Caroline Fenton

Health New Zealand, Christchurch, Canterbury, New Zealand

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Publications (29)114.38 Total impact

  • Caroline Fenton · Caroline M Perry
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    ABSTRACT: Darunavir (TMC114) is a nonpeptidic peptidomimetic HIV protease inhibitor (PI), with a high binding affinity and a close fit within the substrate envelope. ▲ Darunavir shows potent in vitro activity against a broad range of clinical isolates of HIV type 1 (HIV-1), including those with decreased susceptibility to most available PIs. ▲ The bioavailability of oral darunavir is increased when it is coadministered with ritonavir. Thus, darunavir must be administered in combination with low-dose (100mg) ritonavir. ▲ In the POWER 1 and POWER 2 trials, two 144-week randomised phase IIb trials, a reduction in plasma HIV-1 RNA levels of ≥1 log 10 copies/mL (primary endpoint) occurred in 77% and 62% of treatment-experienced recipients of darunavir plus ritonavir (darunavir/ritonavir) 600mg/100mg twice daily (in combination with an optimised background regimen) [vs 25% and 14% of control PI (CPI) recipients; p < 0.001] at week 24. Results are from primary analyses (n = 301 and 201). ▲ In a pooled subgroup analysis of data from the POWER 1 and 2 trials, reductions in HIV-1 RNA levels of ≥1 log 10 copies/mL were achieved in 61% of patients treated with darunavir/ritonavir 600mg/ 100mg twice daily versus 15% of CPI recipients (p < 0.0001) at week 48. ▲ Darunavir/ritonavir 600mg/100mg was generally well tolerated in the POWER 1 and 2 trials, with a tolerability profile similar to that of comparator CPIs.
    No preview · Article · Dec 2007 · Drugs
  • Caroline Fenton · Keri Wellington · Marit D Moen · Dean M Robinson
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    ABSTRACT: Drospirenone 3mg with ethinylestradiol 20µg (Yaz®) is a low-dose combined oral contraceptive (COC) administered in a regimen of 24 days of active tablets followed by a short hormone-free interval (4 days; 24/4 regimen). Drospirenone, unlike other synthetic progestogens used in COCs, is a 17α-spirolactone derivative and a 17α-spironolactone analogue with antimineralocorticoid and antiandrogenic properties. Drospirenone/ethinylestradiol 3mg/20µg (24/4) is approved in the US for the prevention of pregnancy in women, for the treatment of the symptoms of premenstrual dysphoric disorder (PMDD) and for the treatment of moderate acne vulgaris in women who wish to use an oral contraceptive for contraception. Drospirenone/ethinylestradiol 3mg/20µg (24/4) provided 99% contraceptive protection over 1 year of treatment in two large studies. The same treatment regimen over three treatment cycles also significantly improved the emotional and physical symptoms associated with PMDD, and improved moderate acne vulgaris over six treatment cycles in double-blind trials. It was generally well tolerated, with adverse events generally typical of those experienced with other COCs and which were most likely to occur in the first few cycles. Clinical trials indicate that drospirenone/ethinylestradiol 3mg/20µg (24/4) is a good long-term contraceptive option, and additionally offers relief of symptoms that characterise PMDD and has a favourable effect on moderate acne vulgaris. Pharmacological Properties The pharmacological properties of ethinylestradiol are well established. Drospirenone is a 17α-spirolactone derivative and an analogue of 17α-spironolactone that resembles endogenous progesterone and has antimineralocorticoid and antian-drogenic properties. Drospirenone/ethinylestradiol 3mg/20µg administered as a 24/4 (Yaz®) or 21/7 regimen for two treatment cycles suppressed ovarian activity during daily recommended use; however, stronger suppression of ovarian activity was observed with the 24/4 regimen during intentional dosing errors (three active tablets replaced with placebo at the start of a third treatment cycle). Like natural progesterone, drospirenone induces mild natriuresis, which counteracts estrogen-stimulated fluid retention and weight gain. The effects of drospirenone/ethinylestradiol 3mg/20µg on metabolic parameters, including lipoproteins, were generally neutral or favourable, although, as with other COCs, the serum glucose response to an oral glucose tolerance test in healthy women volunteers increased from baseline. As drospirenone is a spironolactone analogue with antimineralocorticoid activity, it has the potential to induce hyperkalaemia in high-risk patients (those with conditions that predispose them to hyperkalaemia [i.e. renal insufficiency, hepatic dysfunction and adrenal insufficiency] or those receiving other medications that may increase serum potassium). Both drospirenone and ethinylestradiol are rapidly absorbed, with maximum serum concentration reached after 1.5 hours. Both are ≥97% plasma bound, with volumes of distribution of ≈4–5 L/kg. Steady-state levels of drospirenone are reached on day 8, and of ethinylestradiol in the second half of the cycle. Metabolism of both components, including first pass metabolism of ethinylestradiol, is extensive. The elimination half-life of drospirenone is ≈30 hours andthat of ethinylestradiol is ≈24 hours. Drospirenone exposure is slightly increased in women with renal impairment and markedly increased in those with hepatic dysfunction, with drospirenone/ethinylestradiol 3mg/20µg (24/4) contraindicated in both of these groups. Therapeutic Efficacy In two 1-year (13 contraceptive treatment cycles), noncomparative, international and EU trials