Biomedical subjects

David P Figgitt

Publications and source records attributed to David P Figgitt.

At least 19 recordsLinked to original sources

PubMed2006

VSL#3 probiotic mixture: a review of its use in chronic inflammatory bowel diseases.

VSL#3 (VSL#3) is a high-concentration probiotic preparation of eight live freeze-dried bacterial species that are normal components of the human gastrointestinal microflora, including four strains of lactobacilli (Lactobacillus casei, L. plantarum, L. acidophilus and L. delbrueckii subsp. bulgaricus), three strains of bifidobacteria (Bifidobacterium longum, B. breve and B. infantis) and Streptococcus salivarius subsp. thermophilus. Data from noncomparative trials suggest that VSL#3 has clinical potential in the treatment of active mild to moderate ulcerative colitis and as maintenance therapy for patients with ulcerative colitis in remission. In addition, a randomised, open-label, multicentre trial showed that VSL#3 in combination with low-dose balsalazide (a prodrug of mesalazine [mesalamine; 5-aminosalicylic acid]) was more effective than standard doses of basalazide or mesalazine monotherapy in the treatment of acute mild to moderate ulcerative colitis. Randomised, double-blind, placebo-controlled studies have shown VSL#3 is effective in preventing the onset of acute pouchitis in patients with newly formed surgical pouches, and in maintaining remission following antibacterial treatment of acute pouchitis in patients with a history of refractory or recurrent pouchitis. Treatment guidelines from the US and the UK include VSL#3 as a therapeutic option for the prevention of pouchitis relapse in patients with chronic pouchitis. In general, VSL#3 was well tolerated in clinical trials. Large, well designed, controlled confirmatory clinical trials will further determine the place of VSL#3 in the treatment of ulcerative colitis.

Colitis, Ulcerative↗

PubMed2005

Oxaliplatin: in operable colorectal cancer.

Oxaliplatin is available in numerous countries for the treatment of metastatic colorectal cancer (in conjunction with fluoropyrimidine therapy). The activity of oxaliplatin in advanced disease has led to investigation of its potential in operable disease. The addition of oxaliplatin to adjuvant therapy with fluorouracil and folinic acid (FOLFOX4 regimen) is associated with a significantly greater disease-free survival at 3 years (78% vs 73%; p = 0.002), according to results of the MOSAIC (Multicenter International Study of Oxaliplatin/5FU/Leucovorin [folinic acid] in the Adjuvant Treatment of Colon Cancer) trial, a study in 2246 patients with stage II or III colon cancer. In addition, a 23% reduction in the risk of disease recurrence after surgery was seen with FOLFOX4 compared with fluorouracil/folinic acid in the MOSAIC trial. Results from several phase I/II studies suggest that the addition of oxaliplatin to preoperative radiochemotherapy may be of benefit in patients with locally advanced lower rectal cancer in terms of disease downstaging and sphincter preservation. Oxaliplatin was generally well tolerated in the MOSAIC trial and neuro- and myelotoxicity with FOLFOX4 were manageable.

Antineoplastic Agents↗

PubMed2005

Linezolid: a pharmacoeconomic review of its use in serious Gram-positive infections.

Linezolid (Zyvox), the first available oxazolidinone antibacterial agent, has good activity against Gram-positive pathogens, including multidrug-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Randomised multicentre trials in patients with various types of serious Gram-positive infections showed that clinical cure rates with linezolid were similar to those with vancomycin or teicoplanin. In some subgroup analyses, which must be interpreted with a degree of caution, clinical advantages were noted for linezolid (e.g. versus vancomycin in confirmed MRSA nosocomial pneumonia and MRSA-complicated skin and soft tissue infections). Although generally well tolerated, gastrointestinal adverse effects are relatively common with linezolid and it has been associated with thrombocytopenia and myelosuppression. The oral bioavailability of linezolid is approximately 100%, thus allowing sequential intravenous-to-oral administration without changing the drug or dosage regimen. Healthcare resource use data from various countries indicate that this practical advantage translates into at least a trend towards reduced length of hospital stay compared with vancomycin, which may offset its several-fold higher acquisition cost. Modelled analyses from the US, despite some limitations, indicate that, compared with vancomycin, linezolid is associated with lower total hospitalisation costs for the treatment of patients with cellulitis and has a favourable incremental cost-effectiveness ratio of approximately US30,000 dollars per QALY gained (2001 value) for patients with ventilator-associated pneumonia. Broadly similar results have also been reported in modelled analyses from other countries. In conclusion, for patients with serious Gram-positive infections, including those caused by suspected or proven multidrug-resistant pathogens such as MRSA, linezolid is an effective and generally well tolerated therapeutic option. Linezolid is currently the only antibacterial agent with good activity against MRSA that can be administered orally (as well as intravenously). It may be particularly useful as an alternative to vancomycin in patients who have impaired renal function, poor or no intravenous access, require outpatient therapy, or who have been unable to tolerate glycopeptides. Healthcare resource use studies and pharmacoeconomic analyses generally support the use of linezolid in some subgroups of patients, although results should be interpreted with due consideration of the study limitations.

Acetamides↗

PubMed2005

Pregabalin: as adjunctive treatment of partial seizures.

Pregabalin, the pharmacologically active S-enantiomer of 3-aminomethyl-5-methylhexanoic acid, possesses anticonvulsant activity. Pregabalin binds with high affinity and specificity to voltage-gated calcium channel alpha(2)-delta proteins. The putative mechanism of action of the drug is reduced excitatory neurotransmitter release caused by binding to the alpha(2)-delta protein, resulting in allosteric modulation of P/Q-type voltage-gated calcium channels. In three well designed trials, oral pregabalin as adjunctive therapy in patients with refractory partial seizures was significantly (p < or = 0.0007) more effective than placebo in reducing seizure frequency when administered at dosages of 150-600 mg/day (as two or three divided doses). Adjunctive pregabalin produced an overall mean 41.3% improvement from baseline in 28-day seizure-free rate in four long-term (maximum exposure 1764 days), open-label studies in 1480 patients. CNS-related effects (e.g. dizziness and somnolence) were the most frequent dose-related treatment-emergent adverse events associated with adjunctive pregabalin therapy.

