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Drug Combinations (drug + combination)
Selected AbstractsRelative mutagenic potencies of several nucleoside analogs, alone or in drug pairs, at the HPRT and TK loci of human TK6 lymphoblastoid cells,ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3-4 2007Meghan M. Carter Abstract Experiments were performed to investigate the impact of didanosine (ddI), lamivudine (3TC), and stavudine (d4T) on cell survival and mutagenicity in two reporter genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK), using a cell cloning assay for assessing the effects of individual nucleoside analogs (NRTIs)/drug combinations in human TK6 B-lymphoblastoid cells. Three-day treatments with 0, 33, 100, or 300 ,M ddI, 3TC, or ddI-3TC produced positive trends for increased HPRT and TK mutant frequencies. While dose-related trends were too small to reach significance after treatments with d4T or d4T-3TC, pairwise comparisons with control cells indicated that exposure to 100 ,M d4T or d4T-3TC caused significant elevations in HPRT mutants. Measurements of mutagenicity in cells exposed to d4T (or d4T-3TC) were complicated by the cytotoxicity of this NRTI. Enhanced increases in mutagenic responses to combined NRTI treatments, compared with single drug treatments, occurred as additive to synergistic effects in the HPRT gene of cells exposed to 100 ,M ddI-3TC or 100 ,M d4T-3TC, and in the TK gene of cells exposed to 100 or 300 ,M ddI-3TC. Comparisons of these data to mutagenicity studies of other NRTIs in the same system (Meng Q et al. [2000c]: Proc Natl Acad Sci USA 97:12667,126671; Torres SM et al. [2007]: Environ Mol Mutagen) indicate that the relative mutagenic potencies for all drugs tested to date are: AZT-ddI > ddI-3TC > AZT-3TC , AZT-3TC-ABC (abacavir) > AZT ,ddI > d4T-3TC > 3TC > d4T , ABC. These collective data suggest that all NRTIs with antiviral activity against HIV-1 may cause host cell DNA damage and mutations, and impose a cancer risk. Environ. Mol. Mutagen., 2007. © 2007 Wiley-Liss, Inc. [source] Rationale and Technique for Single and Multiple Drug Combinations in Long-term Intrathecal InfusionsPAIN PRACTICE, Issue 1 2001Leland Lou MPH First page of article [source] , -hederin potentiates 5-FU antitumor activity in human colon adenocarcinoma cellsPHYTOTHERAPY RESEARCH, Issue 10 2008Sok-Siya Bun Abstract The aim of this study was to investigate the ability of , -hederin to improve the efficacy of widely prescribed 5-fluorouracil (5-FU) in a human colon adenocarcinoma model. Drug combinations of , -hederin and 5-FU using both fixed-concentration and combination index methods were performed in vitro in HT-29 cells. The results showed that , -hederin at sub-IC50 cytotoxic concentrations enhanced 5-FU cytotoxicity about 3.3-fold (p < 0.001). Simultaneous combination of , -hederin and 5-FU at their IC50 ratio showed either a synergistic effect at a moderate cytotoxic range (25% of cell growth inhibition) or an antagonistic effect at a high level of growth inhibition. The data indicate therefore that it is possible to optimize colorectal cancer cell sensitivity to 5-FU with , -hederin. Copyright © 2008 John Wiley & Sons, Ltd. [source] 3465: Medical cancer therapy of lacrimal gland tumoursACTA OPHTHALMOLOGICA, Issue 2010C LE TOURNEAU Purpose The most common malignant epithelial cancer of the lacrimal gland is the adenoid cystic carcinoma (ACC). Despite a slow growth, ACCs are ultimately associated with a poor outcome. Methods Given the rarity of this disease, there are actually no conclusive recommendations for optimal therapy of this tumor. Results Surgery and postoperative radiation therapy is commonly used in the initial local treatment of ACC of the lacrimal gland. In high-risk recurrence patients, concomitant platinum-based chemoradiation should be discussed in an attempt to enhance radiosensitivity. While encouraging responses were reported with intraarterial neoadjuvant chemotherapy, this strategy was associated with substantial toxicity and should not be recommended outside of clinical trials. In the metastatic setting, systemic therapy is the only available option if no surgery and/or radiation is feasible. Although some tumour shrinkage has been reported with intravenous chemotherapy, only dismal objective response rates were achieved. Most active drugs remain anthracyclines and platinum compounds. Drug combinations do not seem to add much efficacy. More recently, non-cytotoxic molecularly targeted agents have emerged and demonstrated significant efficacy in several tumour types. These agents modulate specific targets thought to be essential for tumour proliferation and/or angiogenesis. c-KIT, PDGFR,, EGFR, and VEGFR are transmembrane receptors with oncogenic tyrosine kinase activity that are commonly overexpressed in ACC. The use of drugs triggering these targets has been disappointing so far. Conclusion The recent identification of a hallmark gene fusion transcript thought to activate critical targets involved in apoptosis, cell cycle control, cell growth and angiogenesis, heralds new treatment promise. [source] Unintentional drug overdose death trends in New Mexico, USA, 1990,2005: combinations of heroin, cocaine, prescription opioids and alcoholADDICTION, Issue 1 2008Nina G. Shah ABSTRACT Aims To determine the contribution of heroin, prescription opioids, cocaine and alcohol/drug combinations to the total overdose death rate and identify changes in drug overdose patterns among New Mexico subpopulations. Design We analyzed medical examiner data for all unintentional drug overdose deaths in New Mexico during 1990,2005. Age-adjusted drug overdose death rates were calculated by sex and race/ethnicity; we modeled overall drug overdose death adjusting for age and region. Findings The total unintentional drug overdose death rate in New Mexico increased from 5.6 per 100 000 in 1990 to 15.5 per 100 000 in 2005. Deaths caused by heroin, prescription opioids, cocaine and alcohol/drug combinations together ranged from 89% to 98% of the total. Heroin caused the most deaths during 1990,2005, with a notable rate increase in prescription opioid overdose death during 1998,2005 (58%). During 1990,2005, the 196% increase in single drug category overdose death was driven by prescription opioids alone and heroin alone; the 148% increase in multi-drug category overdose death was driven by heroin/alcohol and heroin/cocaine. Hispanic males had the highest overdose death rate, followed by white males, white females, Hispanic