that apigenin has the synergistic effect with ampicillin and ceftriaxone to reverse bacterial resistance against MRSA.

The Utility of Tacrolimus in the Management of Adults with Difficult-to-Treat Autoimmune Hepatitis: Review of Literature

Introduction: There is paucity of data on alternative drug therapies for patients with autoimmune hepatitis (AIH). Tacrolimus (TAC) has been suggested as a promising salvage agent. Herein we did a literature review on the use of TAC therapy in adults with AIH. Methods: A literature search for studies with keywords “autoimmune hepatitis” and “tacrolimus” was performed. Case reports, and studies of AIH post-transplant, and AIH in children were excluded. The diagnosis of AIH was made based on the criteria established by the International Autoimmune Hepatitis Group. Details of pre- and post- treatment liver biopsy was collected when available. Results: The seven reviewed articles, along with our own patient population, yielded 113 subjects total. Sixty-six of these patients were female, and 42 were male. Average ages ranged from 26 to 63 years. Sixty four percent of the patients were positive for anti-nuclear antibodies, and 41% were positive for antismooth muscle antibodies. 98 (86%) were reported to have pre-treatment liver biopsy, of whom 34 (30%) had stage 3 or 4 fibrosis and 36 (29%) had grade 3 or 4 inflammation. Dosing of TAC were between 1 and 6 mg/day. Tacrolimus was discontinued in 16 (14%) patients for various reasons, mostly due to noncompliance. Renal function remained stable in the 72% of patients. Eighty-seven (76%) patients demonstrated biochemical response to treatment, defined as decrease in AST and ALT serum concentrations. Post therapy liver biopsy was obtained for 44 patients, and 27 (23%) of these patients were noted to have histological remission according to grade of inflammation or stage of fibrosis. Conclusion: Tacrolimus is relatively effective in the treatment of AIH refractory to traditional therapy with corticosteroid plus azathioprine. It appears that liver function can be enhanced at minimal cost to renal function.

CPR: advanced life support

Cardiopulmonary arrest is an emergency situation which can present to any veterinary clinic at any time. The RECOVER guidelines (2012) are an evidence-based consensus for current cardiopulmonary resuscitation (CPR) recommendations for veterinary patients. Basic life support (BLS) includes circulation, airway and breathing. Advanced life support measures involve the administration of emergency drug therapy and cardiorespiratory monitoring. Alternative drug therapies may be beneficial such as electrolyte supplementation or drug antagonist administration. Both electrocardiogram (ECG) and end tidal carbon dioxide (ETCO2) monitoring are recommended during CPR efforts and the veterinary nurse will play a vital role in ensuring that trends are observed. Debriefing is an important part of any CPR event so that the team can critique one another and improve performance in the future.

Luteolin potentiates the effects of aminoglycoside and β-lactam antibiotics against methicillin-resistant Staphylococcus aureus in vitro.

Methicillin-resistant Staphylococcus aureus (MRSA) infection has become a serious clinical problem worldwide, and alternative natural or combination drug therapies are required for its treatment. The aim of the present study was to examined the antimicrobial activity of luteolin (LUT) against MRSA. Luteolin is a polyphenolic flavonoid compound with a wide spectrum of biological activities. The antimicrobial activities of LUT and the antibiotics ampicillin (AM), oxacillin (OX) and gentamicin (GT), used alone or in combination, were evaluated against five clinical MRSA isolates and two reference strains using a minimum inhibitory concentration (MIC) assay, MTT colorimetric assay, checkerboard dilution test and time-kill assay. The MIC of LUT against all strains was found to be 62.5 µg/ml. The combinations of LUT and antibiotics exhibited a synergistic effect against MRSA in the majority of cases, as determined by the checkerboard method. Time-kill curves revealed that a combination of LUT with AM, OX or GT significantly reduced bacterial counts, which dropped below the lowest detectable limit after 24 h. These results indicate that LUT potentiates the effects of β-lactam and aminoglycoside antibiotics against MRSA.

