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Effective Drug (effective + drug)
Selected AbstractsPalatal tremor in childhood: clinical and therapeutic considerationsDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 12 2006J Campistol-Plana PhD Palatal tremor (PT) is a rhythmic movement of the soft palate that often causes an ear click. PT can be symptomatic (SPT) or essential (EPT). The symptomatic form usually occurs in adults and the essential form mainly occurs in children. Several different treatments for EPT in children appear in the literature with variable reported efficacy. This report details four paediatric patients with EPT (three males, one female; mean age 6y 4mo [SD 6mo]; age at onset 6,7y) treated with piracetam (2-oxo-1-pyrrolidine acetamide). Piracetam was used to treat EPT because of its antimyoclonic properties. All children showed a good response to doses of 100 to 300mg/kg/day. EPT relapsed on withdrawal of piracetam and remitted on reintroduction. Piracetam's effect on EPT was sustained. It is concluded that piracetam is an effective drug for the treatment of EPT in children. [source] Drug design: hiding in full viewDRUG DEVELOPMENT RESEARCH, Issue 1 2008Norman S. Radin Abstract Compounds that can produce potent biological effects in cells encompass a variety of structural motifs. Many of these compounds share a structural feature that has rarely been noted. It is an allylic cluster of atoms, a 3-carbon chain with a double bond between two of the atoms and an oxygen atom at the other end. The oxygen can be in a hydroxyl group, or in an ether or ketal or ester linkage, or simply a carbonyl form. In the latter case, the linkage is an allylic ketone (ene-one) structure. Nitrogen is often seen in equivalent forms. Inclusion of at least one allylic moiety appears to be able to turn a modestly active or inert compound into an effective drug or toxin. Some compounds lack the allylic moiety but develop one by enzymatic action, usually via cytochrome P-450 enzymes. These metabolites probably represent the active drug forms. The above concepts seem to be radically simplistic and improbable, but the evidence supporting them and the explanations for the biological activities are hidden "in plain view." Comparisons with the pleiotropic activities of the allylic sphingolipid, ceramide, indicate that many allylic drugs operate by controlling the state of protein phosphorylation, by activating proteases, by generating reactive oxygen species, by slowing mitochondrial electron transport, or by lowering cellular glutathione concentrations. Drug Dev Res 69:15,25, 2008 © 2008 Wiley-Liss, Inc. [source] Reversible Anorgasmia With Topiramate Therapy for Headache: A Report of 7 PatientsHEADACHE, Issue 9 2006Christina Sun MD Objective.,To describe 7 patients who developed new onset anorgasmia while using topiramate therapy for migraine prophylaxis. Background.,Topiramate is an effective drug for the prevention of migraine headaches. Though it is generally well tolerated, it may be associated with a dose-related anorgasmia. Methods.,Case reports Results.,Seven patients (5 women, 2 men), between the ages of 40 and 62, developed anorgasmia while using topiramate for headache prevention. Four women and 2 men had migraine without aura, and 1 woman had migraine with aura. None had a prior history of anorgasmia or sexual dysfunction. Doses associated with this side effect ranged from 45 to 200 mg daily. All subjects had symptom resolution. Six patients had resolution within 7 days of discontinuing or decreasing the medication; the exact time frame of resolution for the seventh patient is unknown. Conclusion.,In our series, anorgasmia was a reversible, dose-related adverse effect of topiramate. Physicians need to be aware of the potential for topiramate to cause sexual side effects, and should inquire about these symptoms in patients for whom this agent has been prescribed. [source] Sumatriptan Scavenges Superoxide, Hydroxyl, and Nitric Oxide Radicals: In Vitro Electron Spin Resonance StudyHEADACHE, Issue 9 2002DMSc, Yukio Ikeda MD Background.,The molecular mechanisms of migraine have not yet been clarified. Oxygen free radicals have been implicated in the genesis of many pathological processes, including migraine. Sumatriptan succinate is known to be a very effective drug for acute relief of migraine attack. Objective.,To investigate the direct scavenging activities of sumatriptan for superoxide, hydroxyl, and nitric oxide (NO) radicals using electron spin resonance (ESR) spectroscopy. Methods.,Measurement of superoxide and hydroxyl radical scavenging activities was performed by ESR using 5,5-dimethyl-1-pyrroline- N -oxide as a spin trap. NO was generated from 1-hydroxy-2-oxo-3-(N -3-methyl-3-aminopropyl)-3-methyl-1-triazene and analyzed by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl produced from the reaction between 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and NO. Results.,The ESR study demonstrated that sumatriptan scavenged superoxide, hydroxyl, and NO in a dose-dependent manner. Conclusion.,Sumatriptan has direct scavenging activity on free radicals and NO. Acute migraine drugs with antioxidant properties may provide heretofore unheralded benefits via this mechanism. [source] Sorafenib: Where do we go from here?,HEPATOLOGY, Issue 1 2010Abby B. Siegel The approval of sorafenib as the first effective drug for the treatment of hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. A better understanding of HCC pathogenesis has led to the development of several novel targeted treatments. HCC is treated in a uniquely multidisciplinary way requiring surgeons, hepatologists, interventional radiologists, and oncologists. This review describes the molecular pathogenesis of HCC, explores current and future treatments based on these pathways, and describes how these new therapies may augment existing approaches to HCC treatment.