females and American Indians. The most common categories causing death were heroin alone and heroin/alcohol among Hispanic males, heroin/alcohol among American Indian males and prescription opioids alone among white males and all female subpopulations. Conclusions Interventions to prevent drug overdose death should be targeted according to use patterns among at-risk subpopulations. A comprehensive approach addressing both illicit and prescription drug users, and people who use these drugs concurrently, is needed to reduce overdose death. [source] Multiple fixed drug eruption due to drug combinationCONTACT DERMATITIS, Issue 6 2005A. Yokoyama We report the case of a multiple fixed drug eruption (FDE) after taking 1 g of PL® and 100 mg of levofloxacin (Cravit®) at the same time. Patch tests with PL® alone, levofloxacin alone and the combination of PL® and levofloxacin were all negative on the involved and uninvolved sites. Lymphocytic stimulation tests were also negative for PL® alone, levofloxacin alone and the combination of PL® and levofloxacin. Oral provocation tests with PL®alone or levofloxacin alone produced no reactivation. However, we could provoke multiple erythematous plaques on the involved areas by taking a 1/10th dose of the combination of PL® and levofloxacin at the same time. Drug eruption due to a drug combination appears to be very rare. This is the first case of multiple FDE caused by taking PL® -levofloxacin combination. [source] Sequence dependence of cell growth inhibition by EGFR,tyrosine kinase inhibitor ZD1839, docetaxel, and cisplatin in head and neck cancerHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 10 2009Carmen M. Klass MD Abstract Background This study was to explore whether the efficacy of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Z, Iressa, gefitinib) plus chemotherapeutic agents docetaxel (D) and cisplatin (P) may benefit from sequencing of the combination. Methods Three head and neck cancer cell lines were used to study the effect of various combinations of and relative sequencing of D, P, and Z in cell growth inhibition. A population pharmacokinetic stimulation study was conducted on Z in silico and used together with the growth inhibition data to derive principles for future in vivo use of this drug combination. Results The inhibitory effects of Z on combinations of D and P were sequence dependent. Treatment simultaneously with DPZ or with DP followed by Z (DP,Z) showed synergistic effects in all 3 cell lines. However, sequencing with Z followed by DP (Z,DP), gave an antagonistic effect, suggesting that D and P should be administered when the effect of Z is low. The induction of apoptosis was also sequence dependent. The in silico pharmacokinetic study suggested the feasibility of deriving a 5-day-on/2-day-off regimen for Z, in which D and P administration commences when levels of Z are low, allowing levels of Z to accumulate sufficiently during the remainder of the cycle. Conclusion These data suggests that it is feasible to design clinical trials with these settings to maximize the efficacy of this combined drug regimen. © 2009 Wiley Periodicals, Inc. Head Neck, 2009 [source] The efficacy of pain control following nonsurgical root canal treatment using ibuprofen or a combination of ibuprofen and acetaminophen in a randomized, double-blind, placebo-controlled studyINTERNATIONAL ENDODONTIC JOURNAL, Issue 8 2004K. A. Menhinick Abstract Aim, To compare ibuprofen, to an ibuprofen/acetaminophen combination in managing postoperative pain following root canal treatment. It is hypothesized that the drug combination will provide more postoperative pain relief than the placebo or ibuprofen alone. Methodology, Patients presenting at the Texas A&M Baylor College of Dentistry's graduate endodontic clinic, experiencing moderate to severe pain, were considered potential candidates. Fifty-seven patients were included based on established criteria. Following administration of local anaesthesia, a pulpectomy was performed. The patients were administered a single dose of either: (i) placebo; (ii) 600 mg ibuprofen; or (iii) 600 mg ibuprofen and 1000 mg of acetaminophen. Patients recorded pain intensity following treatment on a visual analogue scale and a baseline four-point category pain scale as well as pain relief every hour for the first 4 h then every 2 h thereafter for a total of 8 h. A general linear model (GLM) analysis was used to analyse the outcome. Results, Based upon the GLM analysis, there was a significant difference between the ibuprofen and the combination drug group, and between placebo and combination drug groups. There was no significant difference between the placebo and the ibuprofen. Conclusion, The results demonstrate that the combination of ibuprofen with acetaminophen may be more effective than ibuprofen alone for the management of postoperative endodontic pain. [source] Influence of therapy on the antioxidant status in patients with melanomaJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2008V. Gadjeva DSc Summary Background and objective:, Some anticancer drugs can result in increased production of reactive oxygen species (ROS). Alkylating agents are the most frequently used drugs in chemotherapeutic regimens for the treatment of malignant melanoma. It is known that triazenes exhibit in vivo activity by alkylation of nucleic acids and proteins, but there is no data about ROS formation during oxidative metabolism. Single agents of most interest for treatment of malignant melanomas include 5-(3,3-dimethyltriazene-1-yl)-imidazole-4-carboxamide (DTIC) and nitrosoureas such as 1-(2-chloroethyl) -3-cyclohexyl-1-nitrosourea (CCNU), but complete response to these drugs is rare. The present study aimed to determine whether an oxidative stress occurs during the clinical course of melanoma and the influence of therapy on the antioxidant status of patients with melanoma. For this purpose, we investigated plasma concentrations of MDA as indices of the levels of lipid peroxidation products. In addition, we studied the activities of the antioxidant enzymes superoxide dismutases (SOD) and catalase (CAT) in patients with melanoma before any treatment, after surgical removal of melanoma, and after chemotherapy with DTIC or in combination with CCNU of the operated patients. Methods:, Twenty one patients with melanoma were studied. Patients were operated prior to chemotherapy. After recovery for 10,20 days postoperatively, they were studied again for MDA, SOD and CAT activity. The patients