Matrix Metalloproteinases (MMP), a Major Responsible Downstream Signaling Molecule for Cellular Damage - A Review

Matrix metalloproteinase (MMPs) family members are well known signaling molecules. MMPs are involved in tissue remodeling and are affiliated with several pathological, pharmacological and physiological processes. In addition, these also facilitate other downstream pathways such as cellular inflammation. However, members of this family are being investigated in several diseases as a clinical marker. These proteins are often found responsible in the development of various dysfunctions such as cardiovascular, kidney, liver, and nervous system disorder. Evidences also suggest that MMPs take part in organ rejections during organ transplantations. Besides, MMPs also trigger accumulation of unnecessary immune cells which further exacerbate the situation resulting in a drug therapy failure. Furthermore, many harmful downstream kinases are induced by MMPs signaling. Therefore, it has been an imperative issue to establish a noble and alternative drug therapy against MMPs family for ensuring safety against several lives threatening phenomenon. Thus this review will explain the molecular mechanism of MMP family members and few possible drug therapies modulating MMPs function.

In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia.

Key points The mechanism of therapeutic efficacy of flecainide for catecholaminergic polymorphic ventricular tachycardia (CPVT) is unclear.Model predictions suggest that Na+ channel effects are insufficient to explain flecainide efficacy in CPVT.This study represents a first step toward predicting therapeutic mechanisms of drug efficacy in the setting of CPVT and then using these mechanisms to guide modelling and simulation to predict alternative drug therapies. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by fatal ventricular arrhythmias in structurally normal hearts during β‐adrenergic stimulation. Current treatment strategies include β‐blockade, flecainide and ICD implementation – none of which is fully effective and each comes with associated risk. Recently, flecainide has gained considerable interest in CPVT treatment, but its mechanism of action for therapeutic efficacy is unclear. In this study, we performed in silico mutagenesis to construct a CPVT model and then used a computational modelling and simulation approach to make predictions of drug mechanisms and efficacy in the setting of CPVT. Experiments were carried out to validate model results. Our simulations revealed that Na+ channel effects are insufficient to explain flecainide efficacy in CPVT. The pure Na+ channel blocker lidocaine and the antianginal ranolazine were additionally tested and also found to be ineffective. When we tested lower dose combination therapy with flecainide, β‐blockade and CaMKII inhibition, our model predicted superior therapeutic efficacy than with flecainide monotherapy. Simulations indicate a polytherapeutic approach may mitigate side‐effects and proarrhythmic potential plaguing CPVT pharmacological management today. Importantly, our prediction of a novel polytherapy for CPVT was confirmed experimentally. Our simulations suggest that flecainide therapeutic efficacy in CPVT is unlikely to derive from primary interactions with the Na+ channel, and benefit may be gained from an alternative multi‐drug regimen.

Combination of Silver Nanoparticles and Curcumin Nanoparticles for Enhanced Anti-biofilm Activities.

Biofilm tolerance has become a serious clinical concern in the treatment of nosocomial pneumonia owing to the resistance to various antibiotics. There is an urgent need to develop alternative antimicrobial agents or combination drug therapies that are effective via different mechanisms. Silver nanoparticles (AgNPs) have been developed as an anti-biofilm agent for the treatment of infections associated with the use of mechanical ventilations, such as endotracheal intubation. Meanwhile curcumin, a phenolic plant extract, has displayed natural anti-biofilm properties through the inhibition of bacterial quorum sensing systems. The aim of this study was to investigate the possible synergistic/additive interactions of AgNPs and curcumin nanoparticles (Cur-NPs) against both Gram-negative (Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) microorganisms. The combination of AgNPs and Cur-NPs (termed Cur-SNPs) at 100 μg/mL disrupted 50% of established bacterial biofilms (formed on microtiter plates). However, further increase in the concentration of Cur-SNPs failed to effectively eliminate the biofilms. To achieve the same effect, at least 500 μg/mL Cur-NP alone was needed. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) revealed that combination therapy (Cur-SNPs) was the most potent to eradicate preformed biofilm compared to monodrug therapy. These agents are also nontoxic to healthy human bronchial epithelial cells (BEAS2B).

Ginsenoside Rd Improves Learning and Memory Ability in APP Transgenic Mice.