enrolling 1027 and 1101 healthy women aged 17–36 years, oral drospirenone/ethinylestradiol 3mg/20µg (24/4) provided 99% contraceptive protection. The uncorrected Pearl index (PI) in the international trial was 1.29 and the PI adjusted for noncompliance was 0.72; in the EU trial, the uncorrected PI was 0.49. The cumulative pregnancy rates were 1.26% and 0.5% in the international and EU trials. Subjective satisfaction ratings (overall satisfaction, emotional and physical well-being, and interest in continuing medication if available) assessed in the international trial were positive in 73–88% of women. The drospirenone/ethinylestradiol 3mg/20µg (24/4) regimen was shown to improve the emotional and physical symptoms associated with PMDD over three treatment cycles in two double-blind, parallel-group (n = 449) or crossover (n = 64) studies. In both trials, the improvement in overall luteal phase Daily Record of Severity of Problems (DRSP) scores (primary outcome) versus baseline was significantly greater in drospirenone/ethinylestradiol 3mg/20µg (24/4) than placebo recipients, while in the parallel-group trial, scores for physical, behavioural and mood subscales were also significantly improved. In both trials, the improvement from baseline in all individual DRSP items, including premenstrual depression, were significantly greater in drospirenone/ethinylestradiol 3mg/20µg (24/4) than in placebo recipients. In the treatment of moderate acne vulgaris, drospirenone/ethinylestradiol 3mg/20µg (24/4) was generally well tolerated and was more effective than placebo in reducing the number of acne lesions and increasing the proportion of patients with ‘clear’ or ‘almost clear’ ratings on an Investigator Static Global Assessment scale in two large (n = 431 and 458) randomised, double-blind, placebo-controlled multicentre trials over six treatment cycles. Tolerability Once-daily drospirenone/ethinylestradiol 3mg/20µg in a 24/4 day regimen was generally well tolerated. Irregular bleeding (actively solicited), headache, nausea and breast pain were the most common adverse events; all tended to decrease over time in the 1-year, international trial. There were no clinically significant changes in potassium levels or other laboratory investigations and no abnormalities in adequate-sample endometrial biopsies after 13 cycles. Adverse events were generally similar in the double-blind, 3-month studies in PMDD, although irregular bleeding (spontaneously reported) was more common in the parallel-group trial. The proportion of drospirenone/ethinylestradiol 3mg/20µg (24/4) recipients who discontinued treatment for this reason was <4% in the parallel-group PMDD study and <1% in the international contraceptive trial. Other common adverse events were headache, nausea and breast pain in 13–20% of patients.
    No preview · Article · Aug 2007 · Drugs
  • Caroline Fenton · Keri Wellington · Marit D Moen · Dean M Robinson
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    ABSTRACT: Drospirenone 3mg with ethinylestradiol 20microg (Yaz) is a low-dose combined oral contraceptive (COC) administered in a regimen of 24 days of active tablets followed by a short hormone-free interval (4 days; 24/4 regimen). Drospirenone, unlike other synthetic progestogens used in COCs, is a 17alpha-spirolactone derivative and a 17alpha-spironolactone analogue with antimineralocorticoid and antiandrogenic properties. Drospirenone/ethinylestradiol 3mg/20microg (24/4) is approved in the US for the prevention of pregnancy in women, for the treatment of the symptoms of premenstrual dysphoric disorder (PMDD) and for the treatment of moderate acne vulgaris in women who wish to use an oral contraceptive for contraception.Drospirenone/ethinylestradiol 3mg/20microg (24/4) provided 99% contraceptive protection over 1 year of treatment in two large studies. The same treatment regimen over three treatment cycles also significantly improved the emotional and physical symptoms associated with PMDD, and improved moderate acne vulgaris over six treatment cycles in double-blind trials. It was generally well tolerated, with adverse events generally typical of those experienced with other COCs and which were most likely to occur in the first few cycles. Clinical trials indicate that drospirenone/ethinylestradiol 3mg/20microg (24/4) is a good long-term contraceptive option, and additionally offers relief of symptoms that characterise PMDD and has a favourable effect on moderate acne vulgaris.
    No preview · Article · Feb 2007 · Drugs
  • Caroline Fenton · Keri Wellington · Stephanie E Easthope
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    ABSTRACT: 0.4% Nitroglycerin ointment is an intra-anal formulation of nitroglycerin (glyceryl trinitrate) indicated for the treatment of chronic anal fissure pain. ▴ Nitroglycerin is a nitric oxide (NO) donor, which reduces the increased anal canal pressure caused by a hypertonic internal anal sphincter, improving anodermal blood flow. ▴ A twice-daily 375mg application of 0.4% nitroglycerin ointment, delivering a daily nitroglycerin dose of 3mg, significantly increased the rate of decrease in mean visual-analogue-scale pain scores, recorded daily, versus placebo (actual vehicle) over the first 3 and 8 weeks of treatment in patients with chronic anal fissure pain participating in randomised double-blind trials. ▴ Most recipients of 0.4% nitroglycerin ointment experienced headache, which was transient but severe in 20–25% of patients in randomised double-blind trials; however, compliance was generally good with few study withdrawals.
