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Dose Titration (dose + titration)

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Medical Sciences	91%

Selected Abstracts

One-year follow-up of patients with acromegaly treated with fixed or titrated doses of lanreotide Autogel®

CLINICAL ENDOCRINOLOGY, Issue 6 2004
Ph. Caron
Summary objective, Somatostatin analogue treatment is first-line medical therapy for acromegaly. This study compared the efficacy and tolerability of titrated doses of the long-acting somatostatin analogue preparation lanreotide Autogel® with fixed doses and with lanreotide prolonged release (PR) 30 mg microparticles. patients, Patients entering the initial study had received a diagnosis of active acromegaly within the previous 5 years. design, This open, comparative, multicentre study was a 1-year extension of a previous trial during which patients with acromegaly had switched from lanreotide PR 30 mg microparticles injected intramuscularly every 7, 10 or 14 days, for at least 3 months, to one of three fixed doses of lanreotide Autogel® (120, 90, or 60 mg every 28 days, respectively). In this extension study, patients continued to receive 60, 90, or 120 mg of lanreotide Autogel® by deep subcutaneous injection every 28 days for 1 year. Doses could be titrated at entry or after four or eight injections, according to the GH/IGF-I response (dose increased if GH > 2·5 µg/l, or decreased if GH < 1 µg/l with normal IGF-I). measurements, Mean ± SEM GH and IGF-I concentrations were analysed and gallbladder echography performed at weeks 0, 16, 32, and 48. Acromegaly symptoms were recorded monthly and tolerance and side-effects were monitored throughout the study. results, In total, 130 patients entered this extension phase. After 1 year of treatment with titrated doses of lanreotide Autogel®, mean GH (2·4 ± 0·2 µg/l) and IGF-I (287 ± 12 µg/l) concentrations were significantly lower than with lanreotide microparticles (GH, 2·8 ± 0·2 µg/l, P < 0·001; IGF-I, 332 ± 15 µg/l, P < 0·01) or with fixed-dose lanreotide Autogel® (GH, 3·0 ± 0·2 µg/l, P < 0·001; IGF-I, 310 ± 14 µg/l, P = 0·02). GH hypersecretion was reduced to , 2·5 µg/l in 68% of patients with titrated-dose lanreotide Autogel® compared with 49% with microparticles (P < 0·001) and 56% with fixed-dose lanreotide Autogel® (P , 0·005). In the 65 patients who did not require any dose titration, there was no substantial change in serum lanreotide concentration, GH or IGF-I levels over the 12-month study duration. Acromegaly was effectively controlled (GH , 2·5 µg/l and normalized IGF-I) in significantly more patients (43%) compared with microparticles (32%; P < 0·05). There was a trend for improved control of acromegalic symptoms with dose titration, whereas the incidence of gastrointestinal symptoms and local tolerance was similar with lanreotide Autogel® and lanreotide microparticles. Gallbladder echographies showed new lithiasis in 8% of lanreotide Autogel® patients. conclusion, Dose titration of lanreotide Autogel® improved GH and IGF-I control in patients with acromegaly beyond that achieved using fixed doses of lanreotide Autogel® or lanreotide microparticles. Titrated long-term lanreotide Autogel® treatment is well tolerated. [source]

Prophylactic use of anti-emetic medications reduced nausea and vomiting associated with exenatide treatment: a retrospective analysis of an open-label, parallel-group, single-dose study in healthy subjects