Alzheimer's disease (AD) is a complicated neurodegenerative disease which causes memory loss and dementia. Many researchers have revealed the vital roles of β-amyloid proteins (Aβ) in the proceeds of AD. Aβ deposition in AD patients' brains might function as immune stimulus, and inflammation is believed to play an important role in AD pathologically. We experimentally used amyloid β-protein precursor (APP) transgenic (Tg) mice in this study to further clarify the neuroprotective effects of ginsenoside Rd on AD and its possible mechanisms. It was found that Rd could improve learning and memory ability in APP Tg mice, probably through inhibiting the transcription activity of NFκB. With the activation of the NFκB pathway being suppressed, the reduction of pro-inflammatory cytokines and the generation of protective factors had been increased ultimately. In conclusion, Rd had a neuroprotective effect on APP Tg mice, and it can be used as an alternative drug therapy in AD patients for their memory dysfunction.

Abstract 4978: Identification and therapeutic targeting of signaling pathways in Ruxolitinib resistant cells

Abstract Ruxolitinib/Jakafi is a current front line therapy for JAK2-mediated myelofibrosis. Like other chemotherapy agents, prolonged use of the drug confers resistance. However, the mechanisms that allow for the development of Ruxolitinib resistance are poorly understood. Moreover, there is a paucity of alternative treatment options for these drug resistant patients. To address these timely issues, we first took BaF3/JAK2-V617F cells and selected for a Ruxolitinib resistant variant. After selection through increasing concentrations of Ruxolitinib, the cells grow quite rapidly in 500 nM of the drug; normal IC50 is 125 nM. Both the parental and drug resistant cell lines were then subjected to NGS of the whole exome. In the parental cells, JAK2-V617F is the driver mutation. Pathways downstream of JAK2-V617F include the activation of STAT3, STAT5, PI3K/AKT/NFkB and to some extent the SHC1/ERK pathway. Analysis of the variant strain revealed that the cells acquired Ruxolitinib resistance by tuning down all the key pathways downstream of the driver JAK2 mutation. There was low copy number and a consequent knockdown of key genes downstream of JAK2 including STAT3, STAT5, PI3K, SOS1, ELK1, FOS, and MCL1. Additionally there were other newly acquired genomic aberrations including knockdown of dephosphatases DUSP1, PTPRJ, PTPRR; low copy number of epigenetics regulating genes such as TET2 and KAT5; a knockdown of regulators of beta catenin pathway; and also an increase in the copy number of EGFR. Thus, in this model of JAK2 driven tumorigenesis, the cell is dynamically reacting to Ruxolitinib by decreasing flux through the JAK2 signaling pathway and tuning up other pathways that support growth and survival. The signaling network maps for both cell lines were then overlaid onto a list of FDA approved therapeutics that are used for other indications. Predictive simulation modeling of the dys-regulated signaling networks suggested that Roflumilast, a PDE4 inhibitor, and Chloroquine, an autophagy inhibitor, would be highly efficacious in reducing cell viability. When the parental cells were treated individually with Chloroquine (0-40 uM) or Roflumilast (0-40 uM), cell viability was reduced dose-dependently; Chloroquine IC50 = 15 uM and Roflumilast IC50 = 25 uM. Furthermore, when used in combination, the effect of the two agents was synergistic. These drugs also showed efficacy in the Ruxolitinib resistant cell line, but at higher doses. Specifically, the IC50 for Chloroquine doubled to 30 uM in the drug resistant strain while 20 uM Roflumilast only reduced cell viability by ∼25%. Overall, we have created a cell model for Ruxolitinib resistance and identified signaling networks that are dys-regulated in both the drug sensitive and drug resistant cells. Furthermore, using predictive simulation technology, we have begun to identify alternative drug therapies that effectively reduce the viability of both Ruxolitinib sensitive and Ruxolitinib resistant cells. Citation Format: Peter P. Sayeski, Shireen Vali, Ansu Kumar, Neeraj Singh, Susumu Kobayashi, Taher Abbasi. Identification and therapeutic targeting of signaling pathways in Ruxolitinib resistant cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4978. doi:10.1158/1538-7445.AM2015-4978

Effect of Pin1 inhibitor juglone on proliferation, migration and angiogenic ability of breast cancer cell line MCF7Adr