(HHEPATOLOGY 2010;) [source] Effectiveness and safety of eprosartan on pulse pressure for the treatment of hypertensive patientsINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 4 2005N. R. Robles Summary A multicentre, prospective, non-comparative open-label study was conducted to assess the effect of eprosartan, 600 mg/day, on pulse pressure (PP) in patients with hypertension (stage I or II, Joint National Committee, sixth report) treated in the primary care setting, as well as safety and compliance. The duration of treatment was 16 weeks. Eprosartan decreased PP (,13 mmHg), systolic blood pressure (SBP) (,26 mmHg), diastolic blood pressure (DBP) (,13 mmHg) and mean arterial pressure (MAP) (,17.4 mmHg) significantly (p < 0.0001). The PP/MAP ratio changed significantly from 62 to 59%, so that the reduction of PP was 3% higher than the overall decrease in MAP. Twenty adverse events, mostly gastrointestinal complaints, were recorded in 12 patients (1.9%). Compliance with treatment at the end of the study was 94%. Eprosartan was a well-tolerated and an effective drug in reducing PP, SBP and DBP below the recommended levels in patients with mild-to-moderate essential hypertension, allowing a high therapeutic compliance. [source] Tetrathiomolybdate anticopper therapy for Wilson's disease inhibits angiogenesis, fibrosis and inflammationJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2003G. J. Brewer Abstract The need for agents to lower body copper in Wilson's disease, a disease which results from copper toxicity has been the driving force for the development of the effective anticopper drugs penicillamine, trientine, zinc, and now tetrathiomolybdate (TM). Because of its rapid action, potency, and safety, TM is proving to be a very effective drug for initial treatment of acutely ill Wilson's disease patients. Beyond this, TM has antiangiogenic effects, because many proangiogenic cytokines require normal levels of copper. This has led to use of TM in cancer, where it is generally effective in animal tumor models, and has shown efficacy in preliminary clinical studies. Most recently, it has been found that TM has antifibrotic and antiinflammatory effects through inhibition of profibrotic and proinflammatory cytokines. [source] Clinical trial: Inhibitory effect of revaprazan on gastric acid secretion in healthy male subjectsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 10 2010Hyung-Keun Kim Abstract Background and Aim:, Revaprazan is a novel acid pump antagonist. The aim of this study was to investigate the inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects. Methods:, In a double-blind, three-way cross-over study, 30 healthy male volunteers were randomized to 100, 150 or 200 mg of oral revaprazan daily for 7 days. Serum gastrin concentration was measured, and 24-h intragastric pH was recorded at baseline and on days 1 and 7 of each administration period. Serial blood samples were processed for pharmacokinetics. Results:, Median intragastric pH over 24 h and mean percentage time that pH was > 4 increased in a dose-dependent manner and were significantly higher on days 1 and 7 compared with baseline in all groups (P < 0.05). The antisecretory effect of revaprazan was rapid and nearly maximal on day 1 in all groups. Serum gastrin levels were rapidly normalized by 100 and 150 mg/day of revaprazan on days 1 and 7, but were significantly higher in the 200 mg/day revaprazan group. The pharmacokinetic effect was rapidly absorbed and eliminated on days 1 and 7 in all groups. Conclusions:, Revaprazan rapidly and effectively inhibits gastric acid secretion in healthy male subjects. Therefore, revaprazan can be used as an effective drug for acid-related disease. [source] Third S. S. Ratnam Memorial Lecture 2007.JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 3 2009Ovarian cancer: Is there hope for women? Abstract Ovarian cancer is today the most lethal female cancer with an overall survival of only 49.9%. The currently available screening modalities are disappointing in detecting highly curable early stage ovarian cancer. Natural history of ovarian cancer is unknown; it appears it can develop quickly from normal looking ovaries. Timely referral of women with non-specific symptoms (such as abdominal bloating, pelvic pain) for an ultrasound scan or blood CA125 assessments may help in the early diagnosis. Patients with Stage IA or IB disease with grade 1 tumors have a cure rate of >90%; this is likely to be compromised by laparoscopic surgery. In selected patients fertility preservation with good obstetric outcome is possible. However, the relapse rate in ,high risk' early stage ovarian cancers is 40,45%; adjuvant chemotherapy is needed. Only 20,25% of those with stage III and IV disease are cured. Despite a high primary response (70%) majority (70,75%) will relapse and all are likely to succumb. Optimal debulking surgery followed by adjuvant chemotherapy are needed for stages III and IV disease; the outcome is superior if managed by gynecologic oncologists. Where cost of drugs is an important consideration, an alternative is carboplatin (an affordable and equally effective drug). The role of vaccines needs further study. When relapses occur palliation will be the aim in most instances. Oral contraceptives, breast feeding, tubal sterilization and hysterectomy also have a protective effect. Risk-reducing salpingo-oopherectomy has been suggested in women with BRCA mutations. [source] Activity