were divided into two groups according to the chemotherapy (3,7 treatment cycles): with DTIC , given orally daily for 5 days, every 3 weeks as a single 2200 mg/kg dose and with the combination , DTIC (the same dose) + CCNU , administered orally at a dosage of 120 mg/m2 once every 40 days in accordance with protocols, approved by the Bulgarian Ministry of Health. The total amount of lipid peroxidation products in plasma was assayed. Results and discussion:, Plasma levels of MDA and CAT activity were significantly higher, and erythrocyte SOD activity significantly lower, in patients with melanoma, than in control healthy volunteers (P < 0·0001). Ten to twenty days after surgery, oxidative stress decreased but levels of MDA increased as a result of therapy. Important sources of increased ROS production may be the monocytes, phagocytosis of tumour cells and the cancer tissues. Plasma MDA in patients treated with DTIC + CCNU were significantly higher (P < 0·001), but erythrocyte SOD statistically lower (P < 0·00001), compared with patients treated with DTIC only. However, a combination of DTIC + CCNU did not attenuate oxidative stress, or reduced antioxidant status. Patients treated with this combination are at bigger risk of oxidative injury. Therefore, this disturbance might be due to augmented generation of toxic ROS, possibly from the metabolism of CCNU. Conclusion:, Increased oxidative stress follows an imbalance in antioxidant defence in non-treated patients with melanoma. The impaired antioxidant system favours accumulation of ROS, which may promote the cancer process. After complete removal of melanoma tissues, oxidative stress decreased. The antioxidant status of melanoma patients operated on was influenced by the different chemotherapeutic regimens used and may play an important role in the response. Patients on DTIC + CCNU are at higher risk of oxidative injury. This drug combination probably exerts its toxic activity by ROS, which could be products of the metabolism of CCNU. [source] ,2A -Adrenergic Receptor Signaling Underlies Synergistic Enhancement of Ethanol-Induced Behavioral Impairment by ClonidineALCOHOLISM, Issue 3 2009Tara Summer Bender Background:, We tested the hypothesis that central ,2A -adrenergic receptor (,2AAR) signaling plays a key role in clonidine-ethanol evoked synergistic behavioral impairment. Methods:, Male Sprague-Dawley rats, with intracisternal and jugular vein cannulae implanted 6 days earlier, were tested for drug-induced behavioral impairment. The latter was assessed as the duration of loss of righting reflex (LORR) and rotorod performance every 15 minutes until the rat recovered to the baseline walk criterion (180 seconds). In a separate cohort, c-Fos expression in locus coeruleus (LC) and cerebellum was determined as a marker of neuronal activity following drug treatment. Results:, Rats that received clonidine (60 ,g/kg, i.v.) followed by ethanol (1 g/kg, i.v.) exhibited synergistic impairment of rotorod performance and LORR. The mixed ,2AAR and I1 -imidazoline receptor agonist clonidine (30, 60, and 90 ,g/kg) synergistically and dose-dependently enhanced behavioral impairment elicited by ethanol (1 g/kg). Possible involvement of I1 -imidazoline receptors was ruled out because selective I1 -agonist rilmenidine (300 ,g/kg, i.v.) did not cause behavioral impairment alone or enhance ethanol-evoked behavioral impairment. Pharmacological blockade of central ,2AAR (RX821002, 0.3 mg i.c.) abolished the synergy between clonidine and ethanol; the behavioral response caused by the drug combination was similar to that caused by ethanol alone. Conversely, involvement of central ,2BAR in the interaction was ruled out because blockade of central ,2BAR (ARC-239) independently evoked a strong sedative effect. Clonidine (60 ,g/kg) or ethanol (1 g/kg) alone increased, but their combination decreased, c-Fos levels in LC, while inconsistent c-Fos responses were observed in cerebellum. Conclusions:, Central ,2AAR, but not I1 -imidazoline or ,2BAR, signaling is implicated in the synergistic enhancement of ethanol-evoked behavioral impairment by clonidine. Although the mechanism of c-Fos response remains to be investigated, this neurochemical response highlights the LC as a neuroanatomical target for clonidine-ethanol behavioral interaction. [source] Combined Scopolamine and Ethanol Treatment Results in a Locomotor Stimulant Response Suggestive of Synergism That is Not Blocked by Dopamine Receptor AntagonistsALCOHOLISM, Issue 3 2009Angela C. Scibelli Background:, Muscarinic acetylcholine receptors (mAChRs) are well positioned to mediate ethanol's stimulant effects. To investigate this possibility, we examined the effects of scopolamine, a receptor subtype nonselective mAChR antagonist, on ethanol-induced stimulation in genotypes highly sensitive to this effect of ethanol. We also investigated whether the dopamine D1-like receptor antagonist, SCH-23390 or the dopamine D2-like receptor antagonist, haloperidol, could block the extreme stimulant response found following co-administration of scopolamine and ethanol. Methods:, Scopolamine (0, 0.0625, 0.125, 0.25, or 0.5 mg/kg) was given 10 minutes prior to saline or ethanol (0.75 to 2 g/kg) to female FAST (Experiment I) or DBA/2J (Experiment II) mice that were then tested for locomotion for 30 minutes. In Experiments III and IV, respectively, SCH-23390 (0, 0.015, or 0.03 mg/kg) was given 10 minutes prior, and haloperidol (0, 0.08, or 0.16 mg/kg) was given 2 minutes prior, to scopolamine (0 or 0.5 mg/kg), followed 10 minutes later by saline or ethanol (1.5 g/kg) and female DBA/2J mice were tested for locomotion for 30 minutes. Results:, FAST and DBA/2J mice displayed a robust enhancement of the locomotor effects of ethanol following pretreatment with scopolamine that was suggestive of synergism. SCH-23390 had no effect on the response to the scopolamine + ethanol drug combination, nor did it attenuate ethanol- or scopolamine-induced locomotor activity. Haloperidol, while attenuating the effects of ethanol, was not able to block the effects of scopolamine or the robust response to the scopolamine-ethanol drug combination. Conclusions:, These results suggest that while muscarinic receptor antagonism robustly enhances acute locomotor stimulation to ethanol, dopamine receptors are not involved in the super-additive interaction of scopolamine and ethanol treatment. They also suggest that in addition to cautions regarding the use of alcohol when scopolamine is clinically prescribed due to