DIABETIC MEDICINE, Issue 10 2010
C. Ellero
Diabet. Med. 27, 1168,1173 (2010) Abstract Aims, Transient nausea and, to a lesser extent, vomiting are common adverse effects of exenatide that can be mitigated by dose titration and usually do not result in treatment discontinuation. This retrospective analysis of data from a phase 1, open-label, parallel-group, single-dose study in healthy subjects evaluated the effect of oral anti-emetics on exenatide-associated nausea and vomiting and on the pharmacokinetics of exenatide. Methods, A single subcutaneous dose (10 ,g) of exenatide was administered to 120 healthy subjects (19,65 years, BMI 23,35 kg/m2). Incidences of nausea and vomiting were compared between 60 subjects premedicated with two oral anti-emetics 30 min before the exenatide dose and 60 non-premedicated subjects. Similarly, the area under the concentration-time curve (AUC) and the maximum observed concentration (Cmax) of plasma exenatide concentrations over 8 h post-dose were compared. Results, Among all subjects [61% male, 32 ± 12 years, body mass index (BMI) 29.1 ± 3.4 kg/m2 (mean ± sd)], mild to moderate nausea was the most frequent adverse event after exenatide dosing. Vomiting was also observed. Subjects premedicated with anti-emetics experienced significantly less nausea and vomiting (16.7 and 6.7%, respectively) vs. non-premedicated subjects (61.7 and 38.3%, respectively; P -value < 0.0001 for both nausea and vomiting). The mean area under the concentration-time curve and the maximum observed concentration AUC and Cmax of plasma exenatide concentrations during 8 h post-dose were not significantly different between groups. Conclusion, Administration of oral anti-emetics before a single 10-,g exenatide dose was associated with significant reductions in treatment-emergent nausea and vomiting, with no discernible effect on the pharmacokinetics of exenatide. Use of anti-emetic therapy may provide a short-term strategy to minimize the nausea and vomiting associated with exenatide treatment. [source]

Rosiglitazone RECORD study: glucose control outcomes at 18 months

DIABETIC MEDICINE, Issue 6 2007
P. D. Home
Abstract Aims To compare glucose control over 18 months between rosiglitazone oral combination therapy and combination metformin and sulphonylurea in people with Type 2 diabetes. Methods RECORD, a multicentre, parallel-group study of cardiovascular outcomes, enrolled people with an HbA1c of 7.1,9.0% on maximum doses of metformin or sulphonylurea. If on metformin they were randomized to add-on rosiglitazone or sulphonylurea (open label) and if on sulphonylurea to rosiglitazone or metformin. HbA1c was managed to , 7.0% by dose titration. A prospectively defined analysis of glycaemic control on the first 1122 participants is reported here, with a primary outcome assessed against a non-inferiority margin for HbA1c of 0.4%. Results At 18 months, HbA1c reduction on background metformin was similar with rosiglitazone and sulphonylurea [difference 0.07 (95% CI ,0.09, 0.23)%], as was the change when rosiglitazone or metformin was added to sulphonylurea [0.06 (,0.09, 0.20)%]. At 6 months, the effect on HbA1c was greater with add-on sulphonylurea, but was similar whether sulphonylurea was added to rosiglitazone or metformin. Differences in fasting plasma glucose were not statistically significant at 18 months [rosiglitazone vs. sulphonylurea ,0.36 (,0.74, 0.02) mmol/l, rosiglitazone vs. metformin ,0.34 (,0.73, 0.05) mmol/l]. Increased homeostasis model assessment insulin sensitivity and reduced C-reactive protein were greater with rosiglitazone than metformin or sulphonylurea (all P , 0.001). Body weight was significantly increased with rosiglitazone compared with sulphonylurea [difference 1.2 (0.4, 2.0) kg, P = 0.003] and metformin [difference 4.3 (3.6, 5.1) kg, P < 0.001]. Conclusions In people with diabetes, rosiglitazone in combination with metformin or sulphonylurea was demonstrated to be non-inferior to the standard combination of metformin + sulphonylurea in lowering HbA1c over 18 months, and produces greater improvements in C-reactive protein and basal insulin sensitivity but is also associated with greater weight gain. [source]

Safety and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: pooled data from randomised, double-blind, placebo-controlled studies

HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 2 2010
Didier Meulien
Abstract Introduction Extended release quetiapine fumarate (quetiapine XR) is a new formulation that allows once-daily dosing and a titration regimen that is simpler than that of immediate release quetiapine (quetiapine IR) and may potentially increase patients' adherence to their prescribed medication. Methods The tolerability of quetiapine XR was examined in an analysis of pooled data from three Phase III, double-blind, placebo-controlled, randomised studies with quetiapine IR as a reference treatment. Results The overall incidence of adverse events (AEs) was similar for quetiapine XR (69.5%) and quetiapine IR (72.5%). Most AEs were mild to moderate in severity and in line with those observed with quetiapine IR. The more rapid dose titration of quetiapine XR did not produce any new safety concerns and was as well tolerated as the regimen for quetiapine IR. Conclusions The results of this pooled analysis show that quetiapine XR administered once daily is generally as well tolerated as quetiapine IR given twice daily. These data, together with the simpler dose-titration of quetiapine XR that allowed therapeutically effective doses to be reached by Day 2, suggest that this formulation potentially may improve adherence in patients with schizophrenia. Copyright © 2010 John Wiley & Sons, Ltd. [source]