Anticonvulsants↗

PubMed2005

Acamprosate: a review of its use in the maintenance of abstinence in patients with alcohol dependence.

Acamprosate (Campral delayed-release tablet), a synthetic compound with a similar structure to that of the neurotransmitter GABA and the neuromodulator taurine, facilitates the maintenance of abstinence in detoxified alcohol-dependent patients. Although the precise mechanism(s) of action of the drug remains to be fully elucidated, it appears that it most likely involves beneficial modulation of the glutamatergic neurotransmitter system, including antagonism of the mGLu5 metabotropic glutamate receptor, to counteract the imbalance between the glutamatergic and GABAergic systems associated with chronic alcohol exposure and alcohol withdrawal. In several double-blind, placebo-controlled trials of up to 12 months' duration, acamprosate effectively maintained complete abstinence in detoxified alcohol-dependent patients, irrespective of disease severity or the type of psychosocial support. The drug showed better efficacy than placebo and was very well tolerated. Limited data from a relatively well designed trial indicate that the drug has similar efficacy to that of naltrexone and that combination therapy with these two agents provides better efficacy than acamprosate monotherapy, although multicentre direct head-to-head investigations are required to fully establish the potential of this combination. The drug may be particularly useful in those with hepatic impairment and/or liver disease. Thus, in combination with psychosocial and behavioural management programmes, acamprosate is a promising option for the maintenance of abstinence in alcohol-dependent patients after alcohol withdrawal.

Acamprosate↗

PubMed2004

Intravenous esomeprazole.

The proton pump inhibitor esomeprazole comprises the S-isomer of omeprazole. An intravenous formulation of the drug has been developed for use in patients not able to take oral drugs. The level of gastric acid control was similar with intravenous and oral esomeprazole in two studies in healthy volunteers receiving 20 or 40 mg once daily for 5 days. In addition, a similar level of gastric acid control occurred with intravenous esomeprazole 40 mg administered by infusion or injection once daily for 10 days. In healthy volunteers, intravenous esomeprazole provided faster and more effective gastric acid control than intravenous pantoprazole (40 mg once daily for 5 days). In addition, control of basal and pentagastrin-stimulated gastric acid secretion was better with intravenous esomeprazole 40 mg than with intravenous omeprazole 40 mg (single-dose study). Healing rates at 4 weeks were approximate, equals 80% in a well designed study in patients with erosive oesophagitis (n = 246) who received esomeprazole 40 mg once daily intravenously (by injection or infusion) or orally. Intravenous therapy was administered for the first week, after which all patients received oral esomeprazole. Intravenous esomeprazole was generally well tolerated in patients with erosive oesophagitis, with a tolerability profile similar to that of the oral formulation.

Administration, Oral↗

PubMed2004

Micafungin.

Micafungin, an echinocandin antifungal agent with a novel mechanism of action, inhibits beta-(1,3)-D-glucan synthase interfering with fungal cell wall synthesis. It shows excellent antifungal activity against a broad range of Candida spp., including azole-resistant strains, and Aspergillus spp. in in vitro and animal studies. In HIV-positive patients, intravenous micafungin 50-150 mg/day dose-dependently eradicated endoscopically confirmed oesophageal candidiasis, with micafungin 100 and 150 mg/day being more effective than micafungin 50 mg/day and as effective as fluconazole 200 mg/day in a double-blind trial. In nonblind trials, micafungin (monotherapy or combination therapy) was effective against invasive aspergillosis, candidiasis and candidaemia in paediatric and adult patients with newly diagnosed or refractory infections. Micafungin 50 mg/day provided significantly better antifungal prophylaxis than fluconazole 400 mg/day in 882 haematopoietic stem cell transplant recipients in a randomised, double-blind trial. Respective overall success rates were 80% and 73.5%. Micafungin is generally well tolerated. Adverse events were not dose- or infusion-related with micafungin 12.5-900 mg/day; no histamine-like reactions occurred. Micafungin was as well tolerated as fluconazole, with numerically fewer micafungin recipients discontinuing treatment (4.2% vs 7.2%).

Animals↗

PubMed2004

Zoledronic acid: a review of its use in patients with advanced cancer.

Zoledronic acid (Zometa), a parenteral bisphosphonate, is an inhibitor of osteoclast-mediated bone resorption and is used in the management of patients with cancer. Zoledronic acid 4 mg is administered as an intravenous infusion over 15 minutes. In the treatment of bone metastases, zoledronic acid is the first and only bisphosphonate to demonstrate efficacy in patients with a broad range of tumour types and in multiple myeloma. In well-designed trials, a single 4 mg dose of zoledronic acid showed good efficacy in the treatment of patients with hypercalcaemia of malignancy. Zoledronic acid 4 mg was superior to pamidronic acid 90 mg, administered as a 2-hour infusion, as assessed by normalised serum calcium concentrations 10 days after administration. In conjunction with antineoplastic therapy, zoledronic acid was an effective long-term (up to 25 months) treatment for skeletal-related events in patients with bone metastases associated with multiple myeloma or solid tumours. In patients with bone metastases secondary to breast cancer or bone lesions from myeloma, zoledronic acid was at least as effective as pamidronic acid, based on assessments of skeletal-related events 25 months after the start of treatment. In addition, compared with pamidronic acid, the overall risk of developing skeletal complications, including hypercalcaemia of malignancy, was significantly reduced in recipients of zoledronic acid. Compared with pamidronic acid, zoledronic acid reduced the risk of patients with breast cancer developing a skeletal-related event by an additional 20%. Zoledronic acid was significantly more effective than placebo on most efficacy measures in patients with bone metastases secondary to other solid tumours (e.g. lung, prostate) and showed sustained efficacy for up to 15 months. Preliminary data indicate that its efficacy in these patients is sustained for up to 24 months. Estimates of the cost effectiveness of zoledronic acid in the treatment of prostate cancer were consistent with those of other bisphosphonates, and cost-effectiveness ratios were within limits considered acceptable economic value. Zoledronic acid was generally well tolerated, with a tolerability profile similar to that of pamidronic acid and placebo. As with other bisphosphonates, deterioration of renal function has occasionally been reported in patients receiving zoledronic acid and monitoring of serum creatinine is recommended during treatment. The efficacy of zoledronic acid is therefore well established in patients with hypercalcaemia of malignancy and, for up to 25 months, in the treatment of complications arising from metastatic bone disease in patients with multiple myeloma or solid tumours. The clinical profile of zoledronic acid compares favourably with that of pamidronic acid in patients with cancer and zoledronic acid has a more convenient administration schedule with the potential for better compliance. Thus, zoledronic acid is an effective bisphosphonate and is positioned to play an important role in the management of advanced cancer patients with bone metastases.