enhanced sedative effects, enhanced stimulation may also be a concern. [source] Potentially Fatal Interaction Between Azithromycin and DisopyramidePACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 9 2000ERIC V. GRANOWITZ A patient on disopyramide developed disopyramide toxicity when treated concurrently with azithromycin. Evidence of toxicity included an elevated serum disopyramide level and ventricular tachycardia requiring cardioversion. The azalide antibiotic presumably inhibited dealkylation of disopyramide to its major metabolite, mono-N-dealkyldisopyramide. Physicians should avoid using azithromycin in patients on disopvramide. If this drug combination is unavoidable, disopyramide levels must be closely monitored. [source] High rates of adverse effects and patient unawareness of withdrawn lipid-lowering drug combination in a public hospital clinicPHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 8 2002Gordon D. Schiff MD Abstract Purpose Examine use, patient awareness and outcomes of concurrent cerivastatin and gemfibrozil in a public hospital clinic system 2 weeks following cerivastatin withdrawal. Methods Electronic pharmacy records for cerivastatin prescriptions for 1 year preceding withdrawal were downloaded and linked to gemfibrozil prescriptions. Patients with concurrent prescriptions were surveyed for current use, awareness of withdrawal/warnings, adverse effects and creatine phosphokinase (CK) results. Results From August 2000 to August 2001, 29,377 prescriptions for cerivastatin were dispensed for 10,780 unique patients; 211 (2%) also received gemfibrozil. Prescription time frames for the two drugs overlapped for 67 patients. Interview of 47 patients revealed 35 actually taking both. 18/35 (51.4%) were still taking both drugs 2 weeks after market-withdrawal of cerivastatin. Only 7/46 (21.2%) had ,heard the news' about withdrawal. 19/46 (41.3%) described muscle-related symptoms; nine reported severe symptoms. Only 13 (28.3%) had CK monitoring. 5/8 symptomatic patients monitored had CK values >200,U/L. (>1000,U/L in two cases.) Conclusions Despite escalating labeled warnings, nearly 2% of patients prescribed cerivastatin received gemfibrozil prescriptions, 1/3 concurrently. Most were still taking this combination 2 weeks after cerivastatin withdrawal and unaware of publicized warnings. Nearly half experienced muscle-related symptoms. More reliable methods for preventing prescription/dispensing of interacting medications and alerting patients about drug recalls are warranted. Copyright © 2002 John Wiley & Sons, Ltd. [source] In vivo imaging of retinoic acid receptor ,2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cellsTHE PROSTATE, Issue 1 2005David Z. Qian Abstract BACKGROUND In retinoid resistant epithelial tumors, the lack of retinoic acid receptor ,2 (RAR,2) expression due to epigenetic silencing impairs the activation of retinoid target genes including RAR,2, and has been associated with the development of cancer. In this study we developed a strategy to monitor the re-activation of RAR,2 by chromatin remodeling agents combined with retinoids in real time, and to correlate the RAR,2 re-activation with anti-tumor activity. METHODS We selected the RAR,2-negative retinoid resistant human prostate carcinoma cell line PC3 and stably transfected it with a luciferase expression vector under the control of a functional segment of RAR,2 promoter (pGL2-RAR,2-PC3). Then, we used the bioluminescence technology to monitor the reporter gene expression in real time both in vitro and in vivo following combination treatment with the histone deacetylase inhibitor MS-275 and 13- cis retinoic acid (CRA). Based on the effective dose for the RAR,2 re-activation, we tested the anti-tumor activity of this drug combination. RESULTS Following combination treatment with MS-275 and CRA, we observed endogenous RAR,2 re-expression, acetylation at the RAR,2 promoter level, and synergistic activation of the luciferase reporter gene by real time imaging both in vitro and in vivo. Combination treatment with MS-275 and CRA restored retinoid sensitivity in human prostate carcinoma cell lines, and had a greater inhibitory effect on tumor cell growth than single agents in vitro and in vivo. CONCLUSIONS This study provides evidence that HDAC inhibitors restore retinoid sensitivity in prostate cancer cells, and in vivo real time imaging of RAR,2 activation may represent a useful tool to study the pharmacodynamics of combination therapy with HDAC inhibitors and retinoids. © 2005 Wiley-Liss, Inc. [source] Oral administration of a tri-therapy for central pattern generator activation in paraplegic mice: Proof-of-concept of efficacyBIOTECHNOLOGY JOURNAL, Issue 4 2010Pierre A. Guertin Dr. Abstract Spinal cord injury (SCI) is a neurological condition, for which no cure exists, typically leading to an immediate and irreversible loss of sensory and voluntary motor functions accompanied by significant health problems. We conducted proof-of-concept experiments aimed at assessing efficacy upon oral administration of a novel combination therapy for central pattern generator (CPG) activation and corresponding locomotor movement generation in completely paraplegic animals. Co-administration orally (by gavage) of buspirone, levodopa and carbidopa was found to dose-dependently induce episodes of steady weight-bearing stepping in low-thoracic (Th9/10) spinal cord-transected (Tx) mice (with no other form of assistance or training). Robust hindlimb stepping with weight-bearing capabilities was induced with the tri-therapy but not with clinically relevant doses of these compounds administered separately. These results provide evidence suggesting that this drug combination may be ideally suited to constitute a first-in-class therapy (CPG activator) for locomotor activity induction in chronic SCI individuals, given that efficacy was shown using commercially available brain-permeable small molecules, already known as safe for the treatment of various neurological indications. [source] Additive beneficial effects of amlodipine and atorvastatin in reversing advanced cardiac hypertrophy in elderly spontaneously hypertensive ratsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2009Jing-Chao Lu Summary 1Additive beneficial effects on cardiovascular disease have been reported for amlodipine and atorvastatin. However, it is still unclear whether the combination of amlodipine and atorvastatin has additive beneficial effects on the regression of advanced cardiac hypertrophy in hypertension. In the present study, the effects of the drug combination on advanced cardiac hypertrophy were investigated in elderly spontaneously hypertensive rats (SHR). 