This study aimed to evaluate the effects of Pin1 inhibitor Juglone on proliferation, migration and the angiogenic ability of breast cancer cell line MCF7Adr. MCF7Adr cells were cultured and separately treated with Pin1 inhibitor Juglone (treatment group) and DMEM without drug (control group). The cell cycle was examined by flow cytometry. Cell migration was measured by wound-healing assay. Cyclin E protein content was detected by Western blotting. The angiogenesis factor vascular endothelial growth factor (VEGF) in cell media was determined by enzyme linked immunosorbent assay. The results showed that the percentage of cells in G2/M phase in treatment group was significantly higher than that in control group (25.5% vs. 10.1%, P<0.05), and that in G0/G1 phase and S stage in treatment group was significantly lower than that in control group (40.5% vs. 48.2%, and 33.7% vs. 41.7%, P<0.05). Cyclin E protein content in treatment group was significantly lower than that in control group (39.2 ± 7.4 vs. 100 ± 23.1, P<0.05). (A0-A24)/A0 value in treatment group was significantly lower than that in control group (23.9 ± 3.8 vs. 100 ± 14.4, P<0.05). VEGF-A, -B, and -C contents in cell media of treatment group were significantly lower than those in control group (P<0.05). It was suggested that Pin1 inhibitor Juglone can effectively inhibit the proliferation, migration and the angiogenic ability of MCF7Adr cells, and can be used as an alternative drug therapy for breast cancer.

WHY "AMYLOID CASCADE" IS A MISGUIDED HYPOTHESIS OF ALZHEIMER'S DEMENTIA ETIOLOGY

Background: Alzheimer’s dementia(AD) refers to mind disorders characterized by a progressive and irreversible memory loss and mental decline. Causes for AD are not know, and there is no cure or treatment for AD Methods: We argue, research and development of treatments for AD, the way it has been done,is too limited and takes too long time to have any impact on the disease. We revisit recent clinical drug trials to understand why the trials failed and,indeed, why they could not have succeeded in the first place. Results: Did the trials fail simply because our ideas about AD etiology are not correct.Did the trials fail because what was done was too little or too late, at a point of no return for AD.We review alternative on-going drug trials and therapies for preclinical AD, that is,on asymptomatic patients and people at risk, designed to prevent or slow the progression of ADConclusions:We predict these trials are going to fail too because amyloid plaques and neurofibrillary tangles are not causing AD but are the outcome of brain cells dying.

Hematological and Biochemical Parameter Changes Related to Methotrexate Therapy

A clinical trial was conducted to evaluate the hematological and biochemical changes related to methotrexate in the treatment of lichen planus. A total of forty four patients with lichen planus, attendign at the department of Dermatology and Venereology, Bangabandhu Seikha Mujib Medical University (BSMMU), Dhaka, Bangladesh durign the period of january 2009 to December 2010 were enrolled in this study purposively. Of them, 23 patients in group-A (case group) and 21 patients in group-B (control group) were selected randomly. The case group was treated with oral methotrexate and the control group was trated with betamethasone oral mini- pulse therapy. A decreasing trend of hemoglobin level and platet count was observed between two groups. An increasing trend of SGPT was observed among the case adn control up to 6th week of observation and then it decreased. This study also revealed abnormlity in platelet count and liver function test in both the groups. But the overall effects were less in cases than control. So it cand be concluded from this study that methtrexate can be used as an alternative saf drug therapy for the treatmetn of lichen planus. DOI: http://dx.doi.org/10.3329/bmj.v40i3.18674 Bangladesh Medical Journal 2011 Vol.40(3):40-43

In vitro synergistic effect of curcumin in combination with third generation cephalosporins against bacteria associated with infectious diarrhea.

Diarrhea is one of the leading causes of morbidity and mortality in humans in developed and developing countries. Furthermore, increased resistance to antibiotics has resulted in serious challenges in the treatment of this infectious disease worldwide. Therefore, there exists a need to develop alternative natural or combination drug therapies. The aim of the present study was to investigate the synergistic effect of curcumin-1 in combination with three antibiotics against five diarrhea causing bacteria. The antibacterial activity of curcumin-1 and antibiotics was assessed by the broth microdilution method, checkerboard dilution test, and time-kill assay. Antimicrobial activity of curcumin-1 was observed against all tested strains. The MICs of curcumin-1 against test bacteria ranged from 125 to 1000 μg/mL. In the checkerboard test, curcumin-1 markedly reduced the MICs of the antibiotics cefaclor, cefodizime, and cefotaxime. Significant synergistic effect was recorded by curcumin-1 in combination with cefotaxime. The toxicity of curcumin-1 with and without antibiotics was tested against foreskin (FS) normal fibroblast and no significant cytotoxicity was observed. From our result it is evident that curcumin-1 enhances the antibiotic potentials against diarrhea causing bacteria in in vitro condition. This study suggested that curcumin-1 in combination with antibiotics could lead to the development of new combination of antibiotics against diarrhea causing bacteria.