An adaptive clinical Type 1 diabetes control protocol to optimize conventional self-monitoring blood glucose and multiple daily-injection therapy

INTERNATIONAL JOURNAL OF ADAPTIVE CONTROL AND SIGNAL PROCESSING, Issue 5 2009
Xing-Wei Wong
Abstract The objective of this study was to develop a safe, robust and effective protocol for the clinical control of Type 1 diabetes using conventional self-monitoring blood glucose (SMBG) measurements, and multiple daily injection (MDI) with insulin analogues. A virtual patient method is used to develop an in silico simulation tool for Type 1 diabetes using data from a Type 1 diabetes patient cohort (n=40) . The tool is used to test two prandial insulin protocols, an adaptive protocol (AC) and a conventional intensive insulin therapy (IIT) protocol (CC) against results from a representative control cohort as a function of SMBG frequency. With the prandial protocols, optimal and suboptimal basal insulin replacement using a clinically validated, forced-titration regimen is also evaluated. A Monte Carlo (MC) analysis using variability and error distributions derived from the clinical and physiological literature is used to test efficacy and robustness. MC analysis is performed for over 1 400 000 simulated patient hours. All results are compared with control data from which the virtual patients were derived. In conditions of suboptimal basal insulin replacement, the AC protocol significantly decreases HbA1c for SMBG frequencies ,6/day compared with controls and the CC protocol. With optimal basal insulin, mild and severe hypoglycaemia is reduced by 86,100% over controls for all SMBG frequencies. Control with the CC protocol and suboptimal basal insulin replacement saturates at an SMBG frequency of 6/day. The forced-titration regimen requires a minimum SMBG frequency of 6/day to prevent increased hypoglycaemia. Overaggressive basal dose titration with the CC protocol at lower SMBG frequencies is likely caused by uncorrected postprandial hyperglycaemia from the previous night. From the MC analysis, a defined peak in control is achieved at an SMBG frequency of 8/day. However, 90% of the cohort meets American Diabetes Association recommended HbA1c with just 2 measurements a day. A further 7.5% requires 4 measurements a day and only 2.5% (1 patient) required 6 measurements a day. In safety, the AC protocol is the most robust to applied MC error. Over all SMBG frequencies, the median for severe hypoglycaemia increases from 0 to 0.12% and for mild hypoglycaemia by 0,5.19% compared with the unrealistic no error simulation. While statistically significant, these figures are still very low and the distributions are well below those of the controls group. An adaptive control protocol for Type 1 diabetes is tested in silico under conditions of realistic variability and error. The adaptive (AC) protocol is effective and safe compared with conventional IIT (CC) and controls. As the fear of hypoglycaemia is a large psychological barrier to appropriate glycaemic control, adaptive model-based protocols may represent the next evolution of IIT to deliver increased glycaemic control with increased safety over conventional methods, while still utilizing the most commonly used forms of intervention (SMBG and MDI). The use of MC methods to evaluate them provides a relevant robustness test that is not considered in the no error analyses of most other studies. Copyright © 2008 John Wiley & Sons, Ltd. [source]

Improving lipid management , to titrate, combine or switch

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 7 2004
H. Schuster
Summary Despite the benefits of statin therapy, cholesterol management remains suboptimal and many patients do not achieve their recommended low-density lipoprotein cholesterol (LDL-C) goals. The use of insufficient doses, limited drug effectiveness and poor patient compliance may contribute to the treatment gap. Options for improving lipid management include dose titration, combination therapy or prescribing a more efficacious statin. LDL-C reductions are generally modest when patients' current statin dose is titrated, and there may be an increased potential for adverse effects. Combining statin therapy with another lipid-modifying agent can provide additional LDL-C reductions, but cost, tolerability and compliance should be considered. In general, switching to a more efficacious statin is a cost-effective way of enabling more patients to achieve recommended targets without increasing dosages. When considering the options available, physicians should balance efficacy, cost and safety to enable more patients to attain LDL-C goals and achieve greater therapeutic gain from statin treatment. [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]