2Elderly SHR (36 weeks old) were randomly allocated into four groups of 12: (i) a vehicle-treated control group; (ii) an amlodipine (10 mg/kg per day)-treated group; (iii) an atorvastatin (10 mg/kg per day)-treated group; and (iv) a group treated with a combination of amlodipine and atorvastatin (both at 10 mg/kg per day). Drugs were administered by oral gavage every morning for a period of 12 weeks before hearts were harvested for analysis. 3Combined administration of amlodipine and atorvastatin significantly suppressed cardiomyocyte hypertrophy, interstitial fibrosis and upregulation of hypertrophic and profibrotic genes, and also improved left ventricular diastolic dysfunction to a greater extent than did amlodipine monotherapy. Further beneficial effects of combination therapy on advanced cardiac hypertrophy were associated with a greater reduction of NADPH oxidase-mediated increases in cardiac reactive oxygen species (ROS), rather than decreased blood pressure and serum cholesterol levels. 4To elucidate the underlying molecular mechanisms, we examined cardiovascular NADPH oxidase subunits and found that amlodipine clearly attenuated the expression of p47phox and p40phox and slightly but significantly reduced p22phox and Rac-1 levels in heart tissue. Combination treatment with amlodipine plus atorvastatin led to a further reduction in p22phox, p47phox and Rac-1 protein levels compared with amlodipine alone. 5In conclusion, combined amlodipine and atorvastatin treatment has a greater beneficial effect on advanced cardiac hypertrophy compared with amlodipine monotherapy. The benefits are likely to be related to the additive effects of the drugs on the suppression of NADPH oxidase-mediated ROS generation. [source] Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD-1 mice to single agents or drug combinations,,ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3-4 2007Salina M. Torres Abstract Experiments were performed to investigate the impact of zidovudine (AZT), lamivudine (3TC), and abacavir (ABC) on cell survival and mutagenicity in two reporter genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK), using cell cloning assays for assessing the effects of individual drugs/drug combinations in (1) TK6 human lymphoblastoid cells exposed in vitro and (2) splenic lymphocytes from male CD-1 mice exposed transplacentally on days 12,18 of gestation. In TK6 cells, dose-related increases in HPRT and TK mutant frequencies were found following 3 days of exposure to AZT or 3TC alone (33, 100, or 300 ,M), or to equimolar amounts of AZT-3TC. Compared with single drug exposures, AZT-3TC coexposures generally yielded enhanced elevations in HPRT and TK mutant frequencies. Mutagenicity experiments with ABC alone, or in combination with AZT-3TC, were complicated by the extreme cytotoxicity of ABC. Exposure of cells either to relatively high levels of AZT-3TC short-term (100 ,M, 3 days), or to peak plasma-equivalent levels of AZT-3TC for an extended period (10 ,M, 30 days), resulted in similar drug-induced mutagenic responses. Among sets of mice necropsied on days 13, 15, or 21 postpartum, Hprt mutant frequencies in T-cells were significantly elevated in the AZT-only (200 mg/kg bw/day) and AZT-3TC (200 mg AZT + 100 mg 3TC/kg bw/day) groups at 13 days of age. These results suggest that the mutagenicity by these nucleoside analogs is driven by cumulative dose, and raises the question of whether AZT-3TC has greater mutagenic effects than AZT alone in perinatally exposed children. Environ. Mol. Mutagen. © 2007 Wiley-Liss, Inc. [source] Synergistic Combinations of Anticonvulsant Agents: What Is the Evidence from Animal Experiments?EPILEPSIA, Issue 3 2007Daniël M. Jonker Summary:,Purpose: Combination therapy is often used in the treatment of seizures refractory to monotherapy. At the same time, the pharmacodynamic mechanisms that determine the combined efficacy of antiepileptic drugs (AEDs) are unknown, and this prevents a rational use of these drug combinations. We critically evaluate the existing evidence for pharmacodynamic synergism between AEDs from preclinical studies in animal models of epilepsy to identify useful combinations of mechanisms and to determine whether study outcome depends on the various research methods that are in use. Methods: Published articles were included if the studies were placebo-controlled, in vivo, or ex vivo animal studies investigating marketed or experimental AEDs. The animal models that were used in these studies, the primary molecular targets of the tested drugs, and the methods of interpretation were recorded. The potential association of these factors with the study outcome (synergism: yes or no) was assessed through logistic regression analysis. Results: In total, 107 studies were identified, in which 536 interaction experiments were conducted. In 54% of these experiments, the possibility of a pharmacokinetic interaction was not investigated. The majority of studies were conducted in the maximal electroshock model, and other established models were the pentylenetetrazole model, amygdala kindling, and the DBA/2 model. By far the most widely used method for interpretation of the results was evaluation of the effect of a threshold dose of one agent on the median effective dose (ED50) of another agent. Experiments relying on this method found synergism significantly more often compared with experiments relying on other methods (p < 0.001). Furthermore, experiments including antagonists of the AMPA receptor were more likely to find synergism in comparison with all other experiments (p < 0.001). Conclusions: Intensive preclinical research into the effects of AED combinations has not led to an understanding of the pharmacodynamic properties of AED combinations. Specifically, the majority of the preclinical studies are not adequately designed to distinguish between additive, synergistic, and antagonistic interactions. Quantitative pharmacokinetic,pharmacodynamic studies of selectively acting AEDs in a battery of animal models are necessary for the development of truly synergistic drug combinations. [source] Use of morphine and 6-monoacetylmorphine in blood for the evaluation of possible risk factors for sudden death in 192 heroin usersADDICTION, Issue 4 2003Anna Fugelstad Abstract Aims, To detect risk factors for sudden death from heroin injection. Design, Evaluation