and regulation of glycoPEGylated factor VIIa analogsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2008S. GHOSH Summary.,Background:,Recombinant coagulation factor VIIa (rFVIIa) has proven to be a safe and effective drug for treatment of bleeding episodes in hemophilic patients with inhibitors. However, rFVIIa is cleared from the circulation relatively quickly. Protein modification with poly(ethylene glycol) (PEG) can prolong the circulatory lifetime of proteins but it could also impair protein function by molecular shielding of the protein surface. Objectives:, To characterize the interaction of glycoPEGylated rFVIIa , rFVIIa-10K PEG and rFVIIa-40K PEG , with tissue factor (TF), factor X (FX) and plasma inhibitors, tissue factor pathway inhibitor (TFPI) and antithrombin (AT). Methods:, The amidolytic and FX activation assays were employed to investigate the interaction of glycoPEGylated rFVIIa with its macromolecular substrate and inhibitors. Results:, Both the glycoPEGylated rFVIIa analogs exhibited similar amidolytic activity as that of rFVIIa in the absence or the presence of relipidated TF. The analogs were as effective as rFVIIa in activating FX in the absence of TF. In the presence of TF, the glycoPEGylated rFVIIa variants, relative to rFVIIa, were slightly less effective at lower concentrations, but no significant differences were found among them in activating FX at saturating concentrations. Both AT/heparin and TFPI effectively inhibited the glycoPEGylated rFVIIa bound to relipidated TF or TF on stimulated endothelial cells. In contrast to their normal interaction with TF, the glycoPEGylated rFVIIa variants appeared to interact poorly with phospholipids. Conclusions:, The glycoPEGylated rFVIIa variants retained their catalytic activity and interacted efficiently with TF, FX and the plasma inhibitors. Further work with appropriate in vitro and in vivo model systems is needed to determine the feasibility of using glycoPEGylated rFVIIa to improve therapeutic options for bleeding disorders. [source] Efficacy and Pharmacokinetics of Pantoprazole in AlpacasJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 4 2010G.W. Smith Background: Despite frequent clinical use, information about the pharmacokinetics and efficacy of pantoprazole in camelids is not available. Objectives: To examine the pharmacokinetics of both IV and SC pantoprazole and to determine whether pantoprazole administration would increase 3rd compartment pH in alpacas. Animals: Six healthy adult alpacas. Methods: Alpacas were fitted with a 3rd compartment cannula for measuring gastric pH. After recovery, alpacas received 1 mg/kg pantoprazole IV, q24h for 3 days or 2 mg/kg SC q24h for 3 days. Alpacas received both IV and SC pantoprazole, with a minimum of 3 weeks between treatments. Third compartment pH was recorded and plasma samples were taken for pharmacokinetic analysis. Results: Pantoprazole induced a slow but sustained increase in 3rd compartment pH when given by both the IV and SC routes. Third compartment pH was significantly increased as compared with baseline values (1.81 ± 0.7; mean ± SD) at 24 (2.47 ± 0.8), 48 (3.53 ± 1.0) and 72 hours (4.03 ± 1.3) after daily IV administration of pantoprazole. Third compartment pH increased from 1.73 ± 0.6 at baseline to 3.05 ± 1.1, 4.02 ± 1.4, and 3.61 ± 1.6 at 24, 48, and 72 hours after SC administration, respectively. Pharmacokinetic analysis demonstrated that pantoprazole had a short elimination half-life (0.47 + 0.06 h) and a high clearance rate (12.2 ± 2.9 mL/kg/min) after both IV and SC administration. Conclusions and Clinical Relevance: Based on the results of this study, pantoprazole represents a safe and effective drug for increasing 3rd compartment pH in camelids. Either IV or SC administration is likely to be an effective treatment for gastric ulcers. [source] A Phase II Clinical Trial of Vinorelbine in Dogs with Cutaneous Mast Cell TumorsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2008I.A. Grant Background: Few effective drugs are available to treat dogs with locally aggressive or metastatic mast cell disease. Hypothesis: Vinorelbine, a semisynthetic derivative of vinblastine, is an effective drug for the treatment of canine mast cell tumors (MCT). Animals: Twenty-four dogs with cutaneous MCT. Methods: Dogs with at least 1 measurable, cytologically confirmed, and previously untreated cutaneous MCT received a single treatment with vinorelbine at the previously established dosage of 15 mg/m2 IV. Tumor measurements and CBC were evaluated before and 7 days after treatment. Adverse events were graded according to Veterinary Cooperative Oncology Group (VCOG) guidelines. Statistics: Data were accrued in accordance with a Simon's 2-stage design with a noninteresting response rate of .05, a target response of .25, and , and , values of .10. Results: Three of 24 dogs (13%) had a response to treatment, including 1 measurable complete response and 1 measurable partial response. The 3rd dog had microscopic complete response to treatment with stable measurable disease. Twenty other dogs (83%) had stable disease and 1 dog (4%) had progressive disease. Neutropenia occurred in 13 dogs (54%) (grade 1, n = 4; grade 3, n = 6; grade 4, n = 3). Gastrointestinal toxicity occurred in 11 dogs (46%) (anorexia: grade 1, n = 3; grade 2, n = 1; grade 3, n = 1; diarrhea: grade 1, n = 2; grade 3, n = 1; vomiting: grade 1, n = 5; grade 3, n = 1). Conclusions and Clinical Importance: Vinorelbine was associated with an overall response rate of 13% and a high prevalence of neutropenia. Additional studies are indicated to determine if repeated dosing of vinorelbine or combination of vinorelbine with other drugs