Area Under Curve↗

PubMed2004

Brivudin (bromovinyl deoxyuridine).

Brivudin is an oral thymidine analogue indicated for the early treatment of acute herpes zoster in immunocompetent adults. It has high, selective activity against varicella zoster virus (VZV), inhibiting VZV replication, possibly through competitive inhibition of viral DNA polymerase, or by acting as an alternative substrate to deoxythymidine triphosphate, causing viral DNA strand breakage. In a large, 7-day, phase III trial in immunocompetent patients with herpes zoster, once-daily brivudin 125mg was significantly more effective than oral acyclovir 800mg five times daily in reducing the mean time from start of treatment to last vesicular eruption, and was as effective as acyclovir at healing lesions and alleviating acute zoster-related pain. The likelihood of developing post-herpetic neuralgia (PHN) in immunocompetent patients aged > or =50 years was significantly lower with brivudin than with acyclovir. Brivudin was as effective as oral famciclovir 250mg three times daily in terms of the prevalence of PHN, the time to last vesicular eruption and lesion healing in another large, 7-day, phase III study in immunocompetent patients with herpes zoster. Oral brivudin is generally well tolerated, with a similar tolerability profile to those of oral acyclovir or famciclovir. Nausea was the most commonly reported adverse event.

Acute Disease↗

PubMed2004

Repaglinide : a pharmacoeconomic review of its use in type 2 diabetes mellitus.

Repaglinide (Prandin), NovoNorm, GlucoNorm, an oral insulin secretagogue, was the first meglitinide analogue to become available for use in patients with type 2 diabetes mellitus. The drug lowers postprandial glucose excursions by targeting early-phase insulin release, an effect thought to be important in reducing long-term cardiovascular complications of diabetes. Repaglinide provided similar overall glycaemic control to that achieved with glibenclamide (glyburide), as assessed by glycosylated haemoglobin (HbA(1c)) and fasting blood glucose levels, and was generally well tolerated in well designed clinical trials. Its rapid onset and relatively short duration of action allow for flexible meal schedules. Two modelled US cost-effectiveness analyses projected lifetime costs and outcomes for a hypothetical cohort of patients with type 2 diabetes. Both analyses projected long-term complications using data on HbA(1c) level changes from short-term clinical trials. Repaglinide plus rosiglitazone was dominant over rosiglitazone in one analysis, and repaglinide plus metformin was dominant over nateglinide plus metformin in the other. A similar Canadian analysis showed a favourable incremental cost-effectiveness ratio (<dollars US 1000 per QALY gained; 2001 values) for patients who switched from a sulphonylurea to repaglinide versus those who remained on sulphonylurea therapy. Long-term outcomes were projected using short-term clinical trial data on postprandial blood glucose level changes in the Canadian study. All three cost-effectiveness analyses are available as abstracts/posters. Two US cost analyses (both published in full) have also been conducted comparing the short-term costs (<or=3 years) of repaglinide, with or without metformin, versus other oral antidiabetic regimens. Results of these analyses are somewhat equivocal because of study design issues and/or a lack of statistically significant differences between treatment groups. In conclusion, repaglinide as monotherapy or in combination with other antidiabetic agents, such as metformin or rosiglitazone, achieves good metabolic control, similar to that achieved with comparable glibenclamide regimens. Severe hypoglycaemic episodes are less common with repaglinide than some sulphonylureas, including glibenclamide. Modelled cost-effectiveness analyses conducted in North America showed favourable results for repaglinide-containing regimens versus comparators, largely attributed to projected reductions in long-term cardiovascular complications using short-term data on changes in glycaemic parameters from clinical trials. Results of these cost-effectiveness analyses (all of which have been published as abstracts/posters) should be interpreted with caution since various assumptions regarding long-term costs and outcomes were necessarily incorporated into the economic models. While repaglinide is a useful addition to the available treatment options in type 2 diabetes, potential long-term advantages versus other agents, such as reducing cardiovascular complications, require confirmation. The prevalence of diabetes mellitus is projected to increase to over 3% of the world's population ( approximate, equals 220 million people) by the year 2010. Globally, 97% of patients with diabetes have type 2 disease, although in industrialised countries the proportion of type 2 disease is about 90%. In 2010, an estimated 14.85 million individuals in the US and 2.88 million in the UK will be diagnosed with type 2 diabetes. In addition, approximately one-third to one-half of individuals with diabetes are unaware that they have the disease, and are therefore undiagnosed. Diabetes is associated with significant morbidity, mortality and economic consequences. For the year 2002 in the US, direct medical costs associated with diabetes (type 1 and 2) were estimated at dollars US 91.8 billion (70% of total costs) and indirect costs at dollars US 39.8 billion (30%), for a total of dollars US 132 billion. Data from more than 7000 patients in eight European countries indicate tha the mean cost per patient with diabetes was dollars US 2928 annually (1999 values), and the proportion of total healthcare expenditure directed toward diabetes ranged from 1.6% to 6.6% depending on the country. Several analyses focusing specifically on type 2 disease showed, not surprisingly, that costs were higher among patients with diabetic complications than in those without complications. Repaglinide, a meglitinide analogue, is an oral insulin secretagogue that reduces postprandial glucose excursions by targeting postprandial insulin release. In clinical trials in patients with type 2 diabetes, repaglinide was usually administered at a dosage of 0.5-4 mg three times daily before meals as monotherapy or in combination with other agents. In placebo-controlled trials of up to 24 weeks' duration in patients with type 2 diabetes, repaglinide achieved statistically significant improvements in glycaemic control, as assessed by glycosylated haemoglobin (HbA(1c)), fasting blood glucose (FBG) and/or postprandial blood glucose (PPBG) levels compared with placebo. Preprandial administration of repaglinide achieved similar glycaemic control to glibenclamide (glyburide) 1.75-15 mg/day and better glycaemic control than glipizide 5-15 mg/day in 1-year, double-blind, randomised trials in patients with type 2 disease, the vast majority of whom had previously received oral antidiabetic therapy. Several randomised, open-label studies have evaluated repaglinide as part of combination therapy over 3-6 months in patients with type 2 diabetes who had inadequate glycaemic control with previous drug therapy. In general, results showed statistically significant improvements in glycaemic control when repaglinide was used in combination with metformin, various thiazolidinediones, or metformin plus bedtime insulin compared with monotherapy with either comparator drug in each study (or metformin plus bedtime insulin in one trial). Other studies in this patient population indicate that metformin plus repaglinide is associated with significantly better glycaemic control than metformin plus nateglinide 60-120 mg three times daily over 16 weeks, and similar glycaemic control to that achieved with metformin in combination with either glibenclamide or glimepiride for up to 1 year. Good glycaemic control has also been achieved with preprandial administration of repaglinide in flexible meal schedules. This was demonstrated in a placebo-controlled trial and in a large, prospective survey of patients receiving repaglinide in a clinical setting. The tolerability profile of repaglinide is characterised by adverse events of mild-to-moderate intensity similar to those associated with sulphonylureas. The most frequently reported adverse events with repaglinide include hypoglycaemia, upper respiratory infection, headache, other respiratory events, musculoskeletal events and gastrointestinal events. Severe episodes of hypoglycaemia are rare with repaglinide and occur approximately 2-2.5 times less frequently than with sulphonylureas. In addition, available data indicate that repaglinide may be less likely to increase bodyweight than various commonly used sulphonylurea agents. In general, repaglinide is also well tolerated when used as part of combination therapy. Repaglinide is metabolised by the cytochrome P450 (CYP) 3A4 enzyme system and therefore has the potential to interact with other CYP3A4 substrates when administered concurrently. A number of studies in healthy volunteers have shown no clinically significant pharmacokinetic drug interactions when repaglinide was administered concomitantly with digoxin, theophylline, warfarin, cimetidine, ketoconazole, rifampicin (rifampin), ethinylestradiol, simvastatin or nifedipine. However, a clinically significant increase in systemic exposure to repaglinide occurs when clarithromycin and repaglinide are administered concurrently, which may necessitate a reduction in repaglinide dosage. Moreover, a potentially hazardous interaction occurs when gemfibrozil (alone or with itraconazole) is used concomitantly with repaglinide. In view of the marked increase in systemic exposure to repaglinide, the combination of repaglinide and gemfibrozil should be avoided if possible. Pharmacoeconomic Analyses of RepaglinideTwo US cost analyses have been conducted with repaglinide in patients with type 2 diabetes (both published in full). One was a retrospective analysis of pharmacy and medical claims data from a large managed care organisation in which costs were adjusted for age, gender and comorbidities. Total adjusted (year 2000) cost per patient over a 9-month period was numerically lower for those treated with a combination of repaglinide plus metformin (dollars US 8924) than for patients who received metformin only (dollars US 9448), metformin plus glibenclamide (dollars US 9576) or repaglinide only (dollars US 11910), although there were no statistically significant differences between treatment groups. The other study, a literature-based decision-tree analysis, projected the proportion of patients achieving a target HbA(1c) level (<7%) and the associated direct medical costs over a 3-year period from the time of diagnosis. Among six different treatment regimens evaluated, costs ranged from dollars US 6106 with glipizide gastrointestinal therapeutic system (GITS) to dollars US 9298 with repaglinide monotherapy (2001/2002 values). Probabilistic sensitivity analysis indicated that first-line therapy with glipizide GITS or metformin would be associated with lower total medical costs than rosiglitazone or repaglinide monotherapy. Three cost-effectiveness analyses, all of which are modelled studies published as abstracts and/or posters, have been conducted with repaglinide in patients with type 2 diabetes. (ABSTRACT TRUNCATED)