of data from forensic investigations of all fatal cases of suspected heroin death in a metropolitan area. Only cases with detectable morphine and 6-monoacetylmorphine (6-MAM) in blood were included in order to select heroin intoxication cases. Setting, Stockholm, Sweden. Measurements, Autopsy investigation and toxicological analysis of blood and urine; and police reports. Findings, In two-thirds of the 192 cases, death occurred in public places, and mostly without any time delay. Blood concentrations of morphine ranged from 50 to 1200 ng/g, and of 6-MAM from 1 to 80 ng/g. Codeine was detected in 96% of the subjects. In the majority of cases the forensic investigation indicated polydrug use, the most common additional findings being alcohol and benzodiazepines. However, in one-quarter of the cases other drug combinations were found. Previous abstinence from heroin and use of alcohol were identified as risk factors. For 6-MAM there was also a correlation with the presence of THC and benzodiazepines. Despite a high frequency of heart abnormalities (e.g. myocarditis and focal myocardial fibrosis), these conditions did not correlate with morphine or 6-MAM blood concentrations. Conclusions, We confirm that alcohol intake and loss of tolerance are risk factors for death from heroin use, whereas no connection to heart pathology was observed. Further, prospective, studies should focus on other possible risk factors. [source] New drug combinations for the treatment of murine AIDS and macrophage protectionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2001A. Fraternale The failure of highly active antiretroviral therapies (HAART) is mainly due to the existence of latent infected reservoirs, such as macrophages and resting CD4+ T cells. In this paper, we report the results that we obtained in a murine model of AIDS by alternating the administration of the lympholitic drug 2-Fluoro-ara-AMP (Fludarabine) to eliminate the infected cells, with that of Azidothymidine (AZT) plus reduced glutathione (GSH) encapsulated in erythrocytes, to protect lymphocytes and macrophages not yet infected, respectively. Two groups of infected mice were treated as follows: one group was treated by alternating the administration of Fludarabine and AZT (treatment A), while the other group received the same treatment plus GSH-loaded erythrocytes given with AZT (treatment A + L,RBC). Fludarabine was administered intraperitoneally, AZT in the drinking water and GSH was encapsulated in erythrocytes by a procedure of hypotonic dialysis and isotonic resealing. The results obtained show that GSH-loaded erythrocytes provide additive effects in all the parameters examined. Alternation of a lympholitic drug and antiretroviral drug is effective in reducing the progression of murine AIDS. Addition of a system to protect macrophages provides additive effects in almost all the parameters considered, confirming that combination therapies aimed at protecting different infectable cell compartments are better than treatments protecting mainly lymphocytes. [source] Volatile components of Thymus vulgaris L. from wild-growing and cultivated plants in JordanFLAVOUR AND FRAGRANCE JOURNAL, Issue 4 2007M. Hudaib Abstract The composition of the essential oil hydrodistilled from the aerial parts of Thymus vulgaris L. grown in Jordan has been determined by GC and GC,MS. Variations in oil composition and yield between cultivated and wild-growing plants collected from different localities, at different altitudes, have been also evaluated. Higher oil yields were observed in plants growing wild (3.7,5.6% of dried material) than in cultivated plants (1.1,2.0%), and those collected from the Mshaqar region, in the middle of Jordan and at the highest altitude, were the richest in oil (,5.4%). Generally, the oil was characterized by marked levels of phenolic monoterpenoids (mainly thymol and carvacrol) in the range 70.8,89.0%. High levels of the monoterpenoid hydrocarbons p -cymene (3.4,8.2%) and , -terpinene (1.6,7.7%) were also observed. Other major components were 1,8-cineole (up to 2.1%), , -thujone (up to 1.2%), camphor (up to 1.1%) and , -caryophyllene (0.2,2.8%). With the exception of plants growing wild in the Ramtha region, in the far north of Jordan, carvacrol was found as the principal phenol of all other oils (50.6,86.1%) and was dominant (>85%) in wild plant oils. The oil from Ramtha was characterized by the highest level of thymol (,63.8%) as the dominant phenol and was most abundant in p -cymene (8.2%), 1,8-cineole (2.1%) and , -terpinene (7.7%). In addition to assigning carvacrol or thymol chemotypes to the plant, the high content of active monoterpenoid phenols strongly suggests a potential use of Jordanian thyme oil in cough products and antimicrobial,herbal drug combinations. Copyright © 2007 John Wiley & Sons, Ltd. [source] Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients,,§HEPATOLOGY, Issue 6 2008Thomas Kuntzen Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-naïve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multidrug resistance. Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4% of those infected with genotype 1b carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug-resistant viral strains might achieve replication levels comparable to nonresistant viruses in vivo. Conclusion: Naturally occurring dominant STAT-C resistance mutations are common in treatment-naïve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin. (HEPATOLOGY 2008;48:1769,1778.) [source] Community pharmacists' identification of natural health product/drug interactions in older personsINTERNATIONAL JOURNAL OF PHARMACY PRACTICE, Issue 4 2003Ruby E. Grymonpre professor ABSTRACT Objective To document the prevalence and significance of potential natural health products (NHPs)/prescribed drug interactions in a sample of older adults; to determine whether community pharmacists detected these drug interactions; and to characterise users and non-users of NHPs. Setting The project involved 15 community pharmacists providing pharmaceutical care to 213 non-institutionalised older adults. Method The study was a subanalysis of a prospective, non-randomised, before-and-after trial of the provision of pharmaceutical care. Pharmacists documented each time medication-specific information or advice was provided to subjects. The numbers and types of NHPs that clients reported taking and the number of potentially significant NHP/prescribed drug interactions were determined. Whether pharmacists identified