increases the observed biologic activity against canine MCT. [source] Clinical evaluation of a new formulation of propofol in a medium-chain and long-chain triglycerides emulsion in dogsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2007J. I. REDONDO GARCÍA Propofol formulated in a mixed medium-chain and long-chain triglycerides emulsion has been recently introduced for clinical use as an alternative to the conventional long-chain triglycerides formulation. This prospective multicentric study evaluated the clinical effectiveness and the complications associated with the use of this new formulation of propofol in dogs. Forty-six Spanish veterinary clinics participated in this study. A total of 541 anaesthesias (118 ASA I, 290 ASA II, 101 ASA III and 32 ASA IV) performed for various diagnostic and therapeutic purposes were evaluated. The anaesthetic protocol was not controlled, with the exception that propofol had to be used at least for induction of anaesthesia. The induction dose of propofol and the incidence of anaesthetic complications throughout the procedure were recorded. A chi-square test compared the incidence of complications according to the maintenance agent used (propofol vs. inhalatory anaesthesia), anaesthetic risk (ASA classification) and the reason for the anaesthesia. The patients premedicated with ,2 agonists needed lower doses (mean ± SD, 2.9 ± 1.3 mg/kg i.v.) than the animals premedicated with phenothiazines (3.9 ± 1.4 mg/kg i.v.) or benzodiazepines (4.0 ± 1.4 mg/kg i.v.). The most frequent complications were difficult endotracheal intubation (1.3%), postinduction apnoea (11.3%), cyanosis (0.6%), bradypnoea (2.6%), tachypnoea (2.8%), bradycardia (2%), tachycardia (2.6%), hypotension (0.2%), shock (0.2%), vomiting (4.6%), epileptiform seizures (2.8%), premature awakening (7.4%) and delayed recovery (0.9%). There were no cases of pain on injection or aspiration pneumonia. Three dogs died (0.55%), one during induction and two during recovery from anaesthesia. This study demonstrates that the new formulation of propofol is an useful and effective drug to induce general anaesthesia in dogs. [source] Adenosine-Induced Ventricular Arrhythmias in Patients with Supraventricular TachycardiasANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 4 2008Cagatay Ertan M.D. Background: Adenosine is widely used for the diagnosis and the termination of supraventricular arrhythmias. There are many case reports and few series about the proarrhythmic potential of adenosine. We sought to evaluate the proarrhythmic potential of adenosine used to terminate the supraventricular arrhythmias. Methods: The records of all patients that received adenosine for the termination of supraventricular tachycardia were reviewed retrospectively and those with a continuous electrocardiographic (ECG) recording during adenosine administration were included to the study. Results: Our search identified 52 supraventricular episodes of 46 patients with a continuous ECG recording during adenosine administration. Following adenosine administration, premature ventricular contraction (PVC) or ventricular tachycardia (VT) developed in 22 (47.8%) patients and in 26 (50%) tachycardia episodes. No patient had a sustained VT. Nonsustained VT developed in eight (17.4%) patients. All VT episodes were polymorphic, short, and self-terminating. When the basal and demographic properties of patients with PVC or VT and those without PVT or VT were compared, there was no significant difference. Conclusions: Adenosine is a quite safe and effective drug for the termination of narrow QRS complex tachycardia but it often induces nonsustained VT or PVC that are clinically insignificant in the absence of other accompanying heart disease. [source] Use of flubendazole as a therapeutic agent against rotifers (Brachionus plicatilis) in intensive cultures of the harpacticoid copepod Tisbe holothuriaeAQUACULTURE RESEARCH, Issue 7 2010Svend J Steenfeldt Abstract Copepods are well known to be the optimal live feed for most species of marine fish larvae. Still copepods are rarely used in marine hatcheries worldwide. Lack of efficient production techniques are among the reasons for this. Consequently, Artemia and rotifers are utilized in commercial settings. One problem in intensive production of copepods is contamination with rotifers. Rotifers have higher growth rates than copepods and consequently will compete out the copepods when accidentally introduced to the copepod production systems. Once contamination has occurred, the only cure has been to shut down production and subsequently use a therapeutic agent to eliminate all zooplankton in the system before restart with a stock culture free of rotifers. We tested flubendazole as a mean of controlling rotifers (Brachionus plicatilis) in intensive laboratory cultures of the harpacticoid copepod (Tisbe holothuria). Flubendazole was lethal to rotifers in concentrations as low as 0.05 mg L,1. There was no significant effect on the concentration of copepods, even at the highest concentration tested, i.e. 5.0 mg L,1 flubendazole. We conclude that flubendazole is an effective drug for control of B. plicatilis in T. holothuriae batch cultures. [source] Protective Effect of Berberine on Cyclophosphamide-Induced Haemorrhagic Cystitis in RatsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2001Xinyun Xu Administration of 150 mg/kg cyclophosphamide intraperitoneally caused a serious haemorrhagic cystitis in rats after 12 hr, including bladder oedema, haemorrhage, and dramatic elevation of nitric oxide metabolites (nitrite+nitrate) in urine and in plasma. To explore whether cyclophosphamide-induced cystitis could be prevented by