Administration, Oral↗

PubMed2004

Mitoxantrone: a review of its use in multiple sclerosis.

Mitoxantrone (Novantrone), a synthetic anthracenedione derivative, is an antineoplastic, immunomodulatory agent. Its presumed mechanism of action in patients with multiple sclerosis (MS) is via immunomodulatory mechanisms, although these remain to be fully elucidated. Intravenous mitoxantrone treatment improved neurological disability and delayed progression of MS in patients with worsening relapsing-remitting (RR) [also termed progressive-relapsing (PR) MS] or secondary-progressive (SP) disease. In a pivotal randomised, double-blind, multicentre trial, mitoxantrone 12 mg/m(2) administered once every 3 months for 2 years provided significant improvements in neurological disability ratings, including Kurtzke Expanded Disability Status Scale (EDSS), Ambulatory Index (AI) and Standardised Neurological Status (SNS) scores, compared with placebo. The drug also significantly reduced the mean number of corticosteroid-treated relapses and prolonged the time to the first treated relapse, with the beneficial effects on disease progression supported by magnetic resonance imaging. Post hoc analyses suggest that the benefits associated with mitoxantrone treatment may be sustained for at least 12 months after cessation of treatment, mean changes from baseline at 36 months in EDSS, AI and SNS scores of 0.10, 0.61 and 0.19, respectively, in the mitoxantrone group versus 0.46, 1.13 and 3.38 with placebo. Concomitant intravenous mitoxantrone 20mg plus intravenous methylprednisolone 1g once every month for 6 months was more effective than intravenous methylprednisolone monotherapy in preventing the development of new gadolinium-enhanced lesions in patients with very active RRMS or SPMS. The drug was generally well tolerated in patients with MS. Adverse events were generally mild to moderate in severity and usually resolved upon discontinuation of treatment or with appropriate pharmacotherapy. At the recommended dosage, mitoxantrone appears to have a low potential to cause cardiotoxicity. In conclusion, intravenous mitoxantrone reduces the relapse rate and slows progression of the disease in patients with worsening RRMS, PRMS or SPMS; thus providing a new option for the management of these patients. The drug was generally well tolerated at the recommended dosage, although potential cardiotoxicity limits the total cumulative dose to 140 mg/m(2). Further studies are warranted to determine which patients with worsening RRMS, PRMS or SPMS are most likely to benefit from mitoxantrone treatment and to more fully define the long-term safety and tolerability of mitoxantrone, including the use of concomitant cardioprotectants to extend the therapeutic lifespan of the drug. Pharmacodynamic Profile. Mitoxantrone, a synthetic anthracenedione derivative, is an established cytotoxic, antineoplastic agent. Its presumed mechanism of action in multiple sclerosis (MS) is immunosuppression. In antineoplastic studies, the drug showed several immunomodulatory effects, inducing macrophage-mediated suppression of B-cell, T-helper and T-cytotoxic lymphocyte function. Currently, the pharmacodynamic properties of mitoxantrone have not been investigated to any extent in patients with MS. In one study, 6 months' treatment with intravenous mitoxantrone generally had no effect on the distribution of cytokine-positive peripheral blood monocyte cells in patients with MS. In an animal model of the disease, mitoxantrone suppressed the development and progression of both actively and passively induced acute experimental allergic encephalomyelitis (EAE). It appeared to be 10-20 times more effective than cyclophosphamide in the suppression of EAE. Moreover, mitoxantrone approximately doubled the mean time to onset of EAE versus control animals (279 vs 148 days after immunisation; p < 0.00005). In vitro, mitoxantrone 10 and 100 micro g/L inhibited myelin degradation by leucocytes and peritoneal macrophages derived from mice with acute EAE by approximately 60% and 100%. Pharmacokinetic Profile. Currently, there are no published pharmacokinetic data for intravenous mitoxantrone in pitoxantrone in patients with MS, paediatric patients or in those with renal impairment. All studies, to date, have been in patients with cancer receiving a single, approximately 30-minute intravenous infusion of mitoxantrone 5-14 mg/m(2). The drug exhibits triexponential pharmacokinetics, with a rapid initial distribution (alpha) phase, an intermediate distribution (beta) phase and a much slower elimination (gamma) phase. The mean half-life of the alpha phase appears to be 6-12 minutes and that of the beta phase 1.1-3.1 hours. Mitoxantrone has a high affinity for tissue, with a volume of distribution of up to 2248 L/m(2). Mitoxantrone persists for prolonged periods in tissues and was detectable in autopsy tissue from patients who last received the drug up to 272 days before death. At concentrations of 10-10000 ng/mL, the drug was 70-80 % bound to plasma proteins in dogs. Elimination of mitoxantrone occurs predominantly through biliary excretion and may be impaired in patients with hepatic dysfunction or third space abnormalities (e.g. ascites). The mean terminal elimination half-life of mitoxantrone ranged from 23 hours to 215 hours. Renal clearance accounts for 10 % of the total clearance of the drug. Total clearance of mitoxantrone ranged from 13 to 34.2 L/h/m(2) and renal clearance from 0.9 to 2.7 L/h/m(2). The drug appears to have a low potential for interaction with other concomitantly administered agents. Therapeutic Efficacy. Intravenous mitoxantrone (infusion of > or = 5 minutes), either as monotherapy or in combination with intravenous methylprednisolone, delayed the progression of the disease in patients with secondary-progressive (SP) or worsening relapsing-remitting (RR) MS (the latter is also termed progressive-relapsing MS) in comparative, randomised, multicentre trials. In a double-blind, monotherapy trial (Mitoxantrone In Multiple Sclerosis [MIMS] trial), mitoxantrone 12 mg/m(2) (n = 60) once every 3 months for 2 years significantly improved neurological disability relative to placebo (n = 64), as assessed by changes in mean Kurtzke Expanded Disability Status Scale (EDSS) score, mean Ambulatory Index (AI) score and mean Standardised Neurological Status (SNS) score. The drug also significantly reduced the mean number of corticosteroid-treated relapses per patient and prolonged the time to the first treated relapse. A Wei-Lachin multivariate analysis of these five efficacy variables indicated that the global difference between the two treatment groups was 0.30 (p < 0.0001). Mitroxantrone was also more effective than placebo according to secondary endpoints in this study, with fewer mitoxantrone recipients experiencing a relapse, a deterioration of > or =1 EDSS point or a confirmed deterioration in EDSS score over a 3-month period. Mitoxantrone recipients also showed less deterioration in quality-of-life ratings and had fewer hospital admissions, whereas more placebo recipients had new gadolinium-enhanced lesions at study end (the latter parameter was assessed using magnetic resonance imaging [MRI] in a subgroup of 110 patients, including 40 patients who received an exploratory 5 mg/m(2) dose). Furthermore, post hoc analyses indicated that the beneficial effects of mitoxantrone treatment on EDSS, SNS and AI scores were sustained for at least 12 months after cessation of treatment, with mean changes from baseline at 36 months in EDSS, AI and SNS scores of 0.10, 0.61 and 0.19, respectively, in the mitoxantrone group versus 0.46, 1.13 and 3.38 with placebo. Preliminary data from a cost-minimisation analysis based on results from the MIMS trial indicated that approximately half of the cost of mitoxantrone was offset by cost savings in other areas associated with the treatment of MS (direct and indirect major costs), with a total annual incremental cost for mitoxantrone of dollar 1661 per patient. Combination therapy once-monthly with intravenous mitoxantrone 20mg plus intravenous methylprednisolone 1g was more effective than intravenous methylprednisolone 1g once every month in preventing the development of gadolinium-enhanced lesions in patients with very active RRMS or SPMS (double-blind assessment using MRI scans). After 6 months, significantly more combination therapy recipients had no new gadolinium-enhanced lesions (90.5% vs 31.3% with monotherapy; p < 0.001) [primary endpoint]. There were also significant reductions in both the mean number of new enhancing lesions and the total number of gadolinium-enhanced lesions in patients receiving combination therapy versus methylprednisolone monotherapy.Tolerability. Mitoxantrone was generally well tolerated in patients with MS. Treatment-emergent adverse events occurring significantly more frequently with mitoxantrone (12 mg/m(2) once every 3 months for 2 years) than placebo were nausea, alopecia, menstrual disorders, urinary tract infection, amenorrhoea, leucopenia and elevated gamma-glutamyltranspeptidase levels. Adverse events were usually mild to moderate in severity and generally resolved with discontinuation of treatment or when treated with appropriate pharmacotherapy. Eight percent of patients discontinued treatment in the mitoxantrone 12 mg/m(2) group due to an adverse event versus 3% of placebo recipients. The incidence of drug-related acute myelogenous leukaemia was very low (0.12%) in a cohort of 802 patients with MS receiving mitoxantrone. Evidence suggests that the risk of cardiotoxicity is low in patients with MS. After 1 year of monotherapy, 3.4% of mitoxantrone recipients had a reduction in left ventricular ejection fraction (LVEF) to < or =50% compared with 0% of placebo recipients; at the end of the second year, respective incidences were 1.9% and 2.9% (total cumulative dose of mitoxantrone per patient was 96 mg/m(2) after 2 years' treatment). (ABSTRACT TRUNCATED)

Animals↗

PubMed2004

Extended-release metformin hydrochloride. Single-composition osmotic tablet formulation.