    No preview · Article · Sep 2006 · Drugs
  • Article: Verteporfin
    Caroline Fenton · Caroline M. Perry
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    ABSTRACT: Photodynamic therapy (PDT) with verteporfin (Visudyne®), a photosensitising protoporphyrin derivative, is used in the management of subfoveal choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD) or pathological myopia (PM). PDT with verteporfin over 1 and 2 years reduces the decline in visual acuity in patients with classic-containing subfoveal CNV secondary to AMD. Verteporfin is generally well tolerated by most patients. Verteporfin is also effective in patients with CNV secondary to PM, although data in this indication are limited and further controlled studies are required. Although verteporfin has shown efficacy in patients with occult AMD-related subfoveal CNV lesions in early trials, data are currently limited on its first-line use in this indication; fully published data from the Verteporfin In Occult (VIO) trial are therefore awaited with interest. Verteporfin should be considered as a first-line treatment in patients with predominantly classic subfoveal CNV secondary to AMD, and in patients with smaller minimally classic subfoveal CNV lesions. It may also be considered an option for the treatment of patients with occult AMD-related subfoveal CNV in whom visual acuity decreases or predominantly classic features develop over time. Pharmacological Properties Verteporfin is a light-activated photosensitising drug administered in a liposomal formulation, which is preferentially taken up by cells such as neovascular endothelium that have increased expression of low-density-lipoprotein receptors. When activated with a 50 J/cm2 light dose, verteporfin generates singlet oxygen and free radicals that cause endothelial damage and occlude smaller blood vessels. Light activation uses a 689nm wavelength, based on a 680–695nm verteporfin absorption peak that is close to the 700nm at which the best tissue penetration occurs. The maximum plasma concentration of verteporfin occurs at the end of the intravenous infusion of the drug and the elimination half-life is ≈6 hours. The rapid uptake and clearance of verteporfin increases the likelihood of selective damage to neovascular cells, sparing retinal pigment epithelium and the retina. However, patent blood vessels may persist, necessitating repeated treatments in most patients, and angiogenesis may also occur after PDT. Verteporfin is mostly bound to plasma proteins. Only 10% is metabolised; 90% is excreted unchanged in faeces. Pharmacokinetics are not significantly affected by age or sex, and the potential for drug interactions is low. Therapeutic Efficacy PDT using verteporfin 6 mg/m2 activated with a 50 J/cm2 light dose (verteporfin therapy), 3-monthly as required, significantly reduced the loss of best-corrected visual acuity (BCVA) compared with placebo in patients with subfoveal CNV secondary to AMD over 12 months and/or 24 months. In several well designed trials of up to 24 months’ duration, a BCVA loss of <15 letters from baseline (primary efficacy outcome) in correctly enrolled patients occurred in 61% of verteporfin and 46% of placebo recipients with classic-containing CNV lesions over 1 year (primary endpoint) and 53% and 38% over 2 years; in 45% of verteporfin and 32% of placebo recipients with occult lesions over 2 years; and in 78% of verteporfin and 55% of placebo recipients with minimally classic lesions over 1 year (primary endpoint) and 60% and 38% over 2 years. Verteporfin recipients required more treatments (not statistically significant) in year 1 (mean 2.9–3.4) than in year 2 (0.8–2.2); corresponding numbers of annual treatments in placebo recipients were 3.0–3.7 and 1.4–2.8. In an analysis of two of the trials, verteporfin was found to be more effective than placebo in almost all predominantly classic CNV lesions, but only in smaller minimally classic and occult lesions (sized ≤4 or ≤5 Macular Photocoagulation Study disc areas [MPS DA; 1 MPS DA = 2.54mm2 on the retina]). In addition, recent preliminary results of a well designed trial in patients with occult CNV suggest that verteporfin did not significantly improve outcomes versus placebo. Results of a prospective noncomparative case series study have led to a recommendation of continued monitoring, instead of cessation of follow-up, for patients with occult AMD-related subfoveal CNV with no classic lesions. Of note, if visual acuity decreases or predominantly classic features develop in these patients, PDT with verteporfin can be considered as a treatment option. In CNV secondary to PM, verteporfin was significantly better than placebo in reducing mild, moderate or severe loss of visual acuity after 1 year (primary endpoint), but not 2 years, in a well designed but relatively small study. CNV lesions were, however, significantly smaller in verteporfin recipients after 2 years. Tolerability Verteporfin was generally well tolerated in randomised trials. Common non-study-eye adverse events were injection-site reactions, infusion-related back pain, nausea, photosensitivity reactions, asthenia and hypercholesterolaemia, each affecting 1–10% of patients. Hypersensitivity reactions are uncommon but can be severe. Injection-site reactions, which occurred in 13.1% of verteporfin versus 5.6% of placebo recipients in two large trials, and infusion-related back pain, photosensitivity reactions, constipation and sleep disorders (each affecting 1.6–2.4% of verteporfin vs 0–0.3% of placebo recipients) were the only non-ocular events reported significantly more frequently with verteporfin. Study-eye adverse events were also common, with ‘all visual disturbances’ significantly more frequent in verteporfin recipients in one trial (41.7% vs 22.8% with placebo) and numerically more common (22.1% and 15.5%) in another. An acute severe visual acuity decrease (BCVA loss of ≥20 letters within 7 days of verteporfin treatment) was the most serious event, affecting 15 verteporfin and 1 placebo recipients, in several large trials; the incidence was ≈5% in patients with good baseline visual acuity or occult lesions. Most patients subsequently recovered some visual acuity. About 13% of patients with post-verteporfin subfoveal haemorrhage also experienced an acute severe visual acuity decrease in a noncomparative study; haemorrhage was generally resorbed and some visual acuity recovered within 3 months.