berberine, rats were pretreated with a single dose or two doses of berberine at 50, 100, or 200 mg/kg intraperitoneally then challenged with cyclophosphamide (150 mg/kg, intraperitoneally). The results indicated that pretreatment of rats with berberine could reduce cyclophosphamide-induced cystitis in a dose-dependent manner. Furthermore, we found that two doses of berberine showed greater protection against cyclophosphamide urotoxicity than when given a single dose. In addition, our data shows that a single dose of 200 mg/kg berberine, or two doses of 100, and 200 mg/kg berberine could completely block cyclophosphamide-induced bladder oedema and haemorrhage, as well as nitric oxide metabolites increase in rat urine and plasma. In conclusion, our findings suggest that berberine could be a potential effective drug in the treatment of cyclophosphamide-induced cystitis, and provides us with the bright hope in the prevention and treatment of cyclophosphamide urotoxicity. [source] Phase II study of pentostatin in advanced T-cell lymphoid malignanciesCANCER, Issue 2 2004Update of an M. D. Anderson Cancer Center series Abstract BACKGROUND The goal of the current study was to assess the toxicity, safety, and efficacy of pentostatin in patients with T-cell lymphoid malignancies. METHODS Patients were eligible if they had biopsy-proven T-cell lymphoma or leukemia and failure to respond to previous therapy or an expected complete response rate to conventional therapy of < 20%. Pentostatin was administered at an initial dose of 3.75 or 5.0 mg/m2 by intravenous bolus daily over a consecutive 3-day period every 3 weeks. RESULTS Forty-two of 44 patients enrolled in the study were evaluable. The median age of the patients was 62 years (range, 38,86 years). Patients received a median of 3 previous therapies (range, 0,10 previous therapies). Of these patients, 32 (76%) had mycosis fungoides/Sézary syndrome and 10 patients (24%) had other T-cell leukemias or lymphomas. The overall response rate was 54.8% (complete remission, 6 patients [14.3%]; partial remission, 17 patients [40.5%]). Durable responses were observed mainly in patients with Sézary syndrome or peripheral T-cell lymphoma. The median follow-up period for surviving patients was 20 months (range, 1,83+ months). The median duration of response was 4.3 months (range, 1,61 months). The most common toxicities were neutropenia, nausea, and CD4 suppression. A transient early ,flare' of disease was observed in some responders. CONCLUSIONS At these doses, pentostatin was reasonably well tolerated and is an effective drug for the treatment of T-cell lymphomas. Cancer 2004;100:342,9. © 2003 American Cancer Society. [source] Molecular targets of lithium actionACTA NEUROPSYCHIATRICA, Issue 6 2003B Corbella Lithium is an effective drug for both the treatment and prophylaxis of bipolar disorder. However, the precise mechanism of lithium action is not yet well understood. Extensive research aiming to elucidate the molecular mechanisms underlying the therapeutic effects of lithium has revealed several possible targets. The behavioral and physiological manifestations of the illness are complex and are mediated by a network of interconnected neurotransmitter pathways. Thus, lithium's ability to modulate the release of serotonin at presynaptic sites and modulate receptor-mediated supersensitivity in the brain remains a relevant line of investigation. However, it is at the molecular level that some of the most exciting advances in the understanding of the long-term therapeutic action of lithium will continue in the coming years. The lithium cation possesses the selective ability, at clinically relevant concentrations, to alter the PI second-messenger system, potentially altering the activity and dynamic regulation of receptors that are coupled to this intracellular response. Subtypes of muscarinic receptors in the limbic system may represent particularly sensitive targets in this regard. Likewise, preclinical data have shown that lithium regulates arachidonic acid and the protein kinase C signaling cascades. It also indirectly regulates a number of factors involved in cell survival pathways, including cAMP response element binding protein, brain-derived neurotrophic factor, bcl-2 and mitogen-activated protein kinases, and may thus bring about delayed long-term beneficial effects via under-appreciated neurotrophic effects. Identification of the molecular targets for lithium in the brain could lead to the elucidation of the pathophysiology of bipolar disorder and the discovery of a new generation of mood stabilizers, which in turn may lead to improvements in the long-term outcome of this devastating illness (1). [source] Crystal Structure, Lattice Energy, and Standard Molar Enthalpy of Formation of the Complex (C11H18NO)2CuCl4 (s)CHINESE JOURNAL OF CHEMISTRY, Issue 7 2010Wenyan Dan Abstract The complex (C11H18NO)2CuCl4 (s), which may be a potential effective drug, was synthesized. X-ray crystallography, elemental analysis, and chemical analysis were used to characterize the structure and composition of the complex. Lattice energy and ionic radius of the anion of the complex were derived from the crystal data of the title compound. In addition, a reasonable thermochemical cycle was designed, and standard molar enthalpies of dissolution for reactants and products of the synthesis reaction of the complex were measured by an isoperibol solution-reaction calorimeter. The enthalpy change of the reaction was calculated to be ,rH,m=(2.69±0.02) kJ·mol,1 from the data of the above standard molar enthalpies of dissolution. Finally, the standard molar enthalpy of formation of the title compound was determined to be ,rH,m[(C11 H18NO)2CuCl4, s]= , (1822.96±6.80) kJ·mol,1 in accordance with Hess law. [source] KYNURENINE PATHWAY METABOLISM IN PATIENTS WITH OSTEOPOROSIS AFTER 2 YEARS OF DRUG TREATMENTCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2006Caroline M Forrest ABSTRACT 1Metabolism of tryptophan along the oxidative pathway via kynurenine results in the production of quinolinic acid and kynurenic acid, which can act on glutamate receptors in peripheral tissues. We have now measured the concentrations of kynurenine pathway metabolites in the plasma of patients with osteoporosis before treatment with drugs, throughout and after 2 years of treatment with the drugs raloxifene or etidronate. Oxidative stress was assessed by measuring levels of the lipid peroxidation products malondialdehyde and 4-hydroxynonenal. Kynurenines were analysed by HPLC. Bone density was measured using dual-energy X-ray absorptiometry scans. 2Patients with osteoporosis showed significantly lower baseline levels of 3-hydroxyanthranilic acid compared with healthy controls, but significantly higher levels of anthranilic acid and lipid peroxidation products. After 2 years treatment with etidronate and calcium, we observed significant therapeutic responses quantified by bone densitometric scanning. Significant improvements were not seen in patients treated with raloxifene. 3In parallel, the levels of 3-hydroxyanthranilic acid, anthranilic acid and lipid peroxidation products were restored to control values by both drug treatments studied and tryptophan levels were increased significantly compared with baseline values. 4The results suggest that tryptophan metabolism is altered in osteoporosis in a manner that could contribute to the oxidative stress and, thus, to progress of the disease. The oxidative metabolism of tryptophan (the kynurenine pathway) could represent a novel target for the development of new drugs for the treatment of osteoporosis. In addition, we noted that etidronate is a more effective drug than raloxifene, but that the simultaneous use of non-steroidal anti-inflammatory drugs may reduce the efficacy of etidronate. [source] CNS response to a thermal stressor in human volunteers and rats may predict the clinical utility of analgesicsDRUG DEVELOPMENT RESEARCH, Issue 1 2007David Borsook Abstract fMRI was used to test the hypothesis that global brain activation following a stressor (a thermal stimulus) that activates multiple brain circuits in healthy subjects can predict which drugs have higher potential for clinical utility for neuropathic pain. The rationale is that a drug will modulate multiple neural circuits that are activated by the system-specific stressor (e.g., pain). In neuropathic pain, some brain circuits have altered function, but most brain systems are "normal." Thus, the manner in which a drug effect on neural circuits is modulated by the stressor may provide insight into the clinical utility based on the readout of brain activation in response to the stimulus. Six drugs with known clinical efficacy (or lack thereof) in treating neuropathic pain were selected and the CNS response to each drug in the presence or absence of a pain stimulus was examined. The present results suggest that it is possible to identify potentially effective drugs based on patterns of brain activation in healthy human subjects and indicate that CNS activity is a more sensitive measure of drug action than standard psychophysical measures of pain intensity. This approach was repeated in rats and showed that a similar fMRI paradigm segregates these drugs in a similar manner suggesting a potential "translational tool" in evaluating drug efficacy for neuropathic pain. The sensitivity of this paradigm using fMRI allows clinical screening in small groups of healthy subjects, suggesting it could become a useful tool for drug development as well as for elucidating the mechanisms of neuropathic disease and therapy. Drug Dev. Res. 68:23,41, 2007. © 2007 Wiley-Liss, Inc. [source] Upregulation of glycolytic enzymes in proteins secreted from human colon cancer cells with 5-fluorouracil resistanceELECTROPHORESIS, Issue 12 2009Young-Kyoung Shin Abstract 5-Fluorouracil (5-FU) is the most commonly used chemotherapeutic agent for colorectal cancer (CRC). However, resistance to this drug is a major obstacle in CRC chemotherapy. Accurate prediction of response to 5-FU would avoid unnecessary chemotherapy and allow the selection of other effective drugs. To identify a candidate predictor of 5-FU resistance, we isolated secreted proteins that were up- or downregulated in a 5-FU-resistant cancer cell line, compared with the parent cell line (SNU-C4), using a stable isotope-coded labeling protocol. For validating the clinical applicability of this method, levels of the identified proteins were determined in the sera of 46 patients treated with 5-FU. In total, 238 proteins with molecular weights ranging from 50 to 75,kDa were identified. Among these, 45 and 35 secreted proteins were up- and downregulated in the 5-FU-resistant cell line, respectively. We observed significant upregulation of glycolytic enzymes, including glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase M2 (PK-M2), transketolase, and NADP(+)-dependent malic enzyme 1. In particular, the level of PK-M2, a key enzyme in the glycolytic pathway, showed an increasing tendency in both sera and tissues from CRC patients displaying no response to 5-FU-based chemotherapy (progressive and stable disease cases), compared with that in complete or partial responders to 5-FU-based chemotherapy; however, it did not reach the statistical significance. In conclusion, increasing pattern of PK-M2 observed with 5-FU resistance induced