such drug interactions and made the necessary interventions were also documented. Results Forty-two NHPs were reported 96 times by 49 (23%) clients, most commonly glucosamine (n = 10), garlic (n = 10), prune juice (n = 9), and Ginkgo biloba (n = 6). There was a total of 446 possible NHP/prescribed drug combinations in the 49 clients, of which 53 (12%) were considered to be of potential clinical significance. Of these 53 combinations, three pharmacists identified four (8%) potential interactions in three different patients. Although gender, mean age and number of reported medical conditions did not differ between users and non-users of NHPs, users reported taking fewer prescribed drugs compared with non-users (5.0 ± 3.2 vs 6.0 ± 2.9, respectively, P = 0.043) and more non-prescribed drugs (4.2 ± 2.5 vs 2.1 ± 2.0, respectively, P < 0.0001). Conclusion The reported prevalence of NHP and the potential for NHP/prescribed drug interactions in our sample of older adults were high. Pharmacists providing pharmaceutical care did not commonly identify potentially significant NHP/prescribed drug interactions. [source] Beyond the Usual Strategies for Blood Pressure Reduction: Therapeutic Considerations and Combination TherapiesJOURNAL OF CLINICAL HYPERTENSION, Issue 6 2001Thomas D. Giles MD Rapidly accumulating clinical data have repeatedly demonstrated not only the critical importance of even small increases in blood pressure as a pathophysiologic factor in the development of cardiovascular disease, particularly in individuals with diabetes mellitus, but also the therapeutic necessity of more aggressive blood pressure reduction and the achievement of progressively lower blood pressure targets in reducing cardiovascular event rates. JNC VI has defined optimal blood pressure as ,120/80 mm Hg, and Stage 1 hypertension as ,140/80 mm Hg. Target blood pressures are now ,130/80 mm Hg in patients with diabetes and <125/75 mm Hg for patients with hypertensive renal disease with proteinuria of>1 gm/24 hours. Achieving such target pressures is increasingly difficult, particularly in diabetic patients with chronic renal disease, who require complex multidrug antihypertensive regimens. This review attempts to provide some suggestions for constructing such antihypertensive regimens, and provides considerations for the appropriate use of diuretics and the most effective drug combinations. Factors potentially contributing to drug resistant hypertension include such problems as failure to maximize drug dosing, suboptimal diuretic use, noncompliance, and possible confounding effects of such concomitant medications as nonsteroidal and anti-inflammatory drugs or decongestants. The issues underlying drug-resistant hypertension are listed, together with strategies for overcoming this problem. [source] Evaluation of drug therapy and risk factors in diabetic hypertensives: a study of the quality of care provided in diabetic clinics in Bahrain,JOURNAL OF EVALUATION IN CLINICAL PRACTICE, Issue 2 2005Khalid A. Jassim Al Khaja PhD Abstract Objective, To evaluate control of blood pressure (BP) and diabetes and the associated risk factors in diabetic hypertensives treated by diabetic clinic primary care physicians. Methods, A retrospective analysis of the medical records of diabetic hypertensives from six primary care diabetic clinics in Bahrain. Results, The recommended BP target <130/<85 mmHg and of glycosylated haemoglobin (HbA1C) <7% were achieved in 7.5% and 14.5%, respectively. Most of the patients with uncontrolled BP and HbA1C were at high cardiovascular risk. More patients were on antihypertensive monotherapy than on combination therapy (60.6% vs. 36.7%; P < 0.0001). The recommended two- and three-antihypertensive drug combinations were less often prescribed. In high-risk patients glycaemic control achieved was poor: antidiabetic combination therapy vs. monotherapy did not significantly differ. Inappropriate prescribing practices, such as the use of immediate-release nifedipine monotherapy, use of sulphonylurea instead of metformin in obese patients, and a trend towards prescribing of glyburide rather than a gliclazide in the elderly, were observed. Lipid-lowering (13.5%) and antiplatelet (12.8%) drugs were infrequently prescribed. Conclusions, Hypertension and diabetes in patients treated at the primary care diabetic clinics were inadequately controlled. In several instances, mono- and combination antihypertensives prescribed were irrational. Lipid-lowering and platelet aggregation inhibition strategies have received little attention. Intensive antihypertensive and antidiabetic complementary combination therapy should be encouraged. Continuous professional education of diabetic clinic physicians and expert-supervised diabetic clinics are desirable. [source] In vitro analysis of synergism and antagonism of different nucleoside/nucleotide analogue combinations on the inhibition of human immunodeficiency virus type 1 replication,JOURNAL OF MEDICAL VIROLOGY, Issue 2 2009M. Perez-Olmeda Abstract In this study we have developed an in vitro system to evaluate the combined effect of two NRTIs on HIV replication and to assess their antagonism or synergy. Synergy or antagonism effect was determined in peripheral blood mononuclear cells (PBMCs) to approach a more physiological model than T-cell lines. PBMCs were infected with a full-length HIV-1 clone carrying the luciferase gene as a reporter. The following combinations were investigated: zidovudine+stavudine (ZDV,+, d4T), lamivudine,+,abacavir (3TC,+,ABC), lamivudine,+,didanosine (3TC,+,ddI), lamivudine,+ stavudine (3TC,+,d4T), tenofovir,+,stavudine (TDF,+,d4T), tenofovir,+,didanosine (TDF,+,ddI), tenofovir,+,abacavir (TDF,+,ABC), tenofovir,+, lamivudine (TDF,+,3TC), tenofovir,+,zidovudine (TDF,+,ZDV), stavudine,+,didanosine (d4T,+,ddI), zidovudine,+,lamivudine (ZDV,+,3TC), abacavir,+, didanosine (ABC,+,ddI), zidovudine,+,didanosine (ZDV,+,ddI), and abacavir,+,stavudine (ABC,+, d4T). The effect of combining two drugs was evaluated with a quantitative method based on the median-effect principle of Chou and Talalay. A synergistic effect was observed with combinations containing TDF and ZDV or d4T, d4T and ddI and ZDV plus 3TC. In contrast, combinations including TDF,+,ddI, 3TC,+,ddI, ABC,+,ddI, and ZDV,+,ddI showed an antagonistic effect on the inhibition of viral replication at all levels of inhibition tested. Lower antagonistic effect was also found in drug combinations that included 3TC,+,ABC, 3TC,+,TDF, 3TC,+,d4T, and TDF,+, ABC. In conclusion, the method developed allows to measure in vitro the effect of different combinations of two NRTIs on HIV replication. The results suggest that combined therapy including TDF with thymidine analogues may be considered for future therapeutic options in contrast to clearly antagonistic combinations such us TDF plus ddI or 3TC plus ddI, that would explain virological failure in clinical studies when these combinations were used. J. Med. Virol. 