    No preview · Article · May 2006 · Drugs & Aging
  • Article: Moxonidine
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    ABSTRACT: Moxonidine (Physiotens®, Moxon®, Cynt®) is an orally administered imidazoline compound with selective agonist activity at imidazoline I1 receptors and only minor activity at α2-adrenoceptors. Moxonidine acts centrally to reduce peripheral sympathetic activity, thus decreasing peripheral vascular resistance. In patients with mild to moderate hypertension, moxonidine reduces blood pressure (BP) as effectively as most first-line antihypertensives when used as monotherapy and is also an effective adjunctive therapy in combination with other antihypertensive agents. It improves the metabolic profile in patients with hypertension and diabetes mellitus or impaired glucose tolerance, is well tolerated, has a low potential for drug interactions and may be administered once daily in most patients. Thus, moxonidine is a good option in the treatment of patients with mild to moderate hypertension, particularly as adjunctive therapy in patients with the metabolic syndrome. Pharmacological Properties Moxonidine is a centrally acting selective agonist at imidazoline I1 receptors, tor which it has an affinity >30-fold that for α2-adrenoceptors. Moxonidine inhibits peripheral sympathetic activity, which decreases peripheral vascular resistance and results in significant decreases in systolic and diastolic BP (SBP and DBP). Moxonidine has minimal effect on cardiac haemodynamics and reduces left ventricular mass. Markers of endothelial dysfunction and end-organ damage, including microalbuminuria, improved in hypertensive patients who achieved BP control with moxonidine. Moxonidine also improved the metabolic profile of patients with hypertension and type 2 diabetes or impaired glucose tolerance. Oral moxonidine is rapidly absorbed, although the maximum antihypertensive effect occurs 3–4 hours after administration. Oral bioavailability is 88% and is unaffected by food. No first-pass metabolism occurs and moxonidine is mostly excreted unchanged in the urine. Therapeutic Efficacy In well designed, 8-week trials, monotherapy with moxonidine 0.2–0.6 mg/day reduced sitting DBP to a significantly greater extent than placebo (mean change from baseline −10.7 to −13.2 vs −2.3 to −9mm Hg) in patients with mild to moderate essential hypertension. Sitting SBP also improved from baseline to a significantly greater extent with moxonidine than with placebo (mean −19.5 to −24.9 vs −1.2 to −13mm Hg). Reductions in sitting SBP and DBP with moxonidine 0.2–0.8 mg/day at 8 weeks were similar to those with enalapril 5–20mg once daily, atenolol 50–100 mg/day (except in postmenopausal women where atenolol reduced BP to a greater extent than moxonidine), hydrochlorothiazide 25mg once daily and rilmenidine 1–2 mg/day. At 26 weeks, reductions in sitting SBP and DBP with moxonidine 0.2–0.4 mg/day were similar to those with nifedipine sustained release 20–40 mg/day. Once-daily adjunctive moxonidine 0.4mg was also effective in patients with mild to moderate hypertension in well designed trials. In patients who did not respond to moxonidine monotherapy, mean improvements in sitting DBP at 4 weeks were −7.3mm Hg with moxonidine 0.4mg once daily plus amlodipine 5mg once daily, −4.8mm Hg with moxonidine 0.4mg once daily plus enalapril 10mg once daily and −3.2mm Hg with moxonidine 0.4mg once daily plus hydrochlorothiazide 12.5mg once daily. In another trial, changes in sitting SBP and DBP after 8 weeks’ treatment were significantly greater with once-daily moxonidine 0.4mg plus hydrochlorothiazide 25mg than with the respective monotherapies (−27 vs −20 and −22mm Hg and −16 vs −12 and −13mm Hg). Tolerability Moxonidine was generally well tolerated in clinical trials in patients with mild to moderate hypertension. In placebo-controlled monotherapy trials, 36–43% of moxonidine recipients experienced treatment-emergent adverse events versus 22–29% of placebo recipients and ≈32% and 35% of enalapril and hydrochlorothiazide recipients, respectively. Dry mouth was the most common adverse event with moxonidine monotherapy, affecting 11–20% of patients; other all-cause adverse events included diarrhoea, headache, bronchitis, nausea, dizziness and back pain. Other than dry mouth, asthenia and fatigue, adverse events in moxonidine monotherapy recipients were not generally related to α2-adrenoceptor inhibition. No new adverse events were reported in combination therapy trials. Moxonidine was also well tolerated in a pooled analysis of postmarketing surveillance studies in 91 170 patients, about two-thirds of whom received moxonidine as monotherapy. Adverse events affected 9.4% of patients, causing 1.8% to discontinue treatment, and were generally not related to dosage, treatment duration, sex or age; dry mouth affected 4.2% of patients aged >65 years versus 2.7% of those aged <40 years.
    No preview · Article · Mar 2006 · Drugs
  • Caroline Fenton · Caroline M Perry
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    ABSTRACT: Gemtuzumab ozogamicin (Mylotarg®) is a conjugate of a monoclonal antibody and calicheamicin, which targets the membrane antigen CD33 in CD33-positive acute myeloid leukaemia (AML) and, after cell internalization, releases a derivative of the cytotoxic calicheamicin component. In the US, it is approved as monotherapy in patients aged ≥60 years with a first relapse of AML who are ineligible for other cytotoxic therapy. Monotherapy with gemtuzumab ozogamicin results in complete remission (CR) or CR with incomplete platelet recovery (CRp) in ≈25% of adults (including those aged ≥60 years) with CD33-positive AML in first relapse. Preliminary data indicate a potential role for gemtuzumab ozogamicin as a component of induction or consolidation regimens in adults and, based on an early study, in the treatment of children with AML, although randomized, controlled studies are needed. Serious adverse events, notably hepatotoxicity, characterize its tolerability profile, but gemtuzumab ozogamicin is comparatively well tolerated by most patients. Gemtuzumab ozogamicin is a valuable new treatment option for patients aged ≥60 years with CD33-positive AML in first relapse for whom other cytotoxic chemotherapy is not considered appropriate; patients with a first CR (CR1) of >12 months are likely to have the best outcome.