in vitro and in sera and tissues from CRC patients displaying poor response to 5-FU-based chemotherapy suggest the relevance of dysregulated glycolysis and 5-FU-resistant CRC. [source] Therapeutic approaches for newly diagnosed multiple myeloma patients in the era of novel drugsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2010Fortunato Morabito Abstract The treatment of newly diagnosed multiple myeloma (MM) has evolved rapidly over recent years. The availability of new effective drugs with novel mechanisms of action, such as thalidomide, lenalidomide and bortezomib in the last decade, has resulted in a new scenario expected to impact favorably on the outcome of patients with MM. The introduction of new drugs in the treatment of patients eligible for autologous stem cell transplantation (ASCT) has allowed for a significant increase of complete response rate with a positive impact on progression-free survival. In patients not eligible for ASCT, randomized trials have shown that both thalidomide and bortezomib when combined with melphalan and prednisone (MP) are superior to MP and are now considered the standard of care. Ongoing trials are assessing whether MP plus lenalidomide or the combination of lenalidomide plus dexamethasone should be considered an attractive treatment option, while additional studies are needed to determine the role of routine maintenance or consolidation therapy with these new drugs. This new therapeutic armamentarium in light of adequate prophylaxis and supportive care allows clinicians to greatly improve the survival perspectives for both young and elderly patients. In this review, we report updated data for the front-line therapy of MM, examining the role of new drugs either when administered as induction therapy before ASCT in younger patients or when combined with alkylating agents for the treatment of older patients. The most relevant articles on therapy of MM published from November 1982 to January 2010 (selected through PubMed), and recent meeting abstracts were used as sources for this review. [source] The model of fungal population dynamics affected by nystatinINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 1 2010Sergei I. Voychuk Abstract Fungal diseases are acute problems of the up-to-day medicine. Significant increase of resistance of microorganisms to the medically used antibiotics and a lack of new effective drugs follows in a growth of dosage of existing chemicals to solve the problem. Quite often such approach results in side effects on humans. Detailed study of fungi-antibiotic dynamics can identify new mechanisms and bring new ideas to overcome the microbial resistance with a lower dosage of antibiotics. In this study, the dynamics of the microbial population under antibiotic treatment was investigated. The effects of nystatin on the population of Saccharomyces cerevisiae yeasts were used as a model system. Nystatin effects were investigated both in liquid and solid media by viability tests. Dependence of nystatin action on osmotic gradient was evaluated in NaCl solutions. Influences of glucose and yeast extract were additionally analyzed. A "stepwise" pattern of the cell death caused by nystatin was the most intriguing. This pattern manifested in periodical changes of the stages of cell death against stages of resistance to the antibiotic. The mathematical model was proposed to describe cell-antibiotic interactions and nystatin viability effects in the liquid medium. The model implies that antibiotic ability to cause a cells death is significantly affected by the intracellular compounds, which came out of cells after their osmotic barriers were damaged © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010 [source] X-ray crystallographic analysis of the complexes of enoyl acyl carrier protein reductase of Plasmodium falciparum with triclosan variants to elucidate the importance of different functional groups in enzyme inhibitionIUBMB LIFE, Issue 6 2010Koustav Maity Abstract Triclosan, a well-known inhibitor of Enoyl Acyl Carrier Protein Reductase (ENR) from several pathogenic organisms, is a promising lead compound to design effective drugs. We have solved the X-ray crystal structures of Plasmodium falciparum ENR in complex with triclosan variants having different substituted and unsubstituted groups at different key functional locations. The structures revealed that 4 and 2, substituted compounds have more interactions with the protein, cofactor, and solvents when compared with triclosan. New water molecules were found to interact with some of these inhibitors. Substitution at the 2, position of triclosan caused the relocation of a conserved water molecule, leading to an additional hydrogen bond with the inhibitor. This observation can help in conserved water-based inhibitor design. 2, and 4, unsubstituted compounds showed a movement away from the hydrophobic pocket to compensate for the interactions made by the halogen groups of triclosan. This compound also makes additional interactions with the protein and cofactor which compensate for the lost interactions due to the unsubstitution at 2, and 4,. In cell culture, this inhibitor shows less potency, which indicates that the chlorines at 2, and 4, positions increase the ability of the inhibitor to cross multilayered membranes. This knowledge helps us to modify the different functional groups of triclosan to get more potent inhibitors. © 2010 IUBMB IUBMB Life, 467,476, 2010 [source] Advances in the management of irritable bowel syndromeJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 4 2002John E Kellow Abstract Recent advances in different aspects of irritable bowel syndrome have led to a need to reassess