81:211,216, 2009. © 2008 Wiley-Liss, Inc. [source] Influence of dosing schedules on toxicity and antitumour effects of combined cisplatin and docetaxel treatment in miceJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2009Ayumi Kodama Abstract Objectives The combination of cisplatin and docetaxel shows a better cure rate against non-small-cell lung cancer than other drug combinations in clinical studies; however, severe myelosuppression and nephrotoxicity are dose-limiting factors. The purpose of this study was to establish a suitable dosing schedule to reduce adverse effects and improve the antitumour effects. Methods Cisplatin and docetaxel were administered i.p. to male ICR mice simultaneously, or sequentially with either cisplatin or docetaxel first followed by the second drug 12 h later (docetaxel,cisplatin and cisplatin,docetaxel groups). Antitumour effects of these schedules were also tested in C57BL/6N mice bearing Lewis lung carcinomas. Key findings The simultaneous docetaxel/cisplatin group showed the lowest survival rate and the highest blood urea nitrogen (BUN) concentration. Cisplatin concentrations in the plasma and kidney were higher in the simultaneous dosing group than the sequential dosing groups. Antitumour effect was the greatest in the docetaxel,cisplatin group. Conclusions The docetaxel,cisplatin regimen inhibited tumour growth the best and reduced mortality and nephrotoxicity. [source] Pressor Therapy in Critically III PatientsJOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE, Issue 1 2000ACVECC, ACVIM, James S. Wohl DVM Diplomate Summary Vasopressors are agents that increase systemic vascular resistance by increasing vasoconstriction. Therapy with intravenous vasopressors may be required in critically ill patients when efforts to optimize cardiac output and blood pressure with intravascular fluid therapy fail. Increasing systemic vascular resistance can promote a favorable perfusion pressure gradient to vital organs in critically ill patients with severe, unresponsive vasodilation. Improperly administered, vasopressors may impede cardiac output and reduce oxygen transport to vital tissue sites. The understanding of systemic and regional effects of vasopressors is currently evolving. Recent literature of the commonly used agents is reviewed. Individual drugs, drug combinations, and potential new therapies are discussed. (Vet. Emerg. & Crit. Care, 10:19,33, 2000) [source] First-line therapy for chronic myeloid leukemia: Past, present, and future,AMERICAN JOURNAL OF HEMATOLOGY, Issue 5 2009Carolina Pavlovsky The development of Bcr-Abl tyrosine kinase inhibitors has dramatically changed the prognosis of patients with newly diagnosed chronic myeloid leukemia (CML). Standard-dose imatinib (400 mg/day in chronic phase, 600 mg/day in advanced CML) now dominates the management of this disease, producing considerably higher hematologic, cytogenetic, and molecular response rates than seen with previous drug therapies. However, although many patients respond well to standard-dose imatinib initially, some patients do not achieve adequate levels of response or discontinue therapy because of resistance. One approach to improving treatment response with first-line imatinib may be to increase the imatinib dose (800 mg/day), although recent trial data indicate that overall increases in response rates may be modest. Newer Bcr-Abl tyrosine kinase inhibitors can induce responses in patients with all phases of imatinib-resistant CML, even those with imatinib-resistant mutations in the BCR-ABL gene. Furthermore, in initial studies, first-line dasatinib or nilotinib treatment has produced response rates that compare favorably with historical controls treated with imatinib, although confirmation is required from head-to-head clinical trials. Future clinical approaches may include drug combinations, which may allow quiescent leukemia stem cells to be eradicated. Further improvements in drug treatment for first-line CML are expected during the next few years. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] New potential anti-cancer agents synergize with bortezomib and ABT-737 against prostate cancerTHE PROSTATE, Issue 8 2010Bulbul Pandit Abstract BACKGROUND We previously described the identification of a transcriptional inhibitor ARC and FoxM1 inhibitors, thiazole antibiotics, Siomycin A and thiostrepton that were able to induce potent p53-independent apoptosis in cancer cell lines of different origin. Here, we report the characterization of these drugs individually or in combination with ABT-737 and bortezomib on a panel of prostate cancer cell lines. METHODS DU 145, LNCaP and PC-3 prostate cancer cells were treated with ARC, Siomycin A and thiostrepton to evaluate their activity as single agents or in combination with ABT-737 and bortezomib to measure their synergistic potential in anti-proliferative and cell cycle assays. Chou-Talalay method was used to quantitate the synergistic interaction. Western blot method was used to determine Mcl-1 and FoxM1 expression and caspase-3 cleavage. RESULTS We show that ARC inhibited the viability of prostate cancer cells and induced apoptosis in low nanomolar concentration. It potently downregulated the expression of Mcl-1 and showed synergistic combination effect with Bcl-2 inhibitor ABT-737. Thiazole antibiotics, Siomycin A and thiostrepton inhibited growth, FoxM1 expression and induced cell death in prostate cancer cells in low micromolar concentrations. In addition, thiostrepton and ARC synergistically induced apoptosis in prostate cancer cells following combination treatment with proteasome inhibitor bortezomib. Furthermore, we found that all tested drug combinations were able to induce apoptosis selectively in transformed, but not normal cells of the same origin. CONCLUSIONS Based on their in vitro activity as single or combination agents, ARC, Siomycin A and thiostrepton represent potential candidates for drug development against prostate cancer. Prostate 70: 825,833, 2010. © 2010 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||