    No preview · Article · Feb 2006 · BioDrugs
  • Caroline Fenton · Keri Wellington · Stephanie E Easthope
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    ABSTRACT: 0.4% Nitroglycerin ointment is an intra-anal formulation of nitroglycerin (glyceryl trinitrate) indicated for the treatment of chronic anal fissure pain.black triangle Nitroglycerin is a nitric oxide (NO) donor, which reduces the increased anal canal pressure caused by a hypertonic internal anal sphincter, improving anodermal blood flow. A twice-daily 375 mg application of 0.4% nitroglycerin ointment, delivering a daily nitroglycerin dose of 3mg, significantly increased the rate of decrease in mean visual-analogue-scale pain scores, recorded daily, versus placebo (actual vehicle) over the first 3 and 8 weeks of treatment in patients with chronic anal fissure pain participating in randomised double-blind trials. Most recipients of 0.4% nitroglycerin ointment experienced headache, which was transient but severe in 20-25% of patients in randomised double-blind trials; however, compliance was generally good with few study withdrawals. Features and properties of 0.4% nitroglycerin (Rectogesic) rectal ointment Indication Pain associated with chronic anal fissures Mechanism of action Donor of nitric oxide Mediates relaxation of internal anal sphincter Dosage and administration Dosage 375 mg of 0.4% nitroglycerin rectal ointment, delivering nitroglycerin 1.5 mg Frequency Twice daily Route of administration Intra-anal Pharmacokinetic profile Mean bioavailability (0.2% nitroglycerin ointment, 0.75 mg nitroglycerin dose)50%Maximum plasma concentration 0.1 to >1 microg/L Volume of distribution approximate, equals 3 L/kg Clearance approximate, equals 1 L/kg/min Elimination half-life approximate, equals 3 min Most common adverse event Headache.
    No preview · Article · Feb 2006 · Drugs
  • Caroline Fenton · Caroline M Perry
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    ABSTRACT: Photodynamic therapy (PDT) with verteporfin (Visudyne), a photosensitising protoporphyrin derivative, is used in the management of subfoveal choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD) or pathological myopia (PM). PDT with verteporfin over 1 and 2 years reduces the decline in visual acuity in patients with classic-containing subfoveal CNV secondary to AMD. Verteporfin is generally well tolerated by most patients. Verteporfin is also effective in patients with CNV secondary to PM, although data in this indication are limited and further controlled studies are required. Although verteporfin has shown efficacy in patients with occult AMD-related subfoveal CNV lesions in early trials, data are currently limited on its first-line use in this indication; fully published data from the Verteporfin In Occult (VIO) trial are therefore awaited with interest. Verteporfin should be considered as a first-line treatment in patients with predominantly classic subfoveal CNV secondary to AMD, and in patients with smaller minimally classic subfoveal CNV lesions. It may also be considered an option for the treatment of patients with occult AMD-related subfoveal CNV in whom visual acuity decreases or predominantly classic features develop over time.
    No preview · Article · Feb 2006 · Drugs & Aging
  • [Show abstract] [Hide abstract]
    ABSTRACT: Moxonidine (Physiotens, Moxon, Cynt) is an orally administered imidazoline compound with selective agonist activity at imidazoline I1 receptors and only minor activity at alpha2-adrenoceptors. Moxonidine acts centrally to reduce peripheral sympathetic activity, thus decreasing peripheral vascular resistance. In patients with mild to moderate hypertension, moxonidine reduces blood pressure (BP) as effectively as most first-line antihypertensives when used as monotherapy and is also an effective adjunctive therapy in combination with other antihypertensive agents. It improves the metabolic profile in patients with hypertension and diabetes mellitus or impaired glucose tolerance, is well tolerated, has a low potential for drug interactions and may be administered once daily in most patients. Thus, moxonidine is a good option in the treatment of patients with mild to moderate hypertension, particularly as adjunctive therapy in patients with the metabolic syndrome.
    No preview · Article · Feb 2006 · Drugs
  • Article: Docetaxel
    Katherine A Lyseng-Williamson · Caroline Fenton
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    ABSTRACT: Docetaxel (Taxotere®), a cytotoxic taxane, is an antimicrotubule agent effective in the treatment of patients with breast cancer. The clinical profile of docetaxel as an effective cytotoxic agent in the treatment of metastatic breast cancer is well established. As yet, no single standard regimen has been identified as optimal for the treatment of patients with metastatic breast cancer after failure of prior chemotherapy. However, the efficacy of docetaxel monotherapy administered every 3 weeks as a 1-hour infusion is similar to or better than that of doxorubicin, paclitaxel and fluorouracil plus vinorelbine, and better than that of methotrexate plus fluorouracil or mitomycin plus vinblastine. Although docetaxel is associated with neutropenia and other adverse events, its overall tolerability profile is generally acceptable in the majority of patients. Docetaxel, therefore, is an effective option in the treatment of patients with metastatic breast cancer after failure of prior chemotherapy. Pharmacological Properties Docetaxel is an antimicrotubule agent that principally exerts its cytotoxic activity by promoting and stabilising microtubule assembly while simultaneously preventing microtubule depolymerisation. This results in inhibition of normal cell division. In vitro and in vivo, docetaxel has antineoplastic activity against a wide range of cancer cells, demonstrates synergistic activity with several antineoplastic agents and often has greater cytotoxic activity against human breast cancer cell lines than paclitaxel. The pharmacokinetics of docetaxel are linear at clinically relevant doses and are consistent with a three-compartment model. Docetaxel is highly bound to plasma proteins, but has a large volume of distribution at steady state. It is primarily metabolised