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Optimal Dose (optimal + dose)

Distribution by Scientific Domains

Medical Sciences	89%
3 Other Domains	11%

Distribution within Medical Sciences

Allergy & Clinical Immunology	11%
13 Other Subdomains	56%

Selected Abstracts

Determining the Optimal Dose of Intravenous Fat Emulsion for the Treatment of Severe Verapamil Toxicity in a Rodent Model

ACADEMIC EMERGENCY MEDICINE, Issue 12 2008
Eric Perez MD
Abstract Objectives:, Recent animal studies have shown that intravenous fat emulsion (IFE) increases survival and hemodynamics in severe verapamil toxicity. However, the optimal dose of IFE is unknown. The primary objective was to determine the optimal dose of IFE based on survival in severe verapamil toxicity. Secondary objectives were to determine the effects on hemodynamic and metabolic parameters. The hypothesis was that there is a dose-dependent effect of IFE on survival until a maximum dose is reached. Methods:, This was a controlled dose-escalation study. Thirty male rats were anesthetized, ventilated, and instrumented to record mean arterial pressure (MAP) and heart rate (HR). Verapamil toxicity was achieved by a constant infusion of 15 mg/kg/hr. After 5 minutes, a bolus of 20% IFE was given. Animals were divided into six groups based on differing doses of IFE. Arterial base excess (ABE) was measured every 30 minutes. Data were analyzed with analysis of variance. Results:, The mean survival time for each dose of IFE was 0 mL/kg = 34 minutes, 6.2 mL/kg = 58 minutes, 12.4 mL/kg = 63 minutes, 18.6 mL/kg = 143.8 minutes, 24.8 mL/kg = 125.6 minutes, and 37.6 mL/kg = 130 minutes. Post hoc testing determined that the 18.6 mL/kg dose resulted in the greatest survival when compared to other doses. It increased survival 107.2 minutes (p = 0.004), 91.2 minutes (p = 0.001), and 80.8 minutes (p = 0.023) when compared to the lower doses of 0, 6.2, and 12.4 mL/kg, respectively. There was no added benefit to survival for doses greater than 18.6 mL/kg. The secondary outcomes of HR, MAP, and ABE showed the most benefit with 24.8 mL/kg of IFE at both 30 and 60 minutes. Conclusions:, The greatest benefit to survival occurs with 18.6 mL/kg IFE, while the greatest benefit to HR, MAP, and BE occurs at 24.8 mL/kg IFE. The optimal dose for the treatment of severe verapamil toxicity in this murine model was 18.6 mL/kg. [source]

A Comparison of Two Botulinum Type A Toxin Preparations for the Treatment of Glabellar Lines: Double-Blind, Randomized, Pilot Study

DERMATOLOGIC SURGERY, Issue 12 2005
Philippa L. Lowe MB ChB
Background. Botulinum toxins have been proven effective for reducing facial lines. There are two commercial types of botulinum toxin type A available in many countries but no published comparison studies. Objective. To compare the efficacy and tolerability of Botox Cosmetic and Dysport 50 U in the treatment of glabellar lines (using 20 U of Botox Cosmetic, which is the dose approved by the US Food and Drug Administration for the treatment of glabellar lines, and 50 U of Dysport, which has been reported to be the optimal dose for this formulation). Study Design. Parallel-group double-blind pilot study. Evaluation by observing physician, photographic, and patient evaluations. Conclusion. Botox 20 U provided better and more prolonged efficacy than Dysport 50 U in the treatment of glabellar lines. NICHOLAS LOWE, MD, FRCP, AND RICKIE PATNAIK, MD, HAVE RECEIVED RESEARCH GRANTS FROM ALLERGAN INC. NICHOLAS LOWE OWNS STOCK IN ALLERGAN INC AND HAS RECEIVED CONSULTING PAYMENTS AND EDUCATIONAL GRANTS FROM ALLERGAN INC. THIS STUDY WAS FUNDED BY A GRANT FROM ALLERGAN INC. [source]

Cold flow properties of fuel mixtures containing biodiesel derived from animal fatty waste

EUROPEAN JOURNAL OF LIPID SCIENCE AND TECHNOLOGY, Issue 9 2006
Kiril Kazancev
Abstract The aims of the present study were to evaluate the cold temperature behavior of methyl esters of vegetable and animal origin and of their mixtures with fossil diesel fuel, as well as to investigate the effectiveness of different depressants. Various blends of rapeseed oil methyl esters, linseed oil methyl esters, pork lard methyl esters and fossil diesel fuel were prepared, and both cloud point and cold filter plugging point (CFPP) were analyzed. It was found that mixtures with CFPP values of ,5,°C and lower may contain up to 25% of pork lard methyl esters; whereas the ratio of summer fossil diesel fuel and rapeseed oil methyl esters may vary over a wide range, i.e. such mixtures can be used in a diesel engine in the summer. In the transitory periods it is possible to use up to 20% animal and vegetable ester blends (3,:,7) with winter fossil diesel, whereas only up to 5% of esters can be added to the fuel used in winter. In order to improve the cold properties of rapeseed oil, pork lard and linseed oil methyl ester mixtures, various additives were tested. Depressant Viscoplex 10,35 with an optimal dose of 5000,mg/kg was found to be the most effective. [source]

Dose Range-Finding Studies With Frovatriptan in the Acute Treatment of Migraine

HEADACHE, Issue 2002
Alan Rapoport MD
Objective.,To determine the optimum dose of frovatriptan for the acute treatment of migraine. Background.,Frovatriptan is a new triptan developed for the acute treatment of migraine. The dose-response characteristics and safety of frovatriptan have been investigated across a broad range of doses from 0.5 to 40 mg. Design.,Two randomized, placebo-controlled, double-blind, parallel-group trials, with a total of 1453 patients, were performed to determine the optimal dose of the 5-HT1B/1D agonist, frovatriptan, for the acute treatment of migraine. The dose ranges studied were 2.5 to 40 mg in the high-dose study and 0.5 to 5 mg in the low-dose study. Results.,At 2 hours postdosing for initial moderate or severe headache (International Headache Society grades 2 or 3), there was an approximate two-fold difference in the proportion of patients taking frovatriptan doses of 2.5 to 40 mg with mild or no headache compared to placebo. Frovatriptan doses of 0.5 mg and 1 mg were not more effective than placebo at 2 hours postdose, and 2.5 mg was identified as the lowest effective dose for the relief of migraine and accompanying symptoms. Above 2.5 mg, no dose-response relationship was observed for any efficacy parameters. There was an increase in the incidence of adverse events from 10 mg and above, but the vast majority were rated as mild in severity and did not impact upon tolerability in a significant manner. Conclusions.,Frovatriptan was well tolerated throughout the dose range of 0.5 to 40 mg. The 2.5-mg dose confers the optimal balance of efficacy and tolerability for the acute treatment of migraine. [source]

Potential role of CXCL10 in the induction of cell injury and mitochondrial dysfunction

INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 3 2010
Lipi Singh
Summary Chemokines have been known to play a critical role in pathogenesis of chronic pancreatitis and acinar cell death. However, the role played by one of the CXC chemokines: CXCL10 in regulation of acinar cell death has remained unexplored. Hence, this study was designed to assess the role of CXCL10 promoting apoptosis in ex vivo cultured acinar cells. Primary human pancreatic acinar cell cultures were established and exposed to varying doses of CXCL10 for different time intervals. Apoptotic induction was evaluated by both qualitative as well as quantitative analyses. Various mediators of apoptosis were also studied by Western blotting, membrane potential (,m) and ATP depletion in acinar cells. Analysis of apoptosis via DNA ladder and cell death detection , ELISA demonstrated that CXCL10 induced 3.9-fold apoptosis when administrated at an optimal dose of 0.1 ,g of recombinant CXCL10 for 8 h. Quantitative analysis using FACS and dual staining by PI-annexin showed increased apoptosis (48.98 and 53.78% respectively). The involvement of upstream apoptotic regulators like pJNK, p38 and Bax was established on the basis of their increased expression of CXCL10. The change of ,m by 50% was observed in the presence of CXCL10 in treated acinar cells along with enhanced expression of Cytochrome C, apaf-1 and caspase 9/3 activation. In addition, ATP depletion was also noticed in CXCL10 stimulated acinar cells. CXCL10 induces cell death in human cultured pancreatic cells leading to apoptosis and DNA fragmentation via CXCR3 signalling. These signalling mechanisms may play an important role in parenchymal cell loss and injury in pancreatitis. [source]

Aspirin, 110 years later

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2009
C. PATRONO
Summary., Although conceived at the end of the 19th century as a synthetic analgesic agent with improved gastric tolerability vs. naturally occurring salicylates, acetylsalicylic acid (marketed as aspirin in 1899) turned out to be an ideal antiplatelet agent about 90 years later, following the understanding of its mechanism of action, the development of a mechanism-based biomarker for dose-finding studies, and the initiation of a series of appropriately sized, randomized clinical trials to test its efficacy and safety at low doses given once daily. At the turn of its 110th anniversary, aspirin continues to attract heated debates on a number of issues including (i) the optimal dose to maximize efficacy and minimize toxicity; (ii) the possibility that some patients may be ,resistant' to its antiplatelet effects; and (iii) the balance of benefits and risks in primary vs. secondary prevention. [source]

Agreement of efficacy assessments for five-grass pollen sublingual tablet immunotherapy

ALLERGY, Issue 1 2009
A. Didier
Background:, The optimal dose of five-grass pollen sublingual tablet immunotherapy (SLIT) was established recently by the primary criteria Rhinoconjunctivitis Total Symptom Score (RTSS) from the first treatment season. Secondary and exploratory criteria, such as RTSS at peak pollen season, exploratory combined symptom and rescue medication use score, quality of life and immunological markers are calculated and described in this analysis. Methods:, Six hundred and twenty-eight patients with grass pollen rhinoconjunctivitis (,2 years duration) were randomized in a double-blind, placebo-controlled trial conducted in Europe. Patients received once-daily SLIT (Stallergenes, Antony, France) of 100IR, 300IR, 500IR or placebo, starting 4 months before grass pollen season and throughout the 2005 season. Patients were instructed to take rescue medication only if symptoms were severe and record symptom severity on using the RTSS. Results:, Both 300IR and 500IR doses significantly reduced mean RTSS at pollen peak (P = 0.0005 and P = 0.0014, respectively) and the exploratory combined score (P = 0.0001 and P = 0.0026, respectively) compared with placebo. Compared with patients in the placebo group, those who were taking the 300IR and 500IR doses reported significantly improved quality of life using the mean Rhinoconjunctivitis Quality of Life Questionnaire scores during the peak of the pollen season (P < 0.0001) and at the end of the pollen season (P = 0.0031 and P , 0.0001, respectively). Specific immunoglobulin G4 increased significantly depending on the SLIT dose (P < 0.0001). Conclusions:, All secondary efficacy criteria, including efficacy at pollen peak, combined score, quality of life and immunological changes, indicate that 300IR tablets represent the optimal dose and suggest it is appropriate for use in clinical practice. [source]

Double-blind study of pardoprunox, a new partial dopamine agonist, in early Parkinson's disease,

MOVEMENT DISORDERS, Issue 6 2010
Juliana Bronzova MD
Abstract This study examined the efficacy and safety of the partial dopamine agonist, pardoprunox (SLV308), in the treatment of patients with early Parkinson's disease (PD). Patients were randomized to receive pardoprunox (n = 69) or placebo (n = 70). Pardoprunox was titrated to each patient's optimal dose (9,45 mg/d) over 2 to 6 weeks and then maintained at this dose for a further 3 weeks. Concomitant anti-Parkinson treatment was not permitted. In the primary analysis, Unified PD Rating Scale (UPDRS)-Motor score was improved in pardoprunox-treated patients (overall mean dose 23.8 mg/d; ,7.3 points), as compared with placebo (,3.0 points; P = 0.0001), from baseline to end point. At end point, there were more responders (,30% reduction in UPDRS-Motor score) in the pardoprunox group (50.7%) than in the placebo group (15.7%; P < 0.0001). In other secondary analyses, UPDRS-activities of daily living (ADL) and -ADL+Motor scores were also significantly more improved in the pardoprunox group. Nausea was reported by 32 of 68 (47.1%) pardoprunox-treated patients (vs. 3/70, 4.3%, placebo-treated patients), with dizziness, somnolence, headache, and asthenia also reported by ,10 patients. In this exploratory proof-of-concept study, pardoprunox significantly improved motor function in patients with early PD. The efficacy and safety profile of pardoprunox justifies its further investigation in PD. © 2010 Movement Disorder Society [source]

Acotiamide (Z-338) as a possible candidate for the treatment of functional dyspepsia

NEUROGASTROENTEROLOGY & MOTILITY, Issue 6 2010
H. Suzuki
Abstract Acotiamide hydrochloride is a novel upper gastrointestinal (GI) motility modulator and stress regulator currently being developed for the treatment of functional dyspepsia (FD). The mechanism underlying the enhancement of GI motility by this agent has been proposed to be based on its muscarinic antagonism and inhibitory effects on acetylcholinesterase activity. Pathophysiological studies showed that acotiamide significantly improved both delayed gastric emptying and feeding inhibition in restraint stress-induced model, but did not affect both normal gastric emptying and feeding in intact animals, indicating that acotiamide exerted effects only on the impaired gastric emptying and feeding behavior. According to the clinical pilot study in Europe, acotiamide, at the dose of 100 mg t.i.d., showed to improve the symptoms and quality of life of patients with FD, indicating the need for larger scale symptomatic studies on the efficacy of acotiamide in patients with FD. The recent phase II studies conducted in Japan presented in this issue of the journal also confirmed that acotiamide, at the optimal dose of 100 mg, has potential therapeutic efficacy, especially for meal-related FD symptoms. Although a phase III study is on going, acotiamide is now expected as a novel treatment option for FD. [source]

Opioid Rotation in the Management of Chronic Pain: Where Is the Evidence?

PAIN PRACTICE, Issue 2 2010
K.C.P. Vissers MD
Abstract The management of chronic pain remains a challenge because of its complexity and unpredictable response to pharmacological treatment. In addition, accurate pain management may be hindered by the prejudice of physicians and patients that strong opioids, classified as step 3 medications in the World Health Organization ladder for cancer pain management, are reserved for the end stage of life. Recent information indicates the potential value of strong opioids in the treatment of chronic nonmalignant pain. There are, up until now, insufficient data to provide indications about which opioid to use to initiate treatment or the dose to be used for any specific pain syndrome. The strong inter-patient variability in opioid receptor response and in the pharmacokinetic and pharmacodynamic behavior of strong opioids justifies an individual selection of the appropriate opioid and stepwise dose titration. Clinical experience shows that switching from one opioid to another may optimize pain control while maintaining an acceptable side effect profile or even improving the side effects. This treatment strategy, described as opioid rotation or switch, requires a dose calculation for the newly started opioid. Currently, conversion tables and equianalgesic doses are available. However, those recommendations are often based on data derived from studies designed to evaluate acute pain relief, and sometimes on single dose studies, which reduces this information to the level of an indication. In daily practice, the clinician needs to titrate the optimal dose during the opioid rotation from a reduced calculated dose, based on the clinical response of the patient. Further research and studies are needed to optimize the equianalgesic dosing tables. [source]

Two different doses of caudal neostigmine co-administered with levobupivacaine produces analgesia in children

PEDIATRIC ANESTHESIA, Issue 5 2009
KAZIM KARAASLAN MD
Summary Background:, This study was aimed to evaluate the analgesic efficacy, duration of analgesia, and side effects of two different doses of caudal neostigmine used with levobupivacaine in children. Methods:, Sixty boys, between 5 months and 5 years, undergoing genito-urinary surgery were allocated randomly to one of three groups (n = 20 each). Group I patients received caudal 0.25% levobupivacaine (1 ml·kg,1) alone. Groups II and III patients received neostigmine (2 and 4 ,g·kg,1 respectively) together with levobupivacaine used in the same dose as Group I. Pain scores were assessed using Children's and Infant's Postoperative Pain Scale (CHIPPS) at 15th (t1) min after arrival to postanesthetic care unit, and 1st (t2), 2nd (t3), 3rd (t4), 4th (t5), 8th (t6), 16th (t7), and 24th (t8) hour postoperatively. Duration of analgesia, amount of additional analgesic (paracetamol), score of motor blockade and complications were recorded for 24 h postoperatively, and compared between groups. Results:, CHIPPS scores were higher during t2, t3, t6, t7 and t8 periods, duration of analgesia was shorter, and total analgesic consumption was higher in Group I compare to neostigmine groups (P < 0.05). Duration of postoperative analgesia and total analgesic consumption were similar in Groups II and III (P > 0.05). Adverse effects were not different between three groups. Conclusions:, Caudal neostigmine in doses of 2 and 4 ,g·kg,1 with levobupivacaine extends the duration of analgesia without increasing the incidence of adverse effects, and 2 ,g·kg,1 seems to be the optimal dose, as higher dose has no further advantages. [source]

Postoperative continuous intrathecal pain treatment in children after selective dorsal rhizotomy with bupivacaine and two different morphine doses

PEDIATRIC ANESTHESIA, Issue 4 2006
KARIN HESSELGARD RN
Summary Background:, Children undergoing selective dorsal rhizotomy (SDR) experience severe pain postoperatively; a pain related to both the extensive surgical exposure with multilevel laminectomy and nerve root manipulation. We sought to define an optimal dose of continuous intrathecal (IT) morphine and bupivacaine to treat this severe pain. The aim of this study was to compare two different concentrations of morphine in a fixed dose of bupivacaine with regard to the analgesic effect and survey if they differed in side effects. Methods:, Twenty-six children, aged 2.7,7.4 years undergoing SDR were included in this study. Postoperatively 11 children received a continuous infusion of morphine 0.4 ,g.kg,1.h,1 and bupivacaine 40 ,g.kg,1.h,1 (low-dose group) and 15, a continuous infusion of morphine 0.6 ,g.kg,1.h,1 and bupivacaine 40 ,g.kg,1.h,1 (high-dose group). The Behavioral Observational Pain Scale (BOPS) was used to evaluate pain. Results:, Better pain relief was obtained in the high-dose group seen in lower BOPS score compared with the low-dose group [P = 0.03, Fisher's permutation test and P = 0.06 Wilcoxon,Mann,Whitney (WMW) test]. The low-dose group received seven times as much ketobemidone 0.43 ± 0.54 mg.kg,1 48 h,1 compared with 0.06 ± 0.09 mg.kg,1 48 h,1 in the high-dose group (P = 0.0005 Fisher's permutation test, P = 0.0017 WMW test). There was no statistical difference in pruritus and postoperative nausea and vomiting between the groups. Respiratory and hemodynamic depression was not found. Conclusion:, This study shows that, compared with low-dose, the higher dose of continuous IT morphine combined with bupivacaine, significantly reduce pain score and postoperative intravenous analgesic requirements without increasing adverse effects. [source]

ORIGINAL RESEARCH,ED PHARMACOTHERAPY: Psychosocial Outcomes and Drug Attributes Affecting Treatment Choice in Men Receiving Sildenafil Citrate and Tadalafil for the Treatment of Erectile Dysfunction: Results of a Multicenter, Randomized, Open-Label, Crossover Study

THE JOURNAL OF SEXUAL MEDICINE, Issue 4 2006
FRCGP, John Dean MBBS
ABSTRACT Introduction., Although sildenafil citrate (sildenafil) and tadalafil are efficacious and well-tolerated treatments for erectile dysfunction (ED), preference studies have shown that patients may favor one medication over the other. Aim., To determine whether psychosocial outcomes differed when men with ED received tadalafil compared with sildenafil. Main Outcome Measures., Measures included a treatment preference question, Psychological and Interpersonal Relationship Scales (PAIRS), and Drug Attribute Questionnaire. Methods., Randomized, open-label, crossover study. After a 4-week baseline, men with ED (N = 367; mean age = 54 years; naïve to type 5 phosphodiesterase inhibitor therapy) were randomized: tadalafil for 12 weeks then sildenafil for 12 weeks or vice versa (8-week dose optimization/4-week assessment phases). During dose optimization, patients started with 10 mg tadalafil, or 25 or 50 mg sildenafil and could titrate to their optimal dose (10 or 20 mg tadalafil; 25, 50, or 100 mg sildenafil). Medications were taken as needed. Patients completing both 12-week periods chose which medication to continue during an 8-week extension. Results., Of 291 men completing both treatment periods, 71% (N = 206) chose tadalafil and 29% (N = 85) chose sildenafil (P < 0.001) for the 8-week extension. When taking tadalafil compared with sildenafil men had higher mean endpoint scores on PAIRS Sexual Self-Confidence (tadalafil = 2.91 vs. sildenafil = 2.75; P < 0.001) and Spontaneity (tadalafil = 3.32 vs. sildenafil = 3.17; P < 0.001) Domains and a lower mean endpoint score on Time Concerns Domain (tadalafil = 2.2 vs. sildenafil = 2.59; P < 0.001). The two most frequently chosen drug attributes to explain treatment preference were ability to get an erection long after taking the medication and firmness of erections. Tadalafil and sildenafil were well tolerated with 12 (3.3%) patients discontinuing for an adverse event. Conclusions., As measured with PAIRS, men with ED had higher sexual self-confidence and spontaneity and less time concerns related to sexual encounters when treated with tadalafil compared with sildenafil. These psychosocial outcomes may help explain why more men (71%) preferred tadalafil for the treatment of ED in this clinical trial. Dean J, Hackett GI, Gentile V, Pirozzi-Farina F, Rosen RC, Zhao Y, Warner MR, and Beardsworth A. Psychosocial outcomes and drug attributes affecting treatment choice in men receiving sildenafil citrate and tadalafil for the treatment of erectile dysfunction: Results of a multicenter, randomized, open-label, crossover study. J Sex Med 2006;3:650,661. [source]

ORIGINAL ARTICLE: Optimal effect-site concentration of remifentanil for preventing cough during emergence from sevoflurane-remifentanil anaesthesia,

ANAESTHESIA, Issue 9 2010
N. H. Jun
Summary This randomised, double-blinded, controlled trial was designed to identify the optimal dose of remifentanil for cough suppression without adverse effects during emergence from sevoflurane-remifentanil anaesthesia for thyroidectomy. One hundred and four patients were randomly assigned to maintain target effect-site concentrations of remifentanil at 0 (control group), 1.0 (remifentail 1 group), or 1.5 ng.ml,1 (remifentanil 1.5 group) during emergence. The incidence of coughing was lower in the remifentanil 1.5 group (31%) than in the control group (74%) or remifentanil 1 group (63%) (p = 0.0004). In addition, the severity of coughing during extubation was lower in the remifentanil 1.5 group (median (IQR [range]) 0 (0,1 [0,1]) than in the control group (1 (0,2 [0,3])) and remifentanil 1 group (1 (0,2 [0,3])) (p = 0.004). Haemodynamic changes were reduced, but emergence time and stay in the post-anaesthesia care unit was prolonged in the remifentanil 1.5 group. Maintaining the remifentanil effect-site concentration at 1.5 ng.ml,1 during emergence from sevoflurane-remifentanil anaesthesia reduces the incidence and severity of coughing without serious adverse events and may provide haemodynamic stability in patients undergoing thyroidectomy. However, awakening may be delayed. [source]

Review: Biological effects of organic arsenic compounds in seafood,

APPLIED ORGANOMETALLIC CHEMISTRY, Issue 8 2002
Teruaki Sakurai
Abstract This review describes the results of our recent experiments concerning the in vitro biological effects of water-soluble organic arsenic compounds contained in seafood in murine immune effector cells using synthetic pure materials. A dimethyl organic arsenic compound in seaweed, viz. an arsenosugar, was weakly cytotoxic in murine alveolar macrophages during a 72,h incubation (50% lethal concentration in vitro, LC50,=,8,mmol,dm,3); conversely, it increased the cell viability of peritoneal macrophages at an optimal dose of 5,mmol,dm,3. Trimethyl arsenic compounds in marine animals, arsenocholine and arsenobetaine, were less toxic in murine splenocytes, thymocytes, Peyer's patch lymphocytes, peritoneal macrophages and alveolar macrophages in vitro, even over 10,mmol,dm,3. Interestingly, they significantly increased the cell viability of immature bone marrow cells at doses over 100,µmol dm,3, and induced the maturation of bone marrow cells especially into granulocytes. The tetramethyl arsenic compound, tetramethylarsonium hydroxide, isolated from some lower marine animals had no in vitro cytolethality on murine immune effector cells. Taken together, organic arsenic compounds in seafood are not very toxic in living systems. Copyright © 2002 John Wiley & Sons, Ltd. [source]

Supplementing the feed of pikeperch [Sander lucioperca (L.)] juveniles with MacroGard and its influence on nonspecific cellular and humoral defense mechanisms

AQUACULTURE RESEARCH, Issue 4 2009
Andrzej K Siwicki
Abstract This study examined the influence of ,-1.3/1.6-glucan (MacroGard) on the innate immune system in healthy pikeperch (Sander lucioperca) juveniles. MacroGard was fed in a pelleted ration of 1 or 2 g kg,1 feed for 6 weeks. The control group of fish was fed feed with no supplement. Blood, pronephros and spleen samples for the study of nonspecific cellular and humoral defense mechanisms were collected from 10 fish from each group. No changes were observed in either the behaviour or the health of the fish throughout the rearing period. Fish mortality was not noted in any of the groups. Additionally, the supplementation of feed with MacroGard did not have a significant impact on the fish growth rate as expressed in both absolute and relative values (P>0.05). The condition of the fish from the experimental group did not differ from that of the control group specimens, and the feed conversion ratios were also very similar (P>0.05). The results showed that MacroGard administered in two doses significantly (P<0.05) activated the metabolic activity and potential killing activity of spleen phagocytes, compared with the control-fed pikeperch. The highest phagocyte activity was observed with a dose of 2 g kg,1. The proliferative response of pronephros lymphocytes indicated a similar pattern. MacroGard significantly increased proliferative response of lymphocytes stimulated by mitogens (P<0.05). MacroGard also significantly increased the lysozyme activity and total immunoglobulin levels in the serum. In this study neither significantly different ceruloplasmine activity or total protein level in serum were observed. The result showed that MacroGard at the optimal dose of 1 g kg,1 feed and a twofold higher dose does not have a negative influence on the hepatocytes or increased nonspecific cell- and humoral-mediated immunity in healthy pikeperch. [source]

Determining the Optimal Dose of Intravenous Fat Emulsion for the Treatment of Severe Verapamil Toxicity in a Rodent Model

Effects of the PAF receptor antagonist UK74505 on local and remote reperfusion injuries following ischaemia of the superior mesenteric artery in the rat

BRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2000
D G Souza
The effects of the long lasting and potent PAF receptor antagonist UK74505 were assessed on the local and remote injuries following ischaemia and reperfusion (I/R) of the superior mesenteric artery (SMA) in rats. In a severe model of ischaemia (120 min) and reperfusion (120) injury, in addition to the local and remote increases in vascular permeability and neutrophil accumulation, there was significant tissue haemorrhage, blood neutropenia, systemic hypotension and elevated local and systemic TNF-, levels. Post-ischaemic treatment with the selectin blocker fucoidin (10 mg kg,1) prevented neutrophil accumulation in tissue and, in consequence, all the local and systemic injuries following severe I/R. Treatment with an optimal dose of UK74505 (1 mg kg,1) also reversed local and remote neutrophil accumulation, increases in vascular permeability and intestinal haemorrhage. UK74505 partially inhibited blood neutropenia and reperfusion-induced hypotension. Interestingly, both fucoidin and UK74505 prevented the local, but not systemic, increases of TNF-, levels following severe I/R injury, demonstrating an important role of migrating cells for the local production of TNF-,. However, the results do not support a role for PAF as an intermediate molecule in the production of systemic TNF-,. The beneficial effects of UK74505 and other PAF receptor antagonists in models of I/R injury in animals and the safety of UK74505 use in man warrant further investigations of the use of this drug as preventive measure for I/R injury in humans. British Journal of Pharmacology (2000) 131, 1800,1808; doi:10.1038/sj.bjp.0703756 [source]

Circulating biomarkers for vascular endothelial growth factor inhibitors in renal cell carcinoma,

CANCER, Issue S10 2009
Amado J. Zurita MD
Abstract In recent years, there has been significant progress in the clinical development and application of antiangiogenic therapies in renal cell carcinomas, particularly inhibitors of the vascular endothelial growth factor (VEGF) pathway. Despite this progress, no validated methods are currently available for identifying which patients are most likely to respond to treatment or experience toxic effects, selecting the optimal dose, or determining whether the intended molecular target has been effectively inhibited. However, recent studies have suggested that some of the biomarkers currently under investigation in clear cell renal cell carcinoma for VEGF pathway inhibitors are promising. These biomarkers include circulating proangiogenic factors and receptors; markers of hypoxia and endothelial damage; and cellular populations in peripheral blood, such as circulating endothelial cells. Further preclinical and translational validation studies are still needed to determine their practical utility in the clinical setting. Cancer 2009;115(10 suppl):2346-54. © 2009 American Cancer Society. [source]

Treating cancer with PEG Intron

CANCER, Issue 2 2002
Pharmacokinetic profile, dosing guidelines for an improved interferon-alpha-2b formulation
Abstract BACKGROUND PEG Intron (pegylated interferon-alpha-2b [IFN-,-2b]; Schering-Plough, Kenilworth, NJ) has demonstrated delayed clearance and increased area under the curve compared with native IFN-,-2b. Studies in patients with chronic hepatitis C infection and malignancies have demonstrated both biologic and clinical activity of PEG Intron and have provided empiric data to compare the pharmacokinetics (PK) and pharmacodynamics of PEG Intron and IFN-,-2b. METHODS The authors conducted a review of the available data comparing the PK and pharmacodynamic effects of PEG Intron and IFN-,-2b. Safety and efficacy data from Phase I/II studies of PEG Intron in patients with chronic myelogenous leukemia (CML) and solid tumors were also reviewed. RESULTS Data from patients with chronic hepatitis C infection suggest that exposure to IFN at a PEG Intron dose of 0.25 ,g/kg per week is similar to that observed after administration of IFN-,-2b at a dose of 3 million International Units, three times per week. PEG Intron at doses up to 6 ,g/kg per week was well tolerated and demonstrated clinical activity in patients with CML and solid tumors, including metastatic melanoma and renal cell carcinoma. CONCLUSIONS Dose intensification can be achieved safely in patients with CML and solid tumors using PEG Intron, which could improve efficacy. These results provide useful dosing guidelines to clinicians investigating the antitumor activity of PEG Intron in patients with malignancies. More data are needed to determine the optimal dose in various oncologic indications. However, these results provide a sound rationale for further investigation of PEG Intron. Cancer 2002;95:389,96. © 2002 American Cancer Society. DOI 10.1002/cncr.10663 [source]

Phase I clinical trial using peptide vaccine for human vascular endothelial growth factor receptor 2 in combination with gemcitabine for patients with advanced pancreatic cancer

CANCER SCIENCE, Issue 2 2010
Motoki Miyazawa
Vascular endothelial growth factor receptor 2 (VEGFR2) is an essential factor in tumor angiogenesis and in the growth of pancreatic cancer. Immunotherapy using epitope peptide for VEGFR2 (VEGFR2-169) that we identified previously is expected to improve the clinical outcome. Therefore, a phase I clinical trial combining of VEGFR2-169 with gemcitabine was conducted for patients with advanced pancreatic cancer. Patients with metastatic and unresectable pancreatic cancer were eligible for the trial. Gemcitabine was administered at a dose of 1000 mg/m2 on days 1, 8, and 15 in a 28-day cycle. The VEGFR2-169 peptide was subcutaneously injected weekly in a dose-escalation manner (doses of 0.5, 1, and 2 mg/body, six patients/one cohort). Safety and immunological parameters were assessed. No severe adverse effect of grade 4 or higher was observed. Of the 18 patients who completed at least one course of the treatment, 15 (83%) developed immunological reactions at the injection sites. Specific cytotoxic T lymphocytes (CTL) reacting to the VEGFR2-169 peptide were induced in 11 (61%) of the 18 patients. The disease control rate was 67%, and the median overall survival time was 8.7 months. This combination therapy for pancreatic cancer patients was tolerable at all doses. Peptide-specific CTL could be induced by the VEGFR2-169 peptide vaccine at a high rate, even in combination with gemcitabine. From an immunological point of view, the optimal dose for further clinical trials might be 2 mg/body or higher. This trial was registered with ClinicalTrial.gov (no. NCT 00622622). (Cancer Sci 2009) [source]

Effects of a natural extract of (,)-hydroxycitric acid (HCA-SX) and a combination of HCA-SX plus niacin-bound chromium and Gymnema sylvestre extract on weight loss

DIABETES OBESITY & METABOLISM, Issue 3 2004
H. G. Preuss
Aim:, The efficacy of optimal doses of highly bioavailable (,)-hydroxycitric acid (HCA-SX) alone and in combination with niacin-bound chromium (NBC) and a standardized Gymnema sylvestre extract (GSE) on weight loss in moderately obese subjects was evaluated by monitoring changes in body weight, body mass index (BMI), appetite, lipid profiles, serum leptin and excretion of urinary fat metabolites. HCA-SX has been shown to reduce appetite, inhibit fat synthesis and decrease body weight without stimulating the central nervous system. NBC has demonstrated its ability to maintain healthy insulin levels, while GSE has been shown to regulate weight loss and blood sugar levels. Methods:, A randomized, double-blind, placebo-controlled human study was conducted in Elluru, India for 8 weeks in 60 moderately obese subjects (ages 21,50, BMI >26 kg/m2). Subjects were randomly divided into three groups. Group A was administered HCA-SX 4667 mg, group B was administered a combination of HCA-SX 4667 mg, NBC 4 mg and GSE 400 mg, while group C was given placebo daily in three equally divided doses 30,60 min before meals. All subjects received a 2000 kcal diet/day and participated in supervised walking. Results:, At the end of 8 weeks, body weight and BMI decreased by 5,6% in both groups A and B. Food intake, total cholesterol, low-density lipoproteins, triglycerides and serum leptin levels were significantly reduced in both groups, while high-density lipoprotein levels and excretion of urinary fat metabolites increased in both groups. A marginal or non-significant effect was observed in all parameters in group C. Conclusion:, The present study shows that optimal doses of HCA-SX and, to a greater degree, the combination of HCA-SX, NBC and GSE can serve as an effective and safe weight-loss formula that can facilitate a reduction in excess body weight and BMI, while promoting healthy blood lipid levels. [source]

The clinical impact of pharmacogenetics on the treatment of epilepsy

EPILEPSIA, Issue 1 2009
Wolfgang Löscher
Summary Drug treatment of epilepsy is characterized by unpredictability of efficacy, adverse drug reactions, and optimal doses in individual patients, which, at least in part, is a consequence of genetic variation. Since genetic variability in drug metabolism was reported to affect the treatment with phenytoin more than 25 years ago, the ultimate goal of pharmacogenetics is to use the genetic makeup of an individual to predict drug response and efficacy, as well as potential adverse drug events. However, determining the practical relevance of pharmacogenetic variants remains difficult, in part because of problems with study design and replication. This article reviews the published work with particular emphasis on pharmacogenetic alterations that may affect efficacy, tolerability, and safety of antiepileptic drugs (AEDs), including variation in genes encoding drug target (SCN1A), drug transport (ABCB1), drug metabolizing (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins. Although the current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions, several results, for example that Asian patients with a particular HLA allele, HLA-B*1502, are at a higher risk for Stevens-Johnson syndrome when using carbamazepine, are helpful to increase our knowledge how genetic variation affects the treatment of epilepsy. Although genetic testing raises ethical and social issues, a better understanding of the genetic influences on epilepsy outcome is key to developing the much needed new therapeutic strategies for individuals with epilepsy. [source]

Combined R-,,lipoic acid and acetyl-L-carnitine exerts efficient preventative effects in a cellular model of Parkinson's disease

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1-2 2010
Hongyu Zhang
Abstract Mitochondrial dysfunction and oxidative damage are highly involved in the pathogenesis of Parkinson's disease (PD). Some mitochondrial antioxidants/nutrients that can improve mitochondrial function and/or attenuate oxidative damage have been implicated in PD therapy. However, few studies have evaluated the preventative effects of a combination of mitochondrial antioxidants/nutrients against PD, and even fewer have sought to optimize the doses of the combined agents. The present study examined the preventative effects of two mitochondrial antioxidant/nutrients, R-,,lipoic acid (LA) and acetyl-L-carnitine (ALC), in a chronic rotenone-induced cellular model of PD. We demonstrated that 4-week pretreatment with LA and/or ALC effectively protected SK-N-MC human neuroblastoma cells against rotenone-induced mitochondrial dysfunction, oxidative damage and accumulation of ,-synuclein and ubiquitin. Most notably, we found that when combined, LA and ALC worked at 100,1000-fold lower concentrations than they did individually. We also found that pretreatment with combined LA and ALC increased mitochondrial biogenesis and decreased production of reactive oxygen species through the up-regulation of the peroxisome proliferator-activated receptor-, coactivator 1, as a possible underlying mechanism. This study provides important evidence that combining mitochondrial antioxidant/nutrients at optimal doses might be an effective and safe prevention strategy for PD. [source]

Type 2 Diabetes: RENAAL and IDNT,The Emergence of New Treatment Options

JOURNAL OF CLINICAL HYPERTENSION, Issue 1 2002
Domenic A. Sica MD
The Reduction in End Points in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and the Irbesartan Diabetic Nephropathy Trial (IDNT) are two recently reported trials with hard end points, conducted in patients in advanced stages of diabetic nephropathy. Two other studies,the Irbesartan Microalbuminuria Study (IRMA)-2 and the Microalbuminuria Reduction with Valsartan study (MARVAL),were trials conducted in patients with type 2 diabetes with microalbuminuria, a cardiovascular risk factor associated with early-stage diabetic nephropathy. These trials all had a common theme,that is, does an angiotensin receptor blocker (ARB) interfere with the natural history of diabetic nephropathy in a blood pressure-independent fashion? Without question, the results of these trials legitimatize the use of the ARB class in forestalling the deterioration in renal function, which is almost inevitable in the patient with untreated diabetic nephropathy. These data can now be added to the vast array of evidence supporting angiotensin-converting enzyme (ACE) inhibitor use in patients with nephropathy associated with type 1 diabetes. It now appears a safe conclusion that the patient with diabetic nephropathy should receive therapy with an agent that interrupts the renin-angiotensin system. These studies have not resolved the question as to whether an ACE inhibitor or an ARB is the preferred agent in people with nephropathy from type 1 diabetes, though the optimal doses of these drugs remain to be determined. Head-to-head studies comparing ACE inhibitors to ARBs in diabetic nephropathy are not likely to occur, so it is unlikely that comparable information will be forthcoming with ACE inhibitors. An evidence-based therapeutic approach derived from these trials would argue for ARBs to be the foundation of therapy in the patient with type 2 diabetes and nephropathy. [source]

Hepatotoxicity Despite Early Administration of Intravenous N -Acetylcysteine for Acute Acetaminophen Overdose

ACADEMIC EMERGENCY MEDICINE, Issue 1 2009
Suzanne Doyon MD
Abstract Objectives:, The objective was to evaluate the effectiveness of intravenous N -acetylcysteine (IV NAC; 300 mg/kg over 21 hours) in early acute acetaminophen (APAP) overdose patients. Methods:, This observational case series included patients hospitalized between 2004 and 2007 for acute APAP overdoses and who were reported to a regional poison center. Inclusion criteria were plasma APAP concentrations on or above the treatment line on the Rumack-Matthew nomogram, administration of IV NAC within 8 hours of ingestion, and follow-up to known outcome. The hospital chart of each patient who received IV NAC for longer than the standard 21 hours was reviewed. Hepatotoxicity was defined as hepatic aminotransferase levels greater than 1,000 IU/L. Results:, Seventy-seven patients met inclusion criteria and received at least 21 hours of IV NAC for an acute APAP overdose. Seven patients received antidotal therapy for greater than 21 hours. These patients tended to have ingested combination preparations, have very high initial plasma APAP concentrations, and had persistently elevated plasma concentrations during their hospital stay. Hepatotoxicity occurred in 4 patients (5.2%, 95% confidence interval [CI] = 0.2% to 10.1%), including 1 death and 1 liver transplantation. Conclusions:, Hepatotoxicity developed in 5.2% of cases, suggesting that the 21-hour IV NAC regimen is suboptimal in some patients. In addition to high initial plasma APAP concentrations, APAP product formulation and persistently elevated plasma APAP concentrations were identified as factors possibly associated with developing hepatotoxicity. The authors propose a tailored approach to the discontinuation of IV NAC and point out the need for reevaluation of optimal doses and duration of therapy. [source]

Strategies to improve efficacy and safety of a novel class of antiviral hyper-activation-limiting therapeutic agents: the VS411 model HIV/AIDS

BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2010
D De Forni
BACKGROUND AND PURPOSE Antiviral hyper-activation-limiting therapeutic agents (AV-HALTs) are a novel experimental drug class designed to both decrease viral replication and down-regulate excessive immune system activation for the treatment of chronic infections, including human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. VS411, a first-in-class AV-HALT, is a single-dosage form combining didanosine (ddI, 400 mg), an antiviral (AV), and hydroxyurea (HU, 600 mg), a cytostatic agent, designed to provide a slow release of ddI to reduce its maximal plasma concentration (Cmax) to potentially reduce toxicity while maintaining total daily exposure (AUC) and the AV activity. EXPERIMENTAL APPROACH This was a pilot phase I, open-label, randomized, single-dose, four-way crossover trial to investigate the fasted and non-fasted residual variance of AUC, Cmax and the oral bioavailability of ddI and HU, co-formulated as VS411, and administered as two different fixed-dose combination formulations compared to commercially available ddI (Videx EC) and HU (Hydrea) when given simultaneously. KEY RESULTS Formulation VS411-2 had a favourable safety profile, displayed a clear trend for lower ddI Cmax (P= 0.0603) compared to Videx EC, and the 90% confidence intervals around the least square means ratio of Cmax did not include 100%. ddI AUC, was not significantly decreased compared to Videx EC. HU pharmacokinetic parameters were essentially identical to Hydrea, although there was a decrease in HU exposure under fed versus fasted conditions. CONCLUSIONS AND IMPLICATIONS A phase IIa trial utilizing VS411-2 formulation has been fielded to identify the optimal doses of HU plus ddI as an AV-HALT for the treatment of HIV disease. [source]

Comparison of three doses of leuprolide acetate in the treatment of central precocious puberty: preliminary results

CLINICAL ENDOCRINOLOGY, Issue 5 2009
Verónica Mericq
Summary Objective, Depot luteinizing-hormone releasing hormone (LHRH) agonist have been widely used for the treatment of central precocious puberty (CPP), but the optimal doses to obtain hormonal suppression are still unknown, especially in patients with higher weights. The goal of our study was to compare the efficacy of three leuprolide acetate (LA) preparations, suppressing gonadotropin secretion in patients with CPP. Design, In an open 12-month protocol, we evaluated LA 7·5 mg/month, 11·25 and 22·5 every 3 months. Patients, Fourteen girls with CPP and weights over 30 kg. Measurements: Clinical, radiological and laboratory follow-up: GnRH test plus LH, FSH 40 min post analogue was performed periodically. Results, Pretreatment basal and LHRH stimulated LH levels between groups were not different. Basal and LHRH stimulated LH levels decreased significantly between baseline and from 3 up to 12 months of therapy in all groups (P = 0·001). GnRH stimulated LH peak <2 IU/l, the main efficacy criterion was met in 80, 75 and 100% of the children at 6 months in the 7·5, 11·25, 22·5 mg doses respectively. By 12 months, 100% of patients had LH suppressed to <2 IU/l. Conclusions These results affirm that 3-month injections may be a satisfactory alternative for the therapy of children with CPP to avoid monthly injections. In addition, suppression of LH occurs sooner in the 3-month 22·5 mg LA dose compared to the 3-month 11·5 mg; therefore, adequate dosing may be important for optimal outcome. Further investigation is needed in more patients over 30 kg, with longer treatment duration, and ultimately final height consideration. [source]