the overall management of this common, complex disorder. Important areas include: first, the heterogeneity of symptom patterns and the role of specific diagnostic symptom criteria for use in both clinical practice and in clinical research; second, the growing interest in the potential interaction between ,peripheral' and ,central' pathophysiological mechanisms; and third, the development of novel and effective drugs designed to target specific receptor systems in the enteric nervous system. This review covers each of these aspects and emphasizes an approach to management of patients based on pathophysiological considerations. © 2002 Blackwell Publishing Asia Pty Ltd [source] A Phase II Clinical Trial of Vinorelbine in Dogs with Cutaneous Mast Cell TumorsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2008I.A. Grant Background: Few effective drugs are available to treat dogs with locally aggressive or metastatic mast cell disease. Hypothesis: Vinorelbine, a semisynthetic derivative of vinblastine, is an effective drug for the treatment of canine mast cell tumors (MCT). Animals: Twenty-four dogs with cutaneous MCT. Methods: Dogs with at least 1 measurable, cytologically confirmed, and previously untreated cutaneous MCT received a single treatment with vinorelbine at the previously established dosage of 15 mg/m2 IV. Tumor measurements and CBC were evaluated before and 7 days after treatment. Adverse events were graded according to Veterinary Cooperative Oncology Group (VCOG) guidelines. Statistics: Data were accrued in accordance with a Simon's 2-stage design with a noninteresting response rate of .05, a target response of .25, and , and , values of .10. Results: Three of 24 dogs (13%) had a response to treatment, including 1 measurable complete response and 1 measurable partial response. The 3rd dog had microscopic complete response to treatment with stable measurable disease. Twenty other dogs (83%) had stable disease and 1 dog (4%) had progressive disease. Neutropenia occurred in 13 dogs (54%) (grade 1, n = 4; grade 3, n = 6; grade 4, n = 3). Gastrointestinal toxicity occurred in 11 dogs (46%) (anorexia: grade 1, n = 3; grade 2, n = 1; grade 3, n = 1; diarrhea: grade 1, n = 2; grade 3, n = 1; vomiting: grade 1, n = 5; grade 3, n = 1). Conclusions and Clinical Importance: Vinorelbine was associated with an overall response rate of 13% and a high prevalence of neutropenia. Additional studies are indicated to determine if repeated dosing of vinorelbine or combination of vinorelbine with other drugs increases the observed biologic activity against canine MCT. [source] Lack of Clinical Efficacy of a Phosphodiesterase-4 Inhibitor for Treatment of Heaves in HorsesJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2006Jean-Pierre Lavoie Phosphodiesterase-4 (PDE 4) enzyme inhibitors have been shown to have anti-inflammatory properties in various animal disease processes and therefore could be effective drugs for the treatment of equine airway diseases. The purpose of this study was to evaluate the efficacy and adverse effects of the PDE 4 inhibitor L-826,141 in horses with heaves. In a blinded parallel design, horses with heaves exposed daily to moldy hay were given a placebo for 14 days and then administered either L-826,141 (n = 6; loading dose of 1 mg/kg IV followed by 0.5 mg/kg IV q48h) or dexamethasone (n = 6; 0.04 mg/kg IV q24h) from days 15 to 29 (study 1). Pulmonary function and bronchoalveolar (BAL) cytology were evaluated weekly from baseline (day 0) to 29 days. In study 2, horses were treated with L-826,141 (1.0 mg/kg IV q24h) for 8 days. Although ex vivo lipopolysaccharide-induced tumor necrosis factor (TNF)-, and LTB4 production by fresh blood were inhibited up to 90% after repeated administrations of L-826,141, this treatment failed to improve lung function. In contrast, dexamethasone (positive control) treatment resulted in significant improvement in lung mechanics and airway function in all horses. Neither drug had a significant effect on BAL total cell counts and differential cytology. Administration of the PDE 4 inhibitor L-826,141 for up to 14 days to horses with heaves was not associated with an improvement in airway function or inflammation. These findings suggest that the PDE 4 enzyme is not a key mediator of lung inflammation in heaves. [source] Theoretical Prediction of Antiproliferative Activity against Murine Leukemia Tumor Cell Line (L1210).MOLECULAR INFORMATICS, Issue 1 20093D-Morse Descriptor, its Application in Computational Chemistry Abstract Cancer is among the top ten causes of death in the world but in spite of the efforts of the pharmaceutical companies and many governmental organizations, new and more effective drugs are urgently needed. Computer-assisted studies have been widely used to predict anticancer activity taking into account different molecular descriptors, statistical techniques, cell lines, and datasets of congeneric and non-congeneric compounds. [source] Spontaneous animal model, ddY mouse, for studying the pathogenesis and treatment in patients with immunoglobulin A nephropathyNEPHROLOGY, Issue 1 2010YASUHIKO TOMINO ABSTRACT: Immunoglobulin (Ig)A nephropathy has the highest incidence among the various forms glomerulonephritis in the world. The initiating and progressive factors in patients with IgA nephropathy are still obscure. Although there is no specific treatment for patients with IgA nephropathy at present, more clinical trials of new treatments are warranted for such patients. Therefore, it is necessary to clarify those factors and to develop more effective drugs using a spontaneous animal model, the ddY mouse, in the future. [source] | |||||||||||||||||||||||||||||||