UNINTENTIONAL OVERDOSE WITH INTRATHECAL ZICONOTIDE

PAIN MEDICINE, Issue 2 2002
Article first published online: 4 JUL 200
Steven G. Charapata MD, Research Medical Center, Kansas City, MO; David Ellis MD, PhD, Elan Pharmaceuticals, South San Francisco, CA Ziconotide is a novel, N-type, voltage-sensitive calcium channel (VSCC) blocker, with well-documented efficacy as an intrathecal (IT) analgesic. Ziconotide has been administered to over 1000 chronic pain patients in nine clinical trials. Over 350 patients have been on ziconotide IT therapy for more than three months in a long-term safety and tolerability study. Common adverse events for ziconotide include dizziness, nausea, nystagmus, abnormal gait, constipation, urinary retention, somnolence, postural hypotension, vomiting, confusion and abnormal vision. Ziconotide adverse events are recognizable, reversible and manageable, by dose adjustment and slow dose titration. Case reports of unintentional overdose in six chronic pain patients treated with IT ziconotide are presented. These unintentional overdoses were attributable to pump programming or dilution errors; none were lethal. The patient who received the highest overdose was administered 31 mcg/hr over 24 hours, or nearly 750 mcg ziconotide, total. This hourly dose rate is 300-fold the current recommended initial dose rate of 0.1 mcg/hr. This patient was sedated, but arousable; vital signs were stable and patient had no change in blood pressure. His symptoms resolved within 24 hours. His Visual Analog Score of Pain Intensity (VASPI) was reduced from 82 at baseline to 2.5 at the end of the titration period. The patient elected to continue in the long-term IT ziconotide study. The other 5 cases of inadvertent overdose were less severe, with dose rate at 5 mcg/hr or less. Associated adverse events also resolved within 24-hours of discontinuing ziconotide infusion. Unlike an unintentional overdose with IT morphine, which slows respiration and could potentially lead to hypoxia, coma or death; ziconotide does not produce respiratory depression. No tolerance to the analgesic effect of ziconotide, or withdrawal symptoms after discontinuation of the drug have been reported. Ziconotide has a wide margin of safety as an IT analgesic. [source]

Opioids and the Management of Chronic Severe Pain in the Elderly: Consensus Statement of an International Expert Panel with Focus on the Six Clinically Most Often Used World Health Organization step III Opioids (Buprenorphine, Fentanyl, Hydromorphone, Methadone, Morphine, Oxycodone)