by the cytochrome P450 3A4 isoenzyme and is excreted primarily faecally via the biliary tract. Clearance of the drug is a strong independent predictor of severe haematological toxicity in cancer patients. Therapeutic Efficacy In women with metastatic breast cancer previously exposed to anthracyclines or alkylating agents, docetaxel monotherapy was associated with median values for overall survival of 10.4–16.0 months, objective response rate (ORR) of 30.0–47.8% and time to tumour progression (TTP) of 4.4–6.5 months. In head-to-head comparative trials, docetaxel monotherapy was at least as effective (in terms of overall survival time, ORR and TTP) as doxorubicin, paclitaxel and fluorouracil plus vinorelbine, and was more effective than methotrexate plus fluorouracil or mitomycin plus vinblastine. Median values for survival time (15.4 vs 12.7 months), TTP (5.7 vs 3.6 months) and response duration (7.5 vs 4.6 months) were significantly (p ≤ 0.03) longer with docetaxel than with paclitaxel. Differences between docetaxel and comparators in health-related quality-of-life outcomes were generally not significant. In phase III combination therapy studies, docetaxel combined with doxorubicin or epirubicin resulted in similar overall survival to clinically relevant comparator combinations. Outcomes were similar with docetaxel plus either capecitabine or gemcitabine and the former combination was more effective than docetaxel monotherapy. Tolerability While severe adverse events were common, the tolerability of docetaxel in comparative clinical trials was generally acceptable. Severe neutropenia affects most docetaxel recipients, with febrile neutropenia occurring in approximately one-eighth of patients. Dose-cumulative severe fluid retention was reported in 6.5% of docetaxel recipients, despite premedication with prophylactic corticosteroids. Other grade 3 or 4 adverse events include asthenia, stomatitis, infections, neurosensory, cutaneous or gastrointestinal events, nail changes, severe fever in the absence of infection, myalgia and hypersensitivity reactions. In comparative monotherapy trials, neutropenia generally occurred more often with docetaxel than with comparators, excepting doxorubicin, where the incidence was similar. Other severe haematological, cardiac and gastrointestinal adverse events were less frequent with docetaxel than with doxorubicin. Docetaxel was associated with significantly higher incidences of grade 3 or 4 neutropenia and febrile neutropenia and several non-haematological adverse events than paclitaxel; however, patients in the docetaxel arm received more cycles of therapy than those in the paclitaxel arm (six vs four cycles). Docetaxel tolerability in combination therapy regimens was generally similar to that of comparator drugs, apart from a higher incidence of haematological adverse events.
    No preview · Article · Dec 2005 · Drugs
  • Caroline Fenton · Caroline M Perry
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    ABSTRACT: Gemtuzumab ozogamicin (Mylotarg®) is a conjugate of a monoclonal antibody and calicheamicin, which targets the membrane antigen CD33 in CD33-positive acute myeloid leukaemia (AML) and, after cell internalisation, releases a derivative of the cytotoxic calicheamicin component. In the US, it is approved as monotherapy in patients aged ≥60 years with a first relapse of AML who are ineligible for other cytotoxic therapy. Monotherapy with gemtuzumab ozogamicin results in complete remission (CR) or CR with incomplete platelet recovery (CRp) in ≈25% of adults (including those aged ≥60 years) with CD33-positive AML in first relapse. Preliminary data indicate a potential role for gemtuzumab ozogamicin as a component of induction or consolidation regimens in adults and, based on an early study, in the treatment of children with AML, although randomised, controlled studies are needed. Serious adverse events, notably hepatotoxicity, characterise its tolerability profile, but gemtuzumab ozogamicin is comparatively well tolerated by most patients. Gemtuzumab ozogamicin is a valuable new treatment option for patients aged ≥60 years with CD33-positive AML in first relapse for whom other cytotoxic chemotherapy is not considered appropriate; patients with a first CR (CR1) of >12 months are likely to have the best outcome. Pharmacological Properties Gemtuzumab ozogamicin is a humanised monoclonal antibody conjugated to a cytotoxic calicheamicin derivative, which targets the CD33 antigen expressed by leukaemic blasts in most patients with AML. After internalisation by the leukaemic cell, the linker between the antibody and calicheamicin is hydrolysed, calicheamicin dimethyl hydrazide is released and reduced; the reduced species binds to DNA in the minor groove, causing site-specific double-stranded breaks and cell death. In vitro, gemtuzumab ozogamicin displays good activity against certain CD33+ AML cell lines. At low concentrations (0.01–0.025 ng/mL), in vitro sensitivity of AML cells to gemtuzumab ozogamicin correlates with CD33 expression, but at high concentrations (1–10 μg/mL), CD33-independent uptake may occur. Various gemtuzumab ozogamicin resistance mechanisms have been suggested, including cell escape because of surface antigen expression or cell cycle phase, expression of proteins causing drug efflux, altered signalling pathways, antiapoptotic expression and patient antigen load. Sensitivity to gemtuzumab ozogamicin can be enhanced in vitro by ciclosporin, an inhibitor of p-glycoprotein-mediated drug efflux. In patients, a clinical response is inversely correlated with peripheral blood antigen load and drug efflux ratios, and is not predicted by pharmacokinetic parameters. The maximum plasma concentrations of the CD33 antibody (hP67.6) and calicheamicin occur shortly after the end of the intravenous infusion of gemtuzumab ozogamicin. Distribution is mainly within plasma and antibody distribution in bone marrow, spleen and liver occurred in radiolabelling studies. The pharmacokinetic parameters of gemtuzumab ozogamicin differ after the first and second doses and vary widely between patients, particularly after the first dose; however, they do not depend on age or gender. The calicheamicin derivative remains conjugated in plasma and hP67.6 is believed