In the new oral, once-daily, extended-release (ER), single-composition osmotic tablet formulation of the biguanide metformin hydrochloride (metformin XT), metformin is released at a controlled rate from a central osmotic tablet core through a semipermeable coating. A decrease in fasting plasma insulin, a marker of insulin resistance, was seen with metformin XT but not with immediate-release (IR) metformin in one well designed trial, but changes were similar in another. The pharmacokinetics of metformin XT reflect its extended-release characteristics. While the bioavailability (in terms of area under the plasma concentration-time curve) of metformin XT taken after the evening meal is similar to that of the IR formulation taken in divided doses, time to peak plasma concentrations is prolonged. Increases in metformin XT dose from 1000mg to 2500mg resulted in predictable and consistent dose-associated increases in metformin exposure. As with other ER metformin formulations, the bioavailability of metformin XT is increased after food, in contrast to the slight decrease seen with the IR formulation. The efficacy of metformin XT 1000, 1500, 2000, or 2500mg once daily with the evening meal was found not inferior to a similar dose range of metformin IR given in divided doses (measured by changes in glycosylated hemoglobin [HbA(1c)]) in a well designed study of 659 evaluable patients with type 2 (non-insulin-dependent) diabetes mellitus previously stabilized on metformin IR. Metformin XT and IR 2000 or 2500 mg/day had clinically similar efficacy (using changes in HbA(1c) and fasting plasma glucose) in another well designed study of 102 evaluable patients with type 2 diabetes. Like the IR formulation, metformin XT is generally well tolerated; gastro-intestinal adverse events are, however, common.

Delayed-Action Preparations↗

PubMed2004

Rosuvastatin: a review of its use in the management of dyslipidemia.

Rosuvastatin (Crestor), an HMG-CoA reductase inhibitor (statin), has a favorable pharmacologic profile, including its selective uptake by hepatic cells, hydrophilic nature, and lack of metabolism by cytochrome p450 (CYP) 3A4 isoenzyme. This last property means that the potential for CYP3A4-mediated drug interactions and, as a consequence, adverse events is low in those requiring concomitant therapy with a statin and agents metabolized by CYP3A4. In a broad spectrum of adult patients with dyslipidemias, oral rosuvastatin 5-40 mg once daily effectively and rapidly improved lipid profiles in several large, randomized, mainly double-blind, multicenter trials of up to 52 weeks' duration. After 12 weeks' treatment, rosuvastatin was significantly (all p < 0.05) more effective at milligram equivalent dosages than atorvastatin, pravastatin, and simvastatin in improving the overall lipid profiles of patients with hypercholesterolemia (intent-to-treat analyses). Moreover, overall a significantly (all p < 0.001) higher proportion of patients achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III low-density lipoprotein-cholesterol (LDL-C) goals with rosuvastatin 10 mg/day than with therapeutic starting dosages of these other statins after 12 weeks' treatment in pooled analyses. Rosuvastatin treatment for up to 52 weeks was generally well tolerated in patients with dyslipidemias in clinical trials. The most commonly reported treatment-related adverse events were myalgia, constipation, asthenia, abdominal pain, and nausea; these were mostly transient and mild. The incidence of proteinuria or microscopic hematuria with rosuvastatin 10 or 20 mg/day was <1% versus <1.5% with rosuvastatin 40 mg/day; these events were mostly transient and not associated with acute or progressive deterioration in renal function at recommended dosages. Importantly, very few patients experienced elevations in serum creatine phosphokinase (CPK) levels of over [corrected] 10-fold the upper limit of normal (0.2-0.4% of patients) or treatment-related myopathy (<or=0.1%) [i.e. muscle aches or weakness plus the same elevated serum CPK levels] at dosages of 5-40 mg/day. In conclusion, rosuvastatin treatment effectively and rapidly improves the lipid profile in patients with a broad spectrum of dyslipidemias. In those with hypercholesterolemia (including high-risk patients), rosuvastatin was more efficacious than and generally as well tolerated as atorvastatin, simvastatin, and pravastatin, with significantly more rosuvastatin recipients achieving their NCEP ATP III target LDL-C levels. Thus, rosuvastatin has emerged as a valuable choice for first-line treatment in the management of low- to high-risk patients requiring lipid-lowering drug therapy.

Drug Interactions↗

PubMed2003

Memantine.

Memantine, an uncompetitive antagonist with moderate affinity for NMDA receptors, demonstrates voltage-dependency and relatively fast on/off receptor kinetics. Memantine 20 mg/day significantly slowed the rate of deterioration in outpatients with moderate to severe Alzheimer's disease in a 28-week US randomised, double-blind, placebo-controlled, multicentre study. Memantine 10 mg/day improved measures of dementia in care-dependent inpatients with Alzheimer's disease or vascular dementia in a 12-week randomised, double-blind study. Significantly more memantine than placebo recipients were responders according to Clinical Global Impression of Change scores and the Behavioural Rating Scale for Geriatric Patients Care Dependence subscale. Memantine 20 mg/day significantly improved cognition-related outcomes (cognitive subscale of the Alzheimer's Disease Assessment Scale) in patients with vascular dementia in two 28-week randomised, double-blind, placebo-controlled, multicentre trials. No statistically significant between-group difference was seen in other primary endpoints. Adverse events (incidence in memantine recipients greater than in placebo recipients) occurring in patients with moderately severe to severe dementia included diarrhoea, insomnia, dizziness, headache and hallucination.