Evaluation of anthelmintic activity and in silico PASS assisted prediction of Cordia dichotoma (Forst.) root extract.

Background:Worm infection and associated complications are severe problems that afflict a large population worldwide. Failure of synthetic drugs in worm infections because of drug resistance has made alternative drug therapy desirable. Cordia dichotoma (Forst.) is an ethnomedicinal plant which is rich in several secondary metabolites. Traditionally, the plant has been claimed to have high medicinal properties including antimicrobial activity and cytotoxicity.Materials and Methods:The study begun with an aim to explore plant-based natural anthelmintic agents against Pheretima posthuma, an Indian earthworm. Methanol extract of the drug was obtained by successive soxhlet extraction. The extract was tested for different phytochemicals. Worms were exposed to 10 mg/ml, 25 mg/ml, 50 mg/ml, and 75 mg/ml concentrations of extract and standard drug, albendazole. A software-based tool, prediction of activity spectra for substances was used to estimate anthelmintic efficacy of plant metabolites.Result:The phytochemical analysis revealed presence of alkaloids, tannins, glycosides, saponins, flavonoids, and phenols. The extract showed dose-dependent effects, affecting worm motility, viability, and mortality. It was also found that the biological activity spectrum of the plant phytoconstituents such as octacosanol, lupeol, caffeic acid, and hentricontanol were >0.5 (probable activity > 0.5).Conclusion:The findings of the present work suggest that the extract of C. dichotoma significantly interferes with motility pattern of P. posthuma. The paralysis and mortality of P. posthuma might be due to the combined effects different phytoconstituents. The extract of C. dichotoma promises natural sources to control worm infection.

Study of Aetiology and Anti-biogram of Uropathogens in Children-A Retrospective Analysis

Urinary Tract Infections (UTIs) are the most common serious bacterial infections which are seen during infancy. The aim of the present study was to evaluate aetiology, and antimicrobial resistance patterns among infants and children who approached our hospital for treatment of UTIs. In this observational study which was carried out from 2007 to 2010, 1575 urine samples which were collected from children with suspected UTIs were studied. Demographic characteristics, aetiological agents and antimicrobial resistance were evaluated. UTIs were more common in the 0-1 year age group, among males. Among females, UTIs were commonly seen after 2 years of life. The most common isolated pathogen was Escherichia coli spp (45.12%), followed by Klebsiella spp (18.17%) and Enterococcus spp (9.23%). Isolated pathogens were highly resistant to ampicillin, co-trimoxazole, and norfloxacin (82%-98%) and highly sensitive to gentamicin (83%),amikacin (76.5%), and nitrofurantoin (71.5%). The most common pathogen which caused UTIs in children was E. coli spp. The isolated pathogens were highly resistant to commonly used antibiotics, ampicillin and co-trimoxazole, while they were highly sensitive to gentamicin, amikacin and nitrofurantoin. So, these antibiotics may be used as alternative drug therapies for the treatment of UTIs.

Acute and 14-Day Hepatic Venous Pressure Gradient Response to Carvedilol and Nebivolol in Patients With Liver Cirrhosis

Alternative drug therapies are needed for the treatment of portal hypertension. The aim of this randomized study was to evaluate and compare the effects of carvedilol and nebivolol on the hepatic venous pressure gradient (HVPG) response in the patients with liver cirrhosis. In total, 20 cirrhotic patients were randomized into 2 groups and treated with carvedilol (n=10) or nebivolol (n=10). HVPG was measured at baseline, 60 minutes after the administration of carvedilol (25 mg) or nebivolol (5 mg), and after 14 days of carvedilol (25 mg) or nebivolol (5 mg) administered daily. RESULTS. Carvedilol significantly reduced HVPG from 22.2 mm Hg (SD, 4.4) to 15.2 mm Hg (SD, 3.7) after 60 minutes and to 16.4 mm Hg (SD, 2.9) after 14 days (P<0.01). Nebivolol reduced HVPG from 19.7 mm Hg (SD, 2.5) to 15.7 mm Hg (SD, 2.6) and 16.7 mm Hg (SD, 3.2), respectively (P<0.02). Carvedilol effectively decreased HVPG in a greater proportion of the patients after an acute probe (88% vs. 57%) and after 14 days of the treatment (88% vs. 28%, P<0.05) in comparison with nebivolol. Carvedilol and nebivolol reduce HVPG in cirrhotic patients; however, the effect of carvedilol on the HVPG reduction might be superior to that of nebivolol, especially after 14 days of treatment.