PAIN PRACTICE, Issue 4 2008
Joseph Pergolizzi MD
,,Abstract Summary of consensus: 1.,The use of opioids in cancer pain:, The criteria for selecting analgesics for pain treatment in the elderly include, but are not limited to, overall efficacy, overall side-effect profile, onset of action, drug interactions, abuse potential, and practical issues, such as cost and availability of the drug, as well as the severity and type of pain (nociceptive, acute/chronic, etc.). At any given time, the order of choice in the decision-making process can change. This consensus is based on evidence-based literature (extended data are not included and chronic, extended-release opioids are not covered). There are various driving factors relating to prescribing medication, including availability of the compound and cost, which may, at times, be the main driving factor. The transdermal formulation of buprenorphine is available in most European countries, particularly those with high opioid usage, with the exception of France; however, the availability of the sublingual formulation of buprenorphine in Europe is limited, as it is marketed in only a few countries, including Germany and Belgium. The opioid patch is experimental at present in U.S.A. and the sublingual formulation has dispensing restrictions, therefore, its use is limited. It is evident that the population pyramid is upturned. Globally, there is going to be an older population that needs to be cared for in the future. This older population has expectations in life, in that a retiree is no longer an individual who decreases their lifestyle activities. The "baby-boomers" in their 60s and 70s are "baby zoomers"; they want to have a functional active lifestyle. They are willing to make trade-offs regarding treatment choices and understand that they may experience pain, providing that can have increased quality of life and functionality. Therefore, comorbidities,including cancer and noncancer pain, osteoarthritis, rheumatoid arthritis, and postherpetic neuralgia,and patient functional status need to be taken carefully into account when addressing pain in the elderly. World Health Organization step III opioids are the mainstay of pain treatment for cancer patients and morphine has been the most commonly used for decades. In general, high level evidence data (Ib or IIb) exist, although many studies have included only few patients. Based on these studies, all opioids are considered effective in cancer pain management (although parts of cancer pain are not or only partially opioid sensitive), but no well-designed specific studies in the elderly cancer patient are available. Of the 2 opioids that are available in transdermal formulation,fentanyl and buprenorphine,fentanyl is the most investigated, but based on the published data both seem to be effective, with low toxicity and good tolerability profiles, especially at low doses. 2.,The use of opioids in noncancer-related pain:, Evidence is growing that opioids are efficacious in noncancer pain (treatment data mostly level Ib or IIb), but need individual dose titration and consideration of the respective tolerability profiles. Again no specific studies in the elderly have been performed, but it can be concluded that opioids have shown efficacy in noncancer pain, which is often due to diseases typical for an elderly population. When it is not clear which drugs and which regimes are superior in terms of maintaining analgesic efficacy, the appropriate drug should be chosen based on safety and tolerability considerations. Evidence-based medicine, which has been incorporated into best clinical practice guidelines, should serve as a foundation for the decision-making processes in patient care; however, in practice, the art of medicine is realized when we individualize care to the patient. This strikes a balance between the evidence-based medicine and anecdotal experience. Factual recommendations and expert opinion both have a value when applying guidelines in clinical practice. 3.,The use of opioids in neuropathic pain:, The role of opioids in neuropathic pain has been under debate in the past but is nowadays more and more accepted; however, higher opioid doses are often needed for neuropathic pain than for nociceptive pain. Most of the treatment data are level II or III, and suggest that incorporation of opioids earlier on might be beneficial. Buprenorphine shows a distinct benefit in improving neuropathic pain symptoms, which is considered a result of its specific pharmacological profile. 4.,The use of opioids in elderly patients with impaired hepatic and renal function:, Functional impairment of excretory organs is common in the elderly, especially with respect to renal function. For all opioids except buprenorphine, half-life of the active drug and metabolites is increased in the elderly and in patients with renal dysfunction. It is, therefore, recommended that,except for buprenorphine,doses be reduced, a longer time interval be used between doses, and creatinine clearance be monitored. Thus, buprenorphine appears to be the top-line choice for opioid treatment in the elderly. 5.,Opioids and respiratory depression:, Respiratory depression is a significant threat for opioid-treated patients with underlying pulmonary condition or receiving concomitant central nervous system (CNS) drugs associated with hypoventilation. Not all opioids show equal effects on respiratory depression: buprenorphine is the only opioid demonstrating a ceiling for respiratory depression when used without other CNS depressants. The different features of opioids regarding respiratory effects should be considered when treating patients at risk for respiratory problems, therefore careful dosing must be maintained. 6.,Opioids and immunosuppression:, Age is related to a gradual decline in the immune system: immunosenescence, which is associated with increased morbidity and mortality from infectious diseases, autoimmune diseases, and cancer, and decreased efficacy of immunotherapy, such as vaccination. The clinical relevance of the immunosuppressant effects of opioids in the elderly is not fully understood, and pain itself may also cause immunosuppression. Providing adequate analgesia can be achieved without significant adverse events, opioids with minimal immunosuppressive characteristics should be used in the elderly. The immunosuppressive effects of most opioids are poorly described and this is one of the problems in assessing true effect of the opioid spectrum, but there is some indication that higher doses of opioids correlate with increased immunosuppressant effects. Taking into consideration all the very limited available evidence from preclinical and clinical work, buprenorphine can be recommended, while morphine and fentanyl cannot. 7.,Safety and tolerability profile of opioids:, The adverse event profile varies greatly between opioids. As the consequences of adverse events in the elderly can be serious, agents should be used that have a good tolerability profile (especially regarding CNS and gastrointestinal effects) and that are as safe as possible in overdose especially regarding effects on respiration. Slow dose titration helps to reduce the incidence of typical initial adverse events such as nausea and vomiting. Sustained release preparations, including transdermal formulations, increase patient compliance.,, [source]