Alzheimer Disease↗

PubMed2003

Combined two-dose hepatitis A and B vaccine (AmBirix).

One month after the last dose (i.e. at month 7), geometric mean titres (GMTs) of antibodies directed against hepatitis A virus (anti-HAV) were generally greater in participants (aged 12-15 years) receiving combined two-dose (0 and 6 months) hepatitis A and B vaccine (AmBirix) compared with the three-dose (containing one half the dose of the two active components per dose, given at 0, 1 and 6 months; Twinrix Paediatric) schedule. Moreover, at month 7 all patients had seroconverted to anti-HAV. GMTs of antibodies directed against hepatitis B surface antigen greatly exceeded the threshold for seroprotection (>/=10 mIU/mL) 1 month after the last dose of vaccine. Seroprotection rates against hepatitis B virus (HBV) were similar 1 month after completion of either a two- (97.9%) or three-dose (100%) vaccination schedule. At 24 months' follow-up, all patients tested remained positive for anti-HAV, and 93.3% and 96.2% of those treated with the two- and three-dose schedules, respectively, remained above the threshold for seroprotection against HBV. Administering the second dose in the two-dose series at 12 months rather than at 6 months did not compromise the immune response to the combined vaccine in adolescents aged 12-15 years in a randomised, multicentre trial. Local adverse events reported in the 4 days following administration of combined two-dose hepatitis A and B vaccine include pain or soreness, redness and swelling; systemic symptoms included headache, fatigue, gastrointestinal events and fever.

Adolescent↗

PubMed2003

Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.

Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin's lymphoma (NHL) and B-cell chronic lymphocytic leukaemia (CLL). While the optimal use of the drug in many clinical settings has yet to be clarified, two pivotal trials have established rituximab as a viable treatment option in patients with relapsed or refractory indolent NHL, and as a standard first-line treatment option when combined with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (the most common type of aggressive NHL). The former was a noncomparative trial in relapsed indolent NHL (follicular and small lymphocytic subtypes) with clinical responses achieved in about half of patients treated with rituximab 375 mg/m(2) intravenously once weekly for 4 weeks, which was similar to some of the most encouraging results reported with traditional chemotherapeutic agents. The latter was a randomised comparison of eight cycles of CHOP plus rituximab 375 mg/m(2) intravenously (one dose per cycle) versus CHOP alone in previously untreated elderly patients (60 to 80 years of age) with diffuse large B-cell lymphoma. In this pivotal trial, 2-year event-free and overall survival were significantly higher with rituximab plus CHOP, and there was no increase in clinically significant adverse effects compared with CHOP alone. Treatment with rituximab is generally well tolerated, particularly in terms of adverse haematological effects and serious or opportunistic infections relative to standard chemotherapy. Infusion-related reactions occur in the majority of patients treated with rituximab; these are usually mild to moderate flu-like symptoms that decrease in frequency with subsequent infusions. In approximately 10% of patients, however, severe infusion-related reactions develop (e.g. bronchospasm, hypotension). These reactions are usually reversible with appropriate interventions and supportive care but there have been rare reports of fatalities. CONCLUSIONS: Clinical trials with rituximab indicate that the drug has broad application to B-cell malignancies, although further clarification is needed to determine its optimal use in many of these clinical settings. Importantly, rituximab in combination with CHOP chemotherapy has emerged as a new treatment standard for previously untreated diffuse large B-cell lymphoma, at least in elderly patients. Compared with conventional chemotherapy, rituximab is associated with markedly reduced haematological events such as severe neutropenia, as well as associated infections. Rituximab may be particularly suitable for elderly patients or those with poor performance status, and its tolerability profile facilitates its use in combination with cytotoxic drugs. PHARMACODYNAMIC PROPERTIES: Rituximab is a mouse/human chimaeric IgG(1)-kappa monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal B lymphocytes. Although treatment with rituximab induces lymphopenia in most patients, typically lasting about 6 months, a full recovery of B lymphocytes in the peripheral blood is usually seen 9-12 months after therapy, as CD20 is not expressed on haematopoietic stem cells. CD20 is, however, expressed on >90% of B-cell non-Hodgkin's lymphomas (NHL) and to a lesser degree on B-cell chronic lymphocytic leukaemia (CLL) cells. Although not fully elucidated, the cytotoxic effects of rituximab on CD20-positive malignant B cells appears to involve complement-dependent cytotoxicity, complement-dependent cellular cytotoxicity, antibody-dependent cellular cytotoxicity and induction of apoptosis. In addition, in vitro data indicate that rituximab sensitises tumour cells to the effects of conventional chemotherapeutic drugs. PHARMACOKINETIC PROPERTIES: Serum rituximab concentrations increased in proportion to dose across a wide range of single- and multiple-dose intravenous regimens in patients with B-cell NHL. When administll NHL. When administered at a dose of 375 mg/m(2) once weekly