Maintenance therapy with calcium channel blockers for preventing preterm birth after threatened preterm labour

Calcium channel blocker maintenance therapy is one of the types of tocolytic therapy that may be used after an episode of threatened preterm labour (and usually an initial dose of tocolytic therapy) in an attempt to prevent the onset of further preterm contractions. To assess the effects of calcium channel blockers as maintenance therapy on preventing preterm birth after threatened preterm labour. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2013) and reference lists of retrieved studies. Randomised controlled trials of calcium channel blockers used as maintenance therapy to prevent preterm birth after threatened preterm labour, compared with placebo or no treatment. Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of included studies. We included six trials that enrolled 794 women and their babies and all assessed nifedipine as calcium channel blocker maintenance therapy. The six trials were judged to be at a moderate risk of bias overall. No differences in the incidence of preterm birth (risk ratio (RR) 0.97; 95% confidence interval (CI) 0.87 to 1.09; five trials, 681 women), birth within 48 hours of treatment (RR 0.46; 95% CI 0.07 to 3.00; two trials, 128 women) or neonatal mortality (average RR 0.75; 95% CI 0.05 to 11.76; two trials, 133 infants) were seen when nifedipine maintenance therapy was compared with placebo or no treatment. No stillbirths were reported in the one trial that provided data for this outcome. No trials reported on longer-term follow-up of infants.Women receiving nifedipine maintenance therapy were significantly more likely to have their pregnancy prolonged (mean difference (MD) 5.35 days; 95% CI 0.49 to 10.21; four trials, 275 women); however, no differences between groups were shown for birth at less than 34 weeks' gestation, birth at less than 28 weeks' gestation, birth within seven days of treatment, or gestational age at birth. No significant differences were shown between the nifedipine and control groups for any of the secondary neonatal morbidities reported. Similarly, no significant differences were seen for the outcomes relating to the use of health services, except for in one trial, where infants whose mothers received nifedipine were significantly more likely to have a longer length of hospital stay as compared with infants born to mothers who received a placebo (MD 14.00 days; 95% CI 4.21 to 23.79; 60 infants). Based on the current available evidence, maintenance treatment with a calcium channel blocker after threatened preterm labour does not prevent preterm birth or improve maternal or infant outcomes.

Alternative drug therapies are superior to epidermal growth factor receptor -targeted chemotherapeutic drug responses in non-small cell lung cancer

Cancer is one of the major dreaded diseases causing high mortality. Lung cancer is second in position of all cancer related deaths and mainly divided into two morphologic sub-types: small-cell lung cancer and non-small cell lung cancer (NSCLC). NSCLC is an aggressive neoplasm which hardly responds to any conventional chemotherapy. Epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinase that is mainly over-expressed in NSCLC. EGFR is mainly involved in the pathogenesis and progression of different carcinoma. In vivo and in vitro studies suggest that EGFR and EGF like peptides are often over-expressed in human NSCLC and these proteins are able to induce cell transformation. The conventional therapies mostly inhibit the EGFR activity and expression level in human NSCLC with the use of some EGFR-inhibitors like HKI-272, EKB569, CL-387785 etc. and some synthetic chemotherapeutic drugs like erlotinib, gefitinib, plumbagin, docetaxel, cisplatin etc., alone or in combination of two or more drugs. These therapies selectively act by competitive inhibition of the binding of adenosine triphosphate to the tyrosine kinase domain of the EGFR, resulting in inhibition of the EGFR signaling pathway. But these chemotherapeutic drugs have some cytotoxic activities to the normal cells and have some adverse side-effects. Recent studies on some traditional alternative therapies including some herbal and plant extracts, active ingredients like curcumin, different homeopathic drugs, etc. can target EGFR-signalling in NSCLC with less toxic side-effects are being currently developed.