to be eliminated from plasma mainly by binding to CD33 expressed on peripheral blast cells. Therapeutic Efficacy The clinical efficacy of gemtuzumab ozogamicin has been evaluated in noncomparative trials in adults. In a pooled analysis of three trials, one to three doses of gemtuzumab ozogamicin 9 mg/m2 monotherapy 14–28 days apart, each administered as a 2-hour intravenous infusion, resulted in CR in 13% of 277 patients with a first relapse of primary AML and CRp in another 13%, giving an overall remission (OR) rate of 26%. CR and CRp rates in patients aged ≥60 years, representing 57% of the trial population, were 12% and 12%. The OR rate was 34% in patients with a CR1 of ≥1 year and 11 % in those with a CR1 of ≤6 m onths. Median relapse-free survival for all those in OR was 5.2 months. Median overall survival was almost 5 months for the total patient population, and was >1 year in those patients achieving CR or CRp; overall survival was longer in patients in CR or CRp who proceeded to haematopoietic stem cell transplantation (HSCT) than in those receiving no further treatment. In a dose-finding noncomparative trial in 29 children (median age 12 years) with relapsed or refractory AML, 14% achieved CR and 14% CRp after one or two gemtuzumab ozogamicin doses of 6–9 mg/m2, but dose-limiting toxicity occurred. Early-phase trials of gemtuzumab ozogamicin in combination therapy regimens, usually with cytarabine and anthracyclines, resulted in CR rates of 35–83% in adults with primary and secondary AML, including those aged >60 years and, in a consolidation regimen, maintenance of remission in 32% of patients after 1 year. Tolerability One to three doses of gemtuzumab ozogamicin 9 mg/m2 were generally fairly well tolerated in adults with relapsed primary AML, although serious adverse events were reported. Patients receiving gemtuzumab ozogamicin monotherapy plus prior or subsequent HSCT had a 17% incidence of hepatic veno-occlusive disease (VOD) and a 10% VOD-associated fatality rate. VOD also occurred in patients who did not have HSCT; other severe hepatotoxicity has affected recipients of gemtuzumab ozogamicin. Infusion-related events were common but generally transient and reversible. Gemtuzumab ozogamicin has, however, been associated with severe hypersensitivity reactions, including anaphylaxis, infusion reactions and pulmonary events. Almost all patients in phase II trials experienced severe neutropenia and thrombocytopenia, the latter associated with serious bleeding in 13% of patients. Other severe adverse effects had a relatively low incidence; grade 3 or 4 sepsis, pneumonia or nausea or vomiting affected 8–17% of patients. The overall incidence of early treatment-related mortality was 16%. Paediatric patients in a small dose-finding trial experienced similar adverse events, although there was less myelosuppression; VOD occurred at dosages of 6–9 mg/m2 in children and, as in adults, was more common in HSCT recipients, affecting 40%.
    No preview · Article · Nov 2005 · Drugs
  • Caroline Fenton · Lesley J Scott
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    ABSTRACT: Candesartan cilexetil is the orally administered pro-drug of candesartan, a highly selective antagonist of the angiotensin II subtype 1 receptor that mediates the pressor activities of angiotensin II. Candesartan cilexetil is widely used for the treatment of hypertension and has recently been approved in Europe for the treatment of chronic heart failure (CHF) in patients with impaired left ventricular (LV) systolic function. Results of the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) programme suggest that oral candesartan cilexetil reduces morbidity and mortality in patients with CHF and LV ejection fraction (LVEF) ≤40%. There are cardiovascular benefits when candesartan cilexetil is administered as an alternative to an ACE inhibitor, or as an add-on to current treatment regimens that include an ACE inhibitor, in symptomatic CHF. While tolerability is generally good, renal monitoring is required. The recent approval of candesartan cilexetil as both add-on and alternative therapy to ACE inhibitors in patients with CHF and impaired LV systolic function recognises the cardiovascular benefits of candesartan cilexetil in both types of treatment regimens. Pharmacologica Properties As an angiotensin II-receptor antagonist, candesartan cilexetil acts on the renin-angiotensin-aldosterone system, one of the neurohormonal pathways that is activated in CHF. In patients with CHF not receiving ACE inhibitors, orally administered candesartan cilexetil 8–16mg once daily for up to 43 weeks significantly increased angiotensin II levels, had varying effects on the levels of atrial natriuretic factor and pro-atrial natriuretic peptide and, in combination with enalapril, transiently decreased aldosterone levels. LVEF, pulmonary capillary wedge pressure and pulmonary artery pressure improved in candesartan recipients with CHF who were not receiving concomitant ACE inhibitors. LVEF also improved with coadministered candesartan plus enalapril and metoprolol. Progressive LV dilatation was reduced with the treatment combination of candesartan and enalapril. Oral candesartan cilexetil is hydrolysed to candesartan within 1 hour of administration, with oral bioavailability of about 15%. After single or multiple 16mg doses in elderly healthy volunteers, mean times to the maximum plasma concentration (Cmax) were 4.8 and 4.4 hours, and the mean elimination half-life (t1/2β) of a single dose was 12.3 hours. There were no clinically relevant differences between pharmacokinetic parameters in young and elderly healthy volunteers. Most candesartan is eliminated unchanged through urinary and biliary excretion. Clinically significant differences in pharmacokinetic parameters requiring dosage adjustment occurred with candesartan 12 mg/day (single or multiple doses) in patients with severe renal impairment (increased Cmax, area under the plasma concentration-time curve [AUC] and t12gb values) and after a single dose of 16mg in those with moderate hepatic impairment (increased AUC value). Therapeutic Efficacy Oral candesartan cilexetil ≤32mg (mean 23–25mg) once daily significantly improved the combined primary endpoint of cardiovascular death and hospitalisation for worsening CHF in patients with an LVEF ≤40% in CHARM-Added and CHARM-Alternative, two of the three trials in the large (n = 7599) 34- to 41-month CHARM Programme. There was no significant improvement in the same combined primary endpoint in the third component CHARM trial in patients with an LVEF >40% (CHARM-Preserved), although fewer candesartan cilexetil than placebo recipients were admitted for investigator-assessed hospitalisations for worsening CHF (secondary endpoint). In patients with an LVEF ≤40%, reductions in the combined endpoint were significant compared with placebo whether or not candesartan cilexetil recipients were already receiving ACE inhibitors (CHARM-Added) or were intolerant toACE inhibitors (CHARM-Alternative). In the CHARM-Added trial, the reduction was significant in patients who were receiving a β-adrenoceptor antagonist (β-blocker) at baseline (i.e. triple therapy recipients) and in those receiving the recommended CHF ACE inhibitor dosage, indicating a cardiovascular benefit with maximal neurohormonal blockade. In patients with CHF and an LVEF ≤40%, cardiovascular deaths and hospitalisations for worsening CHF were significantly less likely with candesartan cilexetil than with placebo, according to results of a prespecified pooled analysis of all patients in the CHARM programme with this degree of LV dysfunction. This analysis demonstrated a decrease in all-cause mortality in candesartan cilexetilversus placebo recipients. All-cause mortality (primary endpoint) was numerically lower in patients receiving candesartan cilexetil than those receiving placebo in CHARM-Overall (combined results from the three component trials); this did not reach statistical significance. All-cause mortality was affected by the lack of mortality benefit in CHARM-Preserved. Overall, candesartan cilexetil recipients had a higher rate of deaths from cancer than placebo recipients, which contributed to similar non-cardiovascular mortality. However, the incidences of cardiovascular death, hospitalisation for worsening CHF or the combination of these endpoints in CHARM-Overall (secondary endpoints) were significantly lower with candesartan cilexetil than with placebo, as was the incidence of new type 2 diabetes mellitus. In other trials, candesartan cilexetil significantly improved total exercise time and reduced the likelihood of CHF progression compared with placebo. Tolerability Candesartan cilexetil ≤32mg once daily was generally well tolerated, and there was no increase versus placebo in the incidence of cough or angioedema, including in patients previously intolerant to ACE inhibitors. In CHARM-Alternative, in which patients were not receiving ACE inhibitors, the incidence of adverse events with candesartan cilexetil was similar to that with placebo. However, in each of the individual CHARM trials, there were generally significantly more withdrawals for hypotension, increased serum creatinine levels and hyperkalaemia in candesartan cilexetil than placebo recipients, leading to a significantly greater CHARM-Overall withdrawal rate for adverse events in the former (21.0% vs 16.7%) and suggesting that renal monitoring is necessary.
    No preview · Article · Mar 2005 · Drugs
  • Katherine A Lyseng-Williamson · Caroline Fenton
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    ABSTRACT: Docetaxel (Taxotere), a cytotoxic taxane, is an antimicrotubule agent effective in the treatment of patients with breast cancer. The clinical profile of docetaxel as an effective cytotoxic agent in the treatment of metastatic breast cancer is well established. As yet, no single standard regimen has been identified as optimal for the treatment of patients with metastatic breast cancer after failure of prior chemotherapy. However, the efficacy of docetaxel monotherapy administered every 3 weeks as a 1-hour infusion is similar to or better than that of doxorubicin, paclitaxel and fluorouracil plus vinorelbine, and better than that of methotrexate plus fluorouracil or mitomycin plus vinblastine. Although docetaxel is associated with neutropenia and other adverse events, its overall tolerability profile is generally acceptable in the majority of patients. Docetaxel, therefore, is an effective option in the treatment of patients with metastatic breast cancer after failure of prior chemotherapy.
    No preview · Article · Feb 2005 · Drugs
  • Caroline Fenton · Lesley J Scott
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    ABSTRACT: Candesartan cilexetil is the orally administered pro-drug of candesartan, a highly selective antagonist of the angiotensin II subtype 1 receptor that mediates the pressor activities of angiotensin II. Candesartan cilexetil is widely used for the treatment of hypertension and has recently been approved in Europe for the treatment of chronic heart failure (CHF) in patients with impaired left ventricular (LV) systolic function. Results of the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) programme suggest that oral candesartan cilexetil reduces morbidity and mortality in patients with CHF and LV ejection fraction (LVEF) < or =40%. There are cardiovascular benefits when candesartan cilexetil is administered as an alternative to an ACE inhibitor, or as an add-on to current treatment regimens that include an ACE inhibitor, in symptomatic CHF. While tolerability is generally good, renal monitoring is required. The recent approval of candesartan cilexetil as both add-on and alternative therapy to ACE inhibitors in patients with CHF and impaired LV systolic function recognises the cardiovascular benefits of candesartan cilexetil in both types of treatment regimens.
    No preview · Article · Feb 2005 · Drugs
  • Caroline Fenton · Caroline M Perry
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    ABSTRACT: Gemtuzumab ozogamicin (Mylotarg) is a conjugate of a monoclonal antibody and calicheamicin, which targets the membrane antigen CD33 in CD33-positive acute myeloid leukaemia (AML) and, after cell internalisation, releases a derivative of the cytotoxic calicheamicin component. In the US, it is approved as monotherapy in patients aged > or =60 years with a first relapse of AML who are ineligible for other cytotoxic therapy. Monotherapy with gemtuzumab ