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Dose Escalation (dose + escalation)

Distribution by Scientific Domains

Medical Sciences	96%
2 Other Domains	4%

Distribution within Medical Sciences

Oncology & Radiotherapy	21%
Hematology	9%
Gastroenterology	7%
Transplantation	3%
15 Other Subdomains	46%

Kinds of Dose Escalation

rapid dose escalation

Terms modified by Dose Escalation

dose escalation study

Selected Abstracts

Phase I Dose Escalation of Single-Agent Vinblastine in Dogs

JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 6 2008
D.B. Bailey
Background: Vinblastine (VBL) is commonly used in dogs at a dosage of 2.0 mg/m2. The minimal toxicity observed at this dosage indicates that higher dosages might be well tolerated. Hypothesis: The maximum tolerated dosage (MTD) for a single VBL treatment is higher than the previously published dosage of 2.0 mg/m2. Animals: Twenty-three dogs with lymphoma or cutaneous mast cell tumors. Methods: Dogs received 1 single-agent VBL treatment IV. The starting dosage was 3.0 mg/m2, and dosages were increased in increments of 0.5 mg/m2 in cohorts of 3 dogs. Hematologic toxicity was assessed with weekly CBCs. Gastrointestinal toxicity was assessed from medical histories from owners. Once the MTD was determined, additional dogs were treated with VBL at that dosage. Dogs whose cancers responded to VBL continued to receive treatments q2,3 weeks. Results: VBL dosages ranged from 3.0 to 4.0 mg/m2. Neutropenia was the dose-limiting toxicity, with the nadir identified 7 days after treatment and resolving by 14 days after treatment. The MTD was 3.5 mg/m2. Sixteen dogs were treated at this dosage, and 3 experienced severe toxicity characterized by asymptomatic grade 4 neutropenia, febrile grade 4 neutropenia, and death. Gastrointestinal toxicity was mild and self-limiting. Preliminary evidence of antitumor activity was identified in 2 of 12 dogs with lymphoma treated at the MTD. Conclusions and Clinical Importance: In dogs, single-agent VBL is well tolerated at a dosage of 3.5 mg/m2 IV. At this dosage, the minimum safe treatment interval is q2 weeks, and adjunct treatment with prophylactic antibiotics should be considered. [source]

Therapy adapted to molecular response in patients with chronic myelogenous leukaemia in first chronic phase: results of the Duesseldorf study,

HEMATOLOGICAL ONCOLOGY, Issue 4 2008
Frank Neumann
Abstract This study evaluates response-adapted treatment of chronic myelogenous leukaemia (CML) in chronic phase using molecular response criteria. bcr-abl/G6PDH ratios were assessed by Light-Cycler quantitative real-time polymerase chain reaction (PCR( in 277 peripheral blood samples from 33 patients, before and every 3 months during therapy. Sixty-six per cent (22/33) of the patients fulfiled our molecular response criterion of ,1 log decrease in bcr-abl transcript after 6 or ,2 log decrease after 9 and every following 3 months. Dose escalation was necessary for 33% (11/33) of the patients. Of these, 54% (6/11) achieved a reduction of bcr-abl mRNA by ,2 log (n,=,3) or ,3 log (n,=,3) with 800,mg Imatinib. Forty-five per cent (5/11) showed insufficient molecular response with 800,mg Imatinib and received Nilotinib. In conclusion, the assessment of molecular response permits an individual patient-tailored treatment of CML in first chronic phase, resulting in the majority of patients achieving a major molecular response after 2 years of therapy. Copyright © 2008 John Wiley & Sons, Ltd. [source]

Dose escalation of radical radiation therapy in non-small-cell lung cancer using positron emission tomography/computed tomography-defined target volumes: Are class solutions obsolete?

JOURNAL OF MEDICAL IMAGING AND RADIATION ONCOLOGY, Issue 2 2008
S Everitt
Summary This study investigated the maximum theoretical radiation dose that could safely be delivered to 20 patients diagnosed with non-small-cell lung cancer. Two three-dimensional conformal radiation therapy (RT) class-solution techniques (A and B) and an individualized three-dimensional conformal RT technique (C) were compared at the standard dose of 60 Gy (part I). Dose escalation was then attempted for each technique successfully at 60 Gy, constrained by predetermined limits for lung and spinal canal (part II). Part I and part II data were reanalysed to include oesophageal dose constraints (part III). In part I, 60 Gy was successfully planned using techniques A, B and C in 19 (95%), 18 (90%) and 20 (100%) patients, respectively. The mean escalated dose attainable for part II using techniques A, B and C were 76.4, 74 and 97.8 Gy, respectively (P < 0.0005). One (5%) patient was successfully planned for 120 Gy using techniques A and B, whereas four (20%) were successfully planned using technique C. Following the inclusion of additional constraints applied to the oesophagus in part III, the amount of escalated dose remained the same for all patients who were successfully planned at 60 Gy apart from two patients when technique C was applied. In conclusion, individualized three-dimensional conformal RT facilitated greater dose conformation and higher escalation of dose in most patients. With modern planning tools, simple class solutions are obsolete for conventional dose radical RT in non-small-cell lung cancer. Highly individualized conformal planning is essential for dose escalation. [source]

Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe hemophilia A: influences of variance in pharmacokinetics and treatment regimens

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2 2010
P. W. COLLINS
Summary.,Background:,Prophylactic factor (F)VIII has been shown to reduce bleeds and arthropathy in patients with severe hemophilia A. Objectives:,Assuming that the trough FVIII level is an important determinant of the efficacy of prophylaxis, this paper addresses the effect of the inter-patient variability in pharmacokinetics and different dosing regimens on trough levels. Methods:,Simulations used FVIII half-lives and in vivo recoveries (IVR), observed during clinical trials with Advate [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method], and commonly used prophylactic regimens to calculate their effect on FVIII levels during prophylaxis. Results and conclusions:,Half-life and dose frequency had a larger effect on trough FVIII and time per week with FVIII < 1 IU dL,1 than IVR and infused dose per kg. The combined effect of these parameters resulted in substantial inter-patient variability in the amount of FVIII required to sustain a desired trough level. Prophylactic regimens based on Monday, Wednesday, Friday dosing were less cost effective in maintaining a desired trough level throughout the week. Dose escalation on Friday to cover the weekend would require potentially harmful doses of FVIII in many patients, especially in young children where more than 50% would require a Friday dose of over 100 IU kg,1 and some would require more than 400 IU kg,1. Knowledge of individual patients' half-lives and alteration of frequency of infusions may allow the more cost-effective use of FVIII and potentially expand access to prophylaxis to a greater number of patients, especially in regions where healthcare resources are scarce. [source]

Methadone in the Treatment of Chronic Nonmalignant Pain: A 2-Year Follow-up

PAIN MEDICINE, Issue 3 2000
William F. Taylor MD
Objective. To examine the longitudinal use of methadone in a pain clinic. Design. Follow-up study of 40 patients initially treated with methadone and re-evaluated 2 years later, comparing those maintained on methadone with those who were switched to other opioids. Setting. Pain clinic at a university hospital. Results. The 14 patients (35%) who stayed on methadone for the duration of the study, had higher employment rates (P < .05) and higher functional ratings (P < .02) than those on other opioids. Side effects were the most common reason (33.4%) for discontinuation of methadone. Dose escalation occurred in 11 of 14 patients (78.6%). Conclusions. Chronic pain patients may be safely and effectively treated with methadone. Those not responding or tolerating methadone may be benefited by treatment with other opioids. [source]

Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory solid tumors,

PEDIATRIC BLOOD & CANCER, Issue 7 2010
René Y. McNall-Knapp MD
Abstract Background The combination of irinotecan, temozolomide, and vincristine is appealing because of potentially synergistic mechanisms of action and non-overlapping toxicities. This phase I study was designed to determine the toxicity and maximum tolerated dose (MTD) of escalating daily protracted doses of irinotecan given in this combination. With extended accrual, we more fully explored the toxicity of multiple courses at the MTD. Procedure Patients under 22 years with recurrent or refractory solid tumors were eligible. A course of chemotherapy was given every 28 days. Cefpodoxime was given for diarrhea prophylaxis. Vincristine (1.5,mg/m2, max 2,mg) was given intravenously (IV) on days 1 and 8. Temozolomide (100,mg/m2/day) was given orally on days 1,5. Irinotecan was given IV over 1,hr on days 1,5 and 8,12. Dose escalation was done in the standard 3,+,3 cohort design, starting at 15,mg/m2/day. Results Twenty-five of 26 eligible patients were evaluable for toxicity and response. They received 111 courses (1,13, median 4). Dose limiting toxicity (DLT,pancreatitis, transaminitis) was seen in two of three patients at dose level 2 (20,mg/m2). No patients at level 1 had DLT during the first two cycles. Thus, the MTD of irinotecan in this combination is 15,mg/m2/day,×,10 doses. Hematologic toxicity was mild and not prolonged. Grade 3 diarrhea was seen in five courses. Responses included two complete and two partial with 12 stable disease (SD) (median 6 months). Conclusions This combination is safe and shows activity in pediatric patients with recurrent malignancy. Pediatr Blood Cancer 2010;54:909,915 © 2010 Wiley-Liss, Inc. [source]

Learning from previous responses in phase I dose-escalation studies

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2001
John Whitehead
Dose escalation in phase I studies is generally performed on the basis of clinical experience and judgement. In this paper some of the statistical approaches that have been proposed for the formalization of the procedure are described. Apart from the use of the Continual Reassessment Method in oncology studies, such formal methods have received little implementation. The purpose of presenting them here is to promote their further exploration and appropriate implementation. Certain limitations are discussed, which will be best overcome by collaboration between clinical pharmacologists and statisticians. [source]

Phase II study of the histone deacetylase inhibitor MGCD0103 in patients with previously treated chronic lymphocytic leukaemia

BRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2009
Kristie A. Blum
Summary MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre-clinical activity in chronic lymphocytic leukaemia (CLL). A phase II clinical trial was performed, starting at a dose of 85 mg/d, three times per week. Dose escalation to 110 mg or the addition of rituximab was permitted in patients without a response after two or more cycles. MGCD0103 demonstrated pre-clinical activity against CLL cells with a LC50 (concentration lethal to 50%) of 0·23 ,mol/l and increased acetylation of the HDAC class I specific target histone H3. Twenty-one patients received a median of two cycles of MGCD0103 (range, 0,12). All patients had previously received fludarabine, 33% were fludarabine refractory, and 71% had del(11q22·3) or del(17p13·1). No responses according to the National Cancer Institutes 1996 criteria were observed. Three patients received 110 mg and four patients received concomitant rituximab, with no improvement in response. Grade 3,4 toxicity consisted of infections, thrombocytopenia, anaemia, diarrhoea, and fatigue. HDAC inhibition was observed in six out of nine patients on day 8. Limited activity was observed with single agent MGCD0103 in high risk patients with CLL. Future investigations in CLL should focus on broad HDAC inhibition, combination strategies, and approaches to diminish constitutional symptoms associated with this class of drugs. [source]

Exenatide: a review from pharmacology to clinical practice

DIABETES OBESITY & METABOLISM, Issue 6 2009
R. Gentilella
Background:, Exenatide is an incretin mimetic that activates glucagon-like-peptide-1 receptors. It blunts the postprandial rise of plasma glucose by increasing glucose-dependent insulin secretion, suppressing inappropriately high glucagon secretion and delaying gastric emptying. Methods:, In seven clinical trials performed in 2845 adult patients with type 2 diabetes mellitus who were inadequately controlled by a sulphonylurea and/or metformin (glycosylated haemoglobin, HbA1c ,11%), or by thiazolidinediones (with or without metformin) and treated for periods from 16 weeks to 3 years, exenatide (5 ,g b.i.d. s.c. for the first 4 weeks of treatment and 10 ,g b.i.d. s.c. thereafter) reduced HbA1c, fasting and postprandial glucose, and body weight dose dependently, and was similar to insulin glargine and biphasic insulin aspart in reducing HbA1c. Body weight diminished with exenatide, whereas it increased with both insulin preparations. Positive effects on the lipid profile and a reduction in C-reactive protein were also recorded with exenatide. Treatment extensions up to 3 years showed that benefits were maintained in the long term. Adverse events were usually mild to moderate in intensity, and generally the frequency decreased with continued therapy. The most common was nausea (whose incidence may be reduced by gradual dose escalation from 5 ,g b.i.d. to 10 ,g b.i.d.), vomiting, diarrhoea, headache and hypoglycaemia (almost exclusively in patients treated with a sulphonylurea). Results and conclusions:, Exenatide is a new, promising therapeutic option for type 2 diabetic patients inadequately controlled by oral agents, before insulin therapy, offering the added benefits of body weight reduction and tight postprandial glucose control. [source]

Selective dose escalation of chemoradiotherapy for locally advanced esophageal cancer

DISEASES OF THE ESOPHAGUS, Issue 7 2008
S. K. Seung
SUMMARY., This phase II study assessed the use of concurrent continuous infusion of 5-fluorouracil and weekly carboplatin plus paclitaxel with selective radiation dose escalation for patients with localized esophageal cancer. Patients with esophageal carcinoma were staged by thoracic and abdominal computed tomography, endoscopic ultrasound, and positron emission tomography scans. Patients received a continuous infusion of 5-fluorouracil 225 mg/m2 on days 1 to 38 and intravenous paclitaxel 45 mg/m2 and carboplatin AUC 2 on days 1, 8, 15, 22, 29, and 36. Radiotherapy was delivered in 1.8-Gy fractions, 5 d/wk for 5.5 weeks. Six to 8 weeks after initial therapy, patients without metastatic progression but with a positive biopsy, or less than partial response received a 9-Gy boost with the same concurrent chemotherapy. Twenty-four patients were enrolled: 18 patients were enrolled initially; 6 additional patients were enrolled following a protocol amendment designed to reduce the esophagitis by adding the radioprotectant amifostine. Median follow-up was 30 months. Twenty (83%) patients had adenocarcinomas of the lower esophagus/gastroesophageal junction. Seventeen patients (81%) attained at least a partial response. Six patients received boost treatment. At 4 years, overall survival was 28%, cause-specific survival was 38%, locoregional control was 61%, and distant metastasis-free survival was 52%. Radiation delays ranged from 0 to 62 days (median, 8 d), primarily owing to esophagitis. In total, 28% of patients developed esophageal strictures requiring dilatations. There were no differences in esophageal strictures, local control, or survival with the addition of amifostine. [source]

Successful clearance of hepatitis B virus after allogeneic stem cell transplantation: beneficial combination of adoptive immunity transfer and lamivudine

EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2003
Tetsuhiro Chiba
Abstract: We report a 38-yr-old male with acute lymphocytic leukemia (ALL), whose serological tests for the hepatitis B virus (HBV) before transplantation showed a chronic carrier status, and a liver biopsy specimen revealed chronic liver injury because of HBV. The patient underwent allogeneic peripheral blood stem cell transplantation (PBSCT) from his sibling who was hepatitis B surface antibody (HBsAb) positive. He had received lamivudine treatment for the prophylaxis of HBV reactivation during cytotoxic chemotherapy, and lamivudine administration continued after transplantation. Successful engraftment was documented 3 wk after PBSCT, and clearance of the hepatitis B surface antigen (HBsAg) was observed 2 months after PBSCT. Liver function tests transiently showed a mild elevation of aminotransferases on day 25, although this returned to normal after the dose escalation of the immunosuppressive agent. We presume that the combination of adoptive immunity transfer by bone marrow transplantation (BMT) from an HBsAb-positive donor and antiviral drugs such as lamivudine is beneficial in clearing HBV in chronic carriers. [source]

Particle beam radiotherapy for head and neck tumors: Radiobiological basis and clinical experience

HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 8 2006
Barbara Alicja Jereczek-Fossa MD
Abstract Background. Head and neck tumors are often located near critical organs, making it impossible to deliver a dose of conventional radiotherapy high enough to eradicate the disease. Our aim was to review the potential benefits and available clinical experience of particle beam therapy (hadrontherapy) in the treatment of these tumors. Methods. A review of the literature was carried out through a MEDLINE search (publications between 1980 and 2005). Results. A review of the available clinical data shows that particle beam therapy can offer several radiobiological and physical advantages over conventional photon radiotherapy: improved dose distribution permits dose escalation within the target and optimal sparing of normal tissue. Preclinical and clinical studies suggest that there may be benefits to using hadrontherapy for tumors characterized by poor radiosensitivity and critical location. At present, the most used hadrons are protons and, as yet on an experimental basis, carbon ions. It is now well accepted that there are certain indications for using proton therapy for skull base tumors (chordoma and chondrosarcoma), paranasal sinus carcinomas, selected nasopharyngeal tumors, and neutron/ion therapy for salivary gland carcinomas (in particular, adenoid cystic tumors). Its viability in other cases, such as locally advanced squamous cell carcinoma, melanoma, soft tissue sarcoma, and bone sarcoma, is still under investigation. Conclusions. Hadrontherapy can be beneficial in the treatment of tumors characterized by poor radiosensitivity and critical location. Further clinical and radiobiological studies are warranted for improved selection of patient population. © 2006 Wiley Periodicals, Inc. Head Neck, 2006 [source]

Once-daily nevirapine dosing: a pharmacokinetics, efficacy and safety review

HIV MEDICINE, Issue 1 2007
CL Cooper
In the context of attempts to simplify treatment regimens and enhance adherence, there is great interest in once-daily dosing regimens for the treatment of HIV-1 infection. Nevirapine has a long half-life and achieves high steady-state plasma concentrations relative to the concentration required to inhibit 50% viral replication in vitro (IC50) in patients. For this reason, it has been considered as a once-daily antiretroviral. Pharmacokinetic and efficacy data support the use of this dosing approach, but excess rash and lingering concerns over liver toxicity preclude use of once-daily dosed nevirapine at this time. Tolerance to high nevirapine concentrations may develop when dose escalation is used during initiation of therapy. It is theoretically possible that the benefits of once-daily dosing may be achieved without excess toxicity by switching to once-daily nevirapine following several months of twice-daily administration. This dosing strategy is currently under evaluation. [source]

An open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy

INFLAMMATORY BOWEL DISEASES, Issue 3 2001
Dr. Marla C. Dubinsky
Abstract Background and Aims A substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6-mercaptopurine (6-MP) and azathioprine (AZA). Inability to achieve therapeutic 6-thioguanine nucleotide (6-TGN) levels due to the preferential overproduction of 6-methylmercaptopurine ribonucleotides (6-MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6-MP/AZA therapy. Treatment with 6-thioguanine (6-TG), a related thiopurine, which forms 6-TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6-TG in the subgroup of Crohn's disease (CD) patients failing to attain adequate disease control with traditional 6-MP/AZA therapy. Methods Ten CD patients with preferential 6-MMPR production upon 6-MP/AZA dose escalation were enrolled in an open-label pilot study. Seven of 10 patients had experienced dose-related 6-MP toxicities. Results Seventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6-TGN levels were nine-fold higher with 6-TG treatment than with 6-MP, whereas 6-MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity. Conclusions 6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short-and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients. [source]

Intensity-modulated radiotherapy with an integrated boost to the macroscopic tumor volume in the treatment of high-grade gliomas

INTERNATIONAL JOURNAL OF CANCER, Issue 6 2001
Christoph Thilmann M.D.
Abstract Integrated boost radiotherapy (IBRT) delivers a higher fraction size to the gross tumor volume and a conventional fraction size to the surrounding tissue of microscopic spread. We compared stereotactic conformal radiotherapy (SCRT) and intensity-modulated radiotherapy (IMRT) with regard to their suitability for IBRT in the treatment of high-grade gliomas. In 20 patients treated with conventional radiotherapy, an additional treatment plan for IBRT [planning target volume (PTV1) defined as contrast-enhancing lesion plus margin due to setup errors 75 Gy, PTV2 defined as edema plus margin due to microscopic spread and setup error 60 Gy] with 7 non-coplanar beams for IMRT and for SCRT was carried out and compared. The part of the PTV2 irradiated with more than 107% of the prescribed dose was 13.9% for IMRT and 30.9% for SCRT (P < 0.001). Dose coverage of PTV2 (volume above 95% of the prescribed dose) was improved with IMRT (88.4% vs. 75.3% with SCRT, P < 0.001). Dose coverage of PTV1 was slightly higher with SCRT (93.7% vs. 87.5% with IMRT), but the conformity to the boost shape was improved by IMRT [conformity index (COIN95) = 0.85 vs. 0.69 with SCRT]. Simultaneously the brain volume irradiated with > 50 Gy was reduced from 60 to 33 cc (P < 0.001). We conclude that IMRT is suitable for local dose escalation in the enhancing lesion and for delivering a homogeneous dose to the PTV2 outside the PTV1 at the same time. Our encouraging results justify application of IMRT for IBRT in the treatment of high-grade gliomas. For clinical evaluation a phase III study has been initiated. © 2001 Wiley-Liss, Inc. [source]

Effects of flexible-dose fesoterodine on overactive bladder symptoms and treatment satisfaction: an open-label study

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 4 2009
J.-J. Wyndaele
Summary Aims:, To evaluate the efficacy and tolerability of flexible-dose fesoterodine in subjects with overactive bladder (OAB) who were dissatisfied with previous tolterodine treatment. Methods:, This was a 12-week, open-label, flexible-dose study of adults with OAB (, 8 micturitions and , 3 urgency episodes per 24 h) who had been treated with tolterodine (immediate- or extended-release) for OAB within 2 years of screening and reported dissatisfaction with tolterodine treatment. Subjects received fesoterodine 4 mg once daily for 4 weeks; thereafter, daily dosage was maintained at 4 mg or increased to 8 mg based on the subject's and physician's subjective assessment of efficacy and tolerability. Subjects completed 5-day diaries, the Patient Perception of Bladder Condition (PPBC) and the Overactive Bladder Questionnaire (OAB-q) at baseline and week 12 and rated treatment satisfaction at week 12 using the Treatment Satisfaction Question (TSQ). Safety and tolerability were assessed. Results:, Among 516 subjects treated, approximately 50% opted for dose escalation to 8 mg at week 4. Significant improvements from baseline to week 12 were observed in micturitions, urgency urinary incontinence episodes, micturition-related urgency episodes and severe micturition-related urgency episodes per 24 h (all p < 0.0001). Approximately 80% of subjects who responded to the TSQ at week 12 reported satisfaction with treatment; 38% reported being very satisfied. Using the PPBC, 83% of subjects reported improvement at week 12 with 59% reporting improvement , 2 points. Significant improvements from baseline (p < 0.0001) exceeding the minimally important difference (10 points) were observed in OAB-q Symptom Bother and Health-Related Quality of Life (HRQL) scales and all four HRQL domains. Dry mouth (23%) and constipation (5%) were the most common adverse events; no safety issues were identified. Conclusion:, Flexible-dose fesoterodine significantly improved OAB symptoms, HRQL, and rates of treatment satisfaction and was well tolerated in subjects with OAB who were dissatisfied with prior tolterodine therapy. [source]

Dose escalation of radical radiation therapy in non-small-cell lung cancer using positron emission tomography/computed tomography-defined target volumes: Are class solutions obsolete?

Aqueous versus non-aqueous salt delivery strategies to enhance oral bioavailability of a mitogen-activated protein kinase-activated protein kinase (MK-2) inhibitor in rats

JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2009
Po-Chang Chiang
Abstract A potent pyridine-containing MK2 inhibitor has recently been internally discovered. In pre-clinical dosing, the low solubility of the neutral form limited oral bioavailability and dose escalation in toxicity studies. A mesylate salt was developed as part of a formulation strategy to enhance both oral bioavailability and dose escalation orally in pre-clinical rat studies. Several non-aqueous systems were used to deliver the mesylate salt, which resulted in varied oral bioavailability. It was found that administration of an aqueous chaser immediately after dosing drastically increased the oral bioavailability of the salt. This finding implies that the quantity of water present in vivo is an important consideration when evaluating salts of free bases with low aqueous solubility in pre-clinical in vivo rat models where limited aqueous vehicle may be presented. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:248,256, 2009 [source]

Amphetamine-induced chorea in attention deficit,hyperactivity disorder

MOVEMENT DISORDERS, Issue 7 2004
John C. Morgan MD
Abstract Attention deficit,hyperactivity disorder (ADHD) is treated frequently with stimulants in both children and adults. While tics are occasional complications of stimulant therapy, chorea is reported rarely. We describe an adult ADHD patient who developed chorea upon dose escalation of mixed amphetamine salts, which resolved on discontinuation of the drug. © 2004 Movement Disorder Society [source]

Titration with Oxymorphone Extended Release to Achieve Effective Long-Term Pain Relief and Improve Tolerability in Opioid-Naive Patients with Moderate to Severe Pain

PAIN MEDICINE, Issue 7 2008
Richard Rauck MD
ABSTRACT Objective., Assess the effectiveness and tolerability of a program of gradual dose titration with oxymorphone extended release (ER) for treatment of moderate to severe chronic pain in opioid-naive patients. Design., Open-label, nonrandomized 6-month study with a titration/stabilization period of ,1 month followed by a 5-month maintenance period. Setting., Multidisciplinary pain centers in the United States. Patients., Adult opioid-naive patients with moderate to severe chronic pain. Interventions., Patients were gradually titrated from a 5-mg dose of oxymorphone ER (taken every 12 hours) to a stabilized dose that provided effective pain relief and was well tolerated. Outcome Measures., Brief Pain Inventory Short Form questions 5 and 9, patient and physician global assessments of pain relief, adverse events (AEs), and discontinuations. Results., The majority (94/126; 75%) of patients were stabilized on a dose of oxymorphone ER that provided effective pain relief with tolerable AEs. Most (81/94; 86%) required <24 days to reach a stable dose. Sixteen percent of patients in the titration period and 17% of patients in the maintenance period discontinued because of AEs possibly or probably related to oxymorphone ER. Patients completing the entire 5-month maintenance period experienced effective pain relief with significant (>50%) reductions of pain interference with quality-of-life measures. There was minimal dose escalation over the 5 months and low use of rescue medication. Conclusions., Oxymorphone ER provided effective pain relief from moderate to severe chronic pain in opioid-naive patients. Gradual titration was well tolerated, with a low rate of discontinuations caused by AEs. [source]

Improved Cancer Pain Treatment Using Combined Fentanyl-TTS and Tramadol

PAIN PRACTICE, Issue 4 2007
Franco Marinangeli MD
,,Abstract: The aim of the study was to facilitate dose escalation of strong opioids. In this randomized open-label study the influence of tramadol on dose adjustment of transdermal fentanyl in advanced cancer pain control was prospectively evaluated. Seventy patients affected by intractable cancer disease with visual analog scale (VAS) score >3 were enrolled. Thirty-five patients were treated conventionally with increasing transdermal fentanyl dosage as required (group F) and 35 patients received oral tramadol added to their transdermal fentanyl before each increment of the transdermal opioid dosage (group T). Pain control was equally satisfactory in the two groups. VAS scores at baseline (T: 4.36 ± 1.53; F: 4.51 ± 1.36; n.s.) and at the end of the study (T: 1.8 ± 1.6; F: 1.6 ± 1.5; n.s.) did not differ. However, in the tramadol group this level of pain control was achieved with much slower dose escalation of fentanyl. The mean application time of the fentanyl-Transdermal Therapeutic System patch for each dosage (25, 50, 75 ,g/hour) was significantly greater in patients receiving tramadol. No patient in group T escalated to the 100 ,g/hour patch, while in 12 patients of group F the 100 ,g/hour patch was applied after a 75 ,g/hour patch mean application period of 18.6 ± 4.7 days. The number of fentanyl-TTS dosage changes was significantly lower in group T (1.2 ± 0.4 vs. 2.3 ± 0.5; P < 0.05). The mean total duration of treatment in group T, was 37.1 ± 11.6 days. The amount of fentanyl used at study end was 56.6 ± 11.2 ,g/hour plus 141.1 ± 151.9 mg tramadol per day (median: 200 mg/day) in group T patients compared with 84.1 ± 12.2 ,g/hour in group F patients (P < 0.05). The combination of a strong opioid with a weak opioid to treat severe cancer pain allowed a more gradual increase of analgesic delivery than was possible using fentanyl-TTS alone, minimizing periods of under- and overdosing. In addition, it considerably slowed the pace of fentanyl dose escalation. In conclusion, this TTS fentanyl-tramadol analgesic protocol provides a useful alternative to the usual treatment of cancer pain with fentanyl-TTS alone, especially in case of quick progression of disease and pain.,, [source]

Imatinib dose escalation in 74 failure or suboptimal response chronic myeloid leukaemia patients at 3-year follow-up,

AMERICAN JOURNAL OF HEMATOLOGY, Issue 5 2010
Massimo Breccia
No abstract is available for this article. [source]

Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): A report from the therapeutic advances in childhood leukemia (TACL) consortium,

PEDIATRIC BLOOD & CANCER, Issue 2 2010
Yoav Messinger MD
Abstract Background Outcomes remain poor for children after relapse of acute lymphoblastic leukemia (ALL), especially after early marrow relapse. Bortezomib is a proteasome inhibitor with in vitro synergy with corticosteroids and clinical activity in human lymphoid malignancies. Procedure This is a Phase I study of escalating doses bortezomib administered days 1, 4, 8, and 11, added to 4-drug induction chemotherapy with vincristine, dexamethasone, pegylated L -asparaginase, and doxorubicin (VXLD) in children with relapsed ALL. Results Ten patients were enrolled, five in first marrow relapse, and five in second relapse. Four patients were enrolled at dose level 1 (bortezomib 1,mg/m2). One patient was not evaluable for toxicity because of omitted dexamethasone doses. No dose-limiting toxicity (DLT) was observed. Six patients were enrolled at dose level 2 (bortezomib 1.3,mg/m2). One patient had dose-limiting hypophosphatemia and rhabdomyolysis after 1 dose of bortezomib, and died from a diffuse zygomyces infection on day 17. Five additional patients were enrolled with no subsequent DLTs. As planned, no further dose escalation was pursued. The regimen had predictable toxicity related to the chemotherapy drugs. Two patients had mild peripheral neuropathy (grades 1 and 2). Six of nine evaluable patients (67%) achieved a complete response (CR), and one had a bone marrow CR with persistent central nervous system leukemia. Conclusions The combination of bortezomib (1.3,mg/m2) with VXLD is active with acceptable toxicity in pretreated pediatric patients with relapsed ALL. We are expanding the 1.3,mg/m2 cohort for a phase II estimate of response. Study registered at ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00440726). Pediatr Blood Cancer 2010;55:254,259. © 2010 Wiley-Liss, Inc. [source]

Phase I study of paclitaxel with standard dose ifosfamide in children with refractory solid tumors: A Pediatric Oncology Group study (POG 9376)

PEDIATRIC BLOOD & CANCER, Issue 3 2009
James I. Geller MD
Abstract Purpose A dose-escalation Phase I study of taxol (paclitaxel) administered in combination with standard dose ifosfamide was conducted in children with relapsed or refractory solid tumors. Primary objectives were to estimate the maximum tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs). Patients and Methods Paclitaxel was administered as a 6-hr continuous infusion (hr 0,6), followed by intravenous ifosfamide (2 g/m2/day,×,3 days) over 1 hr at hours 6,7, 24,25, and 48,49. Patients at dose level 1 received 250 mg/m2 paclitaxel. Subsequent dose escalation proceeded using a standard 3,×,3 Phase I design. Results Fifteen patients received a combined 46 courses of therapy. The median age was 14.5 years (range, 2,19 years), and diagnoses included sarcoma (7), neuroblastoma (3), and other (5). Three patients received paclitaxel at 250 mg/m2 (10 courses), six at 325 mg/m2 (19 courses), three at 425 mg/m2 (8 courses), and three at 550 mg/m2 (9 courses). DLTs occurred in 2/3 patients at 550 mg/m2 paclitaxel during cycle 1, including grade 3 hypotension and grade 4 anaphylaxis in 1 patient each. Common non-dose-limiting toxicities included bone marrow suppression and peripheral neuropathy. Response was evaluable in 14 patients and included mixed response (3), stable disease (5), and progressive disease (6). Conclusion Paclitaxel hypersensitivity reactions were dose limiting when the drug was administered as a 6-hr infusion. The MTD and recommended Phase II dose of paclitaxel administered as a 6-hr continuous intravenous infusion followed by standard dose intravenous ifosfamide is 425 mg/m2 paclitaxel. Pediatr Blood Cancer 2009;52:346,350. © 2008 Wiley-Liss, Inc. [source]

Utility of azathioprine metabolite measurements in post-transplant recurrent autoimmune and immune-mediated hepatitis

PEDIATRIC TRANSPLANTATION, Issue 6 2004
Carolina Rumbo
Abstract:, Patients with post-transplant immune-mediated hepatitis (IMH) and recurrent autoimmune hepatitis (RAIH) have a poor outcome and a higher need for retransplantation. Azathioprine (AZA) is used as adjunctive immunosuppression after transplantation; optimizing its dose may be a key point in preserving graft function. Complications of high AZA dosing make dose escalation potentially problematic. Our aim was to correlate AZA metabolite levels with therapeutic effects, toxicity, and adherence to medication in children with IMH and RAIH. Charts of 14 patients were retrospectively reviewed. The post-transplant diagnosis was based on liver biopsy and autoimmune markers. AZA was prescribed after establishing the post-transplant diagnosis. AZA was started at 1.1 (1.0,1.8) mg/kg/day. Routine biochemical studies, tacrolimus levels, 6-thioguanine (6-TG) and 6-methylmercaptopurine levels were assessed every 8 wk. AZA dose was routinely adjusted to achieve 6-TG levels between 235 and 450 pmol per 8 × 108 RBC. A total of 92 samples from 14 patients were reviewed. Four patients were excluded because of non-adherence. AZA dose was increased by 245% resulting in eight of 10 patients in the target range; no hepatic or bone marrow toxicity was observed. ALT levels and steroid requirements were significantly reduced (p < 0.05). The AZA dose required to achieve target 6-TG levels was significantly greater in children <10 yr. AZA metabolite testing in children post-liver transplant is useful in assessing adherence to medication and it is potentially helpful in optimizing medication dosing. In younger children the AZA dose requirements were two to four times higher than previously reported standard doses. [source]

A Phase II intra-patient dose-escalation trial of weight-based darbepoetin alfa with or without granulocyte-colony stimulating factor in myelodysplastic syndromes,

AMERICAN JOURNAL OF HEMATOLOGY, Issue 1 2009
Jason Gotlib
This Phase II study evaluated darbepoetin alfa (DA) in 24 patients with predominantly low or intermediate-1 risk myelodysplastic syndrome (MDS). Intra-patient dose escalation of DA was undertaken in three 6-week dose cohorts until a major erythroid response was achieved: 4.5 mcg/kg/week, 9 mcg/kg/week, and 9 mcg/kg/week plus granulocyte-colony stimulating factor (G-CSF) 2.5 mcg/kg twice weekly. Patients with refractory anemia with ringed sideroblasts (RARS) commenced DA at 9 mcg/kg/week. The weight-based dosing regimen translated into a median starting DA dose of 390 mcg/week. Erythroid responses were observed in 16/24 patients (67%; 12 major and 4 minor), with a median response duration of 11 months in major responders. Addition of G-CSF generated a major erythroid response in 7/15 patients (47%) who suboptimally responded to DA alone. DA was well tolerated, except for worsening of baseline mild hypertension and renal insufficiency in one patient with diabetes. IPSS score <0.5 and RBC transfusions <2 units/month increased the probability of an erythroid response. A minority of subjects (12%) developed low-level non-neutralizing anti-DA antibodies. Our data indicate that weekly weight-based dosing of DA, with the addition of G-CSF in selected individuals, can be an effective erythropoietic option in a high proportion of lower-risk MDS patients. Am. J. Hematol, 2009. © 2008 Wiley-Liss, Inc. [source]

Characterisation of a P140K mutant O6 -methylguanine-DNA-methyltransferase (MGMT)-expressing transgenic mouse line with drug-selectable bone marrow

THE JOURNAL OF GENE MEDICINE, Issue 9 2006
Belinda A. Kramer
Abstract Background Gene transfer of the P140K mutant of O6 -methylguanine-DNA-methyltransferase (MGMT(P140K)) into hematopoietic stem cells (HSC) provides a mechanism for drug resistance and the selective expansion of gene-modified cells in vivo. Possible clinical applications for this strategy include chemoprotection to allow dose escalation of alkylating chemotherapy, or combining MGMT(P140K) expression with a therapeutic gene in the treatment of genetic diseases. Our aim is to use MGMT(P140K)-driven in vivo selection to develop allogeneic micro-transplantation protocols that rely on post-engraftment selection to overcome the requirement for highly toxic pre-transplant conditioning, and to establish and maintain predictable levels of donor/recipient chimerism. Methods Using stably transfected murine embryonic stem (ES) cells, we have generated a C57BL/6 transgenic mouse line with expression of MGMT(P140K) within the hematopoietic compartment for use as a standard source of donor HSC in such models. Functional characterisation of transgene expression was carried out in chemotherapy-treated transgenic mice and in allogeneic recipients of transgenic HSC. Results Expression of the transgene provided chemoprotection and allowed in vivo selection of MGMT(P140K)-expressing cells in transgenic mice after exposure to O6 -benzylguanine (BG) and N,N,-bis(2-chloroethyl)- N -nitrosourea (BCNU). In an allogeneic transplant experiment in which transgenic HSC were engrafted into 129 strain recipients following low intensity conditioning (Busulfan, anti-CD8, anti-CD40Ligand), MGMT(P140K)-expressing cells could be selected using chemotherapy. Conclusions This MGMT(P140K) transgenic mouse line provides a useful source of drug-selectable donor cells for the development of non-myeloablative allogeneic transplant models in which variation in transplant conditioning elements can be investigated independently of gene transfer efficiency. Copyright © 2006 John Wiley & Sons, Ltd. [source]

Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: Results of a randomized, double-blind, placebo-controlled trial,

ARTHRITIS & RHEUMATISM, Issue 9 2010
Lesley M. Arnold
Objective To assess the efficacy and safety of milnacipran at a dosage of 100 mg/day (50 mg twice daily) for monotherapy treatment of fibromyalgia. Methods A double-blind, placebo-controlled trial was performed to assess 1,025 patients with fibromyalgia who were randomized to receive milnacipran 100 mg/day (n = 516) or placebo (n = 509). Patients underwent 4,6 weeks of flexible dose escalation followed by 12 weeks of stable-dose treatment. Two composite responder definitions were used as primary end points to classify the response to treatment. The 2-measure composite response required achievement of ,30% improvement from baseline in the pain score and a rating of "very much improved" or "much improved" on the Patient's Global Impression of Change (PGIC) scale. The 3-measure composite response required satisfaction of these same 2 improvement criteria for pain and global status as well as improvement in physical function on the Short Form 36 (SF-36) physical component summary (PCS) score. Results After 12 weeks of stable-dose treatment, a significantly greater proportion of milnacipran-treated patients compared with placebo-treated patients showed clinically meaningful improvements, as evidenced by the proportion of patients meeting the 2-measure composite responder criteria (P < 0.001 in the baseline observation carried forward [BOCF] analysis) and 3-measure composite responder criteria (P < 0.001 in the BOCF). Milnacipran-treated patients also demonstrated significantly greater improvements from baseline on multiple secondary outcomes, including 24-hour and weekly recall pain score, PGIC score, SF-36 PCS and mental component summary scores, average pain severity score on the Brief Pain Inventory, Fibromyalgia Impact Questionnaire total score (all P < 0.001 versus placebo), and Multidimensional Fatigue Inventory total score (P = 0.036 versus placebo). Milnacipran was well tolerated by most patients, with nausea being the most commonly reported adverse event (placebo-adjusted rate of 15.8%). Conclusion Milnacipran administered at a dosage of 100 mg/day improved pain, global status, fatigue, and physical and mental function in patients with fibromyalgia. [source]

Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis,

ARTHRITIS & RHEUMATISM, Issue 11 2008
Judith M. Dalrymple
Objective There is evidence supporting a therapeutic range for methotrexate polyglutamate (MTXGlu) concentrations in the treatment of rheumatoid arthritis (RA). Knowledge of the pharmacokinetics of MTXGlu1,5 is required for optimal timing of blood sampling. The aim of this study was to determine the time to steady state and the half-life of accumulation of red blood cell (RBC) MTXGlu1,5 in patients with RA commencing oral MTX, and the time for RBC MTXGlu1,5 to become undetectable and the half-life of elimination of RBC MTXGlu1,5 in patients ceasing treatment with oral MTX. Methods Ten patients beginning treatment and 10 patients stopping treatment with low-dose oral MTX were recruited. Blood samples were initially collected weekly, with gradual extension to monthly collection over the study period. RBC MTXGlu1,5 concentrations were assayed by high-performance liquid chromatography. Results were analyzed using a first-order exponential method. Results The median times to reach steady state in RBCs (defined as 90% of the maximum concentration) were 6.2, 10.6, 41.2, 149, and 139.8 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half-life of accumulation for RBC MTXGlu1,5 ranged from 1.9 weeks to 45.2 weeks. The median times for MTXGlus to become undetectable in RBCs were 4.5, 5.5, 10, 6, and 4 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half-life of elimination for RBC MTXGlu1,5 ranged from 1.2 weeks to 4.3 weeks. Conclusion There is wide interpatient variability of RBC MTXGlu1,5 accumulation and elimination in adults with RA. These data also suggest that after a dose change, >6 months are required for RBC MTXGlu1,5 to reach steady state. Such delays in achieving steady state suggest that more rapid dose escalation or subcutaneous administration from the outset should be considered. [source]

Low molecular weight heparin (dalteparin) for the treatment of venous thromboembolism in pregnancy

BJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 2 2003
Anne Flem Jacobsen
Objective To evaluate the effect and dose of dalteparin given to pregnant women with acute venous thromboembolism. Design An observational study of pregnant women in Norway. Setting Delivery and haematological departments in Norway. Population Twenty women, aged 22,41 years, with acute venous thromboembolism verified by objective means. Methods Patients were treated with dalteparin from diagnosis until delivery. Treatment was monitored with anti-activated factor Xa (anti-Xa) activity, and the dose was adjusted to achieve target 0.5,1.0 U/mL 2,3 hours post-injection. Main outcome measure Anti-Xa activity and side effects. Result None of the patients suffered recurrent venous thromboembolism or major bleeding complications. In 9 of 13 women starting with conventional dose of dalteparin (100 iu/kg bd), dose escalation was necessary to reach target anti-Xa activity. None of the six women who started with 105,118 iu/kg bd required dose escalation. One woman who started with 133 iu/kg bd required dose reduction. Bioaccumulation of dalteparin was not observed. Conclusion Our study suggests that dalteparin may be used for the treatment of acute venous thromboembolism in pregnancy. Approximately 10,20% higher doses of dalteparin may be needed as compared with non-pregnant individuals. [source]