for 4 weeks in a pivotal trial in patients with relapsed or refractory indolent B-cell NHL (follicular or small lymphocytic subtypes), peak serum concentrations essentially doubled from the first (239.1 mg/L) to the fourth (460.7 mg/L) infusion, while elimination half-life (t(1/2)) increased from 76.3 to 205.8 hours (3.2 to 8.6 days). The concomitant increase in serum rituximab concentrations and t(1/2) with each successive infusion may be due, at least in part, to the elimination of circulating CD20-positive B cells and reduction or saturation of CD20-binding sites after the initial infusions of rituximab. The pharmacokinetic properties of rituximab are also characterised by wide inter-individual variability, and serum drug concentrations that are correlated with clinical response. Although pharmacokinetic data are limited in patients with aggressive forms of NHL, such as diffuse large B-cell lymphoma, rituximab appears to have a similar pharmacokinetic profile in these patients to that in patients with indolent B-cell NHL. The pharmacokinetics of rituximab are also reported to be similar whether the drug is administered with or without cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy. THERAPEUTIC USE: A number of studies have demonstrated efficacy of intravenous rituximab in patients with various lymphoid malignancies of B-cell origin, including indolent (e.g. follicular lymphoma) and aggressive (e.g. diffuse large B-cell lymphoma) forms of NHL, and CLL, but the drug has not yet been approved for use in CLL, and approved indications in NHL vary between countries. In the US, for example, rituximab is available for the treatment of patients with low-grade or follicular, relapsed or refractory, CD20-positive B-cell NHL. In Europe, the drug has similar approval for relapsed or refractory follicular NHL as in the US, but has also been approved for use in combination with CHOP chemotherapy for the most common aggressive form of NHL (CD20-positive, diffuse large B-cell lymphoma). Rituximab was approved for these indications primarily on the basis of results from two pivotal trials. In Japan, rituximab has been approved for indolent B-cell NHL and mantle cell lymphoma (an aggressive form of B-cell NHL), primarily on the basis of results of a Japanese phase II trial. Indolent NHL: Results of several studies evaluating rituximab 375 mg/m(2) once weekly for 4 weeks in patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic lymphomas) showed objective response (OR) rates ranging from approximately 40-60% in those receiving the drug for relapsed or refractory indolent B-cell NHL, and slightly higher (50-70%) for those receiving rituximab as first-line therapy. In a pivotal trial in 166 patients with relapsed or refractory low-grade or follicular B-cell NHL, intent-to-treat (ITT) analysis showed an OR rate of 48%, and a projected median time to progression of 13 months. Encouraging data are also emerging on the use of rituximab in combination with chemotherapeutic agents (e.g. CHOP, fludarabine-containing regimens) or other drugs (e.g. interferon-alpha2a) in previously untreated patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic subtypes). Rates for OR were consistently around 95%, with the majority being complete responses (CRs). Follow-up data from a study in 40 patients with low-grade or follicular B-cell NHL treated with rituximab plus CHOP as first-line therapy showed that responses were durable with a progression-free survival and median duration of response >5 years.Bcl-2 gene rearrangement (t14;18) occurs in malignant cells in up to 85% of patients with follicular lymphoma, and minimal residual disease in peripheral blood and bone marrow can be monitored using polymerase chain reaction (PCR). In several studies assessing blood and/or bone marrow, rituximab has achieved molecular response (conversion from PCR-positive to PCR-negative bcl-2 status) in at least half of the patients. Aggressive NHL: Studies with rituximab as monotherapy in aggressive B-cell NHL, a potentially curable disorder, have generally been restricted to patients with relapsed or recurrent disease, since CHOP has traditionally been the standard first-line treatment regimen. However, promising results from phase II monotherapy studies prompted further clinical investigation of rituximab in conjunction with chemotherapy. Thus, most studies with rituximab in patients with aggressive forms of B-cell NHL have involved combination therapy, including a pivotal randomised trial comparing eight cycles of standard CHOP therapy plus rituximab 375 mg/m(2) (one dose per cycle) versus CHOP alone in 399 previously untreated elderly patients (60-80 years of age) with diffuse large B-cell lymphoma. Results of the pivotal trial showed a clear advantage for rituximab plus CHOP versus CHOP in terms of event-free survival (primary endpoint) at 2 years (57% vs 38%, p < 0.001). Overall survival at 2 years (70% vs 57%, p < 0.01) and CR rate (76% vs 63%, p < 0.01) were also higher with the rituximab-CHOP combination. Other, smaller trials with rituximab in combination with CHOP or other chemotherapeutic regimens, either as first-line therapy or for patients with relapsed or refractory aggressive B-cell NHL, have also shown promising results in terms of clinical response rates.CLL: In relatively small trials (n < 40) conducted primarily in patients with relapsed or refractory B-cell CLL, rituximab monotherapy (various regimens) achieved OR rates of 23-45%, with median duration of response ranging from approximately 3-10 months. (ABSTRACT TRUNCATED)

Antibodies, Monoclonal↗

PubMed2003

Tipranavir.

Tipranavir is a potent and selective non-peptidic HIV-1 protease inhibitor with a markedly improved resistance profile compared with traditional, peptidomimetic protease inhibitors. The presence of five or fewer protease gene mutations or one or two protease inhibitor resistance-associated mutations (PRAMs) is associated with reduced susceptibility to currently available protease inhibitors. However, 16-20 mutations (including three or more PRAMs) may be needed to confer resistance to tipranavir. Tipranavir-based therapy achieved sustained viral suppression for more than 48 weeks in a small phase II trial in multiple protease inhibitor-experienced HIV-infected patients. A large dose-finding study demonstrated potent virological reduction through 14 days of functional monotherapy in heavily pretreated HIV-infected patients with 6 to >20 protease gene mutations at baseline. Two large, ongoing, phase III trials in patients with multi-drug resistant HIV infection are comparing the efficacy of tipranavir/ritonavir 500/200mg twice daily plus a patient-individualised background antiretroviral regimen versus other ritonavir-boosted protease inhibitor regimens. In general, tipranavir has been well tolerated in clinical trials. As with other protease inhibitors, the most common adverse events with tipranavir have been gastrointestinal disturbances.

Clinical Trials as Topic↗

PubMed2003

Oral fludarabine.

Fludarabine is an antimetabolite antineoplastic agent used in the treatment of various haematological malignancies, particularly B-cell chronic lymphocytic leukaemia (CLL). An oral formulation of fludarabine has recently become available in the majority of European countries for the treatment of patients with relapsed or refractory B-cell CLL after initial treatment with an alkylating agent-based regimen. It is the first oral formulation of a purine analogue available for clinical use in B-cell CLL. Pharmacokinetic studies evaluating the bioavailability of oral fludarabine indicate that an oral dose of 40 mg/m2/day would provide similar systemic drug exposure to the standard intravenous dose of 25 mg/m2/day. A phase II study evaluated the clinical efficacy of six to eight cycles of oral fludarabine 40 mg/m2/day for 5 days of each 28-day cycle in 78 patients with previously treated B-cell CLL. Depending on the criteria used, the overall response rate was 46.2% (20.5% complete response [CR], 25.6% partial response [PR]) or 51.3% (17.9% CR, 33.3% PR). These results were similar to the 48% overall response rate reported in a similar historical control group treated with intravenous fludarabine. Myelosuppression (WHO grade 3 or 4) was the most frequently reported adverse effect with oral fludarabine therapy. Other common adverse effects included infection and gastrointestinal disturbances, although these were usually of mild to moderate severity (WHO grade 1 or 2). Overall, the tolerability profile of oral fludarabine is similar to that of the intravenous formulation.

Administration, Oral↗