Latest news and product developments

PRESCRIBER, Issue 6 2008
Article first published online: 24 APR 200
Government responds to NICE report The Government has published its response to the Health Select Committee's report into NICE, broadly arguing that the Committee's recommendations are either already being dealt with or are not appropriate. The Committee recommended appraisals for all new drugs, shorter, rapid appraisals to coincide with their launch, and improved mechanisms for setting drug prices. The Government says its negotiations on the PPRS preclude a detailed response but suggests a rapid system may not be transparent or legally robust. It is exploring how high-cost drugs can be brought within the payment-by-results tariff. While defending NICE's reliance on QALYs, the Government accepts the need to explore how wider economic factors can be considered. As for the threshold cost per QALY by which NICE defines cost effectiveness, it says this is being validated scientifically and NICE will continue to determine the threshold. More topically, the Committee criticised the quality of clinical trial data available to NICE. The Government sees no need to compel pharmaceutical companies to disclose information and says NICE is already becoming more involved with research programmes. All clinical trials must be registered (confidentially) with the EU and the Government believes mandatory registration in the UK would be ineffective and illegal. Prescription charge up again from April The Government has raised the prescription charge by 25p to £7.10 per item with effect from 1 April. Prescription prepayment certificates will cost £27.85 for three months and £102.50 for 12 months. The increase, below the annual rate of inflation for the 10th successive year, will be levied on the 12 per cent of prescriptions that are liable for the charge: 5 per cent via prepayment certificates and 7 per cent from other prescriptions. The charge will generate £435 million in England in 2008/09; this excludes money from prescriptions written by dispensing doctors, which is retained by the PCT. Following criticism of the charge by the Health Select Committee, the Government says it has reviewed the charge and is now consulting on ,cost-neutral' options. MHRA safety update The MHRA warns of possible dose errors associated with Boots Medisure Domiciliary Dosage System in its latest issue of Drug Safety Update (2008;1:issue 8). One case has been reported in which incomplete sealing allowed tablets to mix between compartments. No other cases are known and the MHRA says no harm was reported but the risk is serious. The system should be carefully sealed and inspected visually and physically. The MHRA reaffirms its plans to reclassify all pseudoephedrine and ephedrine products to prescription-only status in 2009 if the new restrictions on sales do not reduce misuse. Other topics in this month's Update include revised indications for oral ketoconazole (Nizoral), restricting its use to selected conditions unresponsive to topical therapy; reformulation of the injectable antibiotic Tazocin (piperacillin plus tazobactum); the risk of peripheral neuropathy associated with pegylated interferon and telbivudine (Sebivo) in the treatment of hepatitis B; and serious adverse events associated with modafinil (Provigil). First oral anticoagulant since warfarin In January this year the EMEA issued a positive opinion to recommend marketing authorisation of the oral, fixed-dose, direct thrombin inhibitor dabigatran etexilate (Pradaxa) for the primary prevention of venous thromboembolism (VTE) in adult patients that have undergone elective knee or hip replacement surgery. Marketing authorisation for the EU (including the UK) is expected from the European Commission in the next few weeks, making dabigatran the first oral anticoagulant since warfarin was introduced in 1954. Dabigatran etexilate has been shown to be as safe and effective as enoxaparin (Clexane) with a similar adverse event profile in the noninferiority phase III RENOVATE (Lancet 2007;370: 949-56) and RE-MODEL (J Throm Haemost 2007;5:217885) trials, which investigated the efficacy and safety of dabigatran compared to enoxaparin in reducing the risk of VTE after total hip and knee surgery respectively. Dabigatran has the practical advantage over low-molecular-weight heparin of oral postoperative administration and no risk of heparin-induced thrombocytopenia and, unlike warfarin, does not require monitoring or dose titration. Risk scale predicts anticholinergic effects US investigators have developed a scale for predicting the risk of anticholinergic side-effects from older patients' medicines (Arch Intern Med 2008;168: 508-13). The scale assigns a score from 1 (low) to 3 (high) for the risk of anticholinergic effects such as dry mouth, constipation and dizziness associated with commonly prescribed medicines. Checking the scale retrospectively in older patients in residential care, a higher score was associated with a 30 per cent increased risk of side-effects after adjustment for age and number of medicines. When this was repeated prospectively in a primary-care cohort, the increased risk was 90 per cent. HRT cancer risk persists The latest analysis of the Women's Health Initiative (WHI) trial of HRT shows that the small increase in the risk of cancer persists for up to three years after stopping treatment (J Am Med Assoc 2008;299:1036-45). WHI was stopped after 5.6 years' follow-up when it became clear the risks of HRT outweighed its benefits. This follow-up after a further three years (mean 2.4) involved 15 730 women. The annual risk of cardiovascular events was similar for HRT (1.97 per cent) and placebo (1.91 per cent). Cancers were more common among women who had taken HRT (1.56 vs 1.26 per cent), in particular breast cancer (0.42 vs 0.33 per cent). All-cause mortality was higher, but not statistically significantly so, with HRT (1.20 vs 1.06 per cent). Tight glycaemic control may increase falls Maintaining HbA1C at or below 6 per cent with insulin is associated with an increased risk of falls, a US study suggests (Diabetes Care 2008;31:391-6). The Health, Aging and Composition study involved 446 older people with type 2 diabetes (mean age 74) followed up for approximately five years. The incidence of falls ranged from 22 to 30 per cent annually. Comparing subgroups with HbA1C of ,6 per cent and >8 per cent, an increased risk of falls was associated with insulin use (odds ratio 4.4) but not oral hypoglycaemic drugs. Copyright © 2008 Wiley Interface Ltd [source]

An investigation of dose titration with darifenacin, an M3 -selective receptor antagonist

BJU INTERNATIONAL, Issue 4 2005
William Steers
OBJECTIVES To evaluate the efficacy, tolerability and safety of a flexible-dosing strategy with darifenacin, an M3 -selective receptor antagonist, in patients with symptoms of overactive bladder (OAB). PATIENTS AND METHODS In this multicentre double-blind 12-week study, 395 patients (aged 22,89 years; 84% female) with OAB symptoms for >6 months were randomized (2 : 1) and received once-daily treatment with darifenacin controlled-release tablets 7.5 mg (268 patients) or matching placebo (127). After 2 weeks of treatment, the efficacy, safety and tolerability were assessed and the dose increased to 15 mg once daily (pseudo-increase for placebo recipients) if additional efficacy was required by both the patient and physician. In the week before clinic visits (at 2 and 12 weeks), patients recorded incontinence episodes (primary efficacy endpoint) and several secondary efficacy variables in an electronic daily diary. Safety and tolerability were evaluated from withdrawal rates and adverse-event reports. RESULTS The treatment groups had comparable baseline characteristics. Similar proportions of darifenacin (59%) and placebo (68%) recipients increased the dose at 2 weeks; at 12 weeks patients on darifenacin (overall group) had a significantly greater reduction in the median number of incontinence episodes per week than had those on placebo, at ,,8.2 (,62.9%) and ,,6.0 (,48.1%), respectively (P = 0.035). There were also significant improvements in voiding frequency (P = 0.001), bladder capacity (volume voided; P=,0.036), frequency of urgency (P < 0.001), severity of urgency (P = 0.013) and number of significant leaks/week (i.e. incontinence episodes needing a change of clothing or pads, per week; P = 0.010) for darifenacin over placebo. Subset analysis suggested that some patients (those remaining on darifenacin 7.5 mg) were more sensitive to darifenacin than those who increased the dose, based on both efficacy and adverse events. Continued treatment with 7.5 mg for ,sensitive' patients, and an increased dose (to 15 mg) for remaining patients, resulted in comparable outcomes by 12 weeks. The most common treatment-related adverse events were mild-to-moderate dry mouth and constipation, which led to discontinuation in <,3.0% of darifenacin-treated patients and <1.0% of the placebo group. Central nervous system and cardiovascular adverse events were comparable to those with placebo. CONCLUSIONS Darifenacin appears to be an effective, well-tolerated and flexible treatment for patients with OAB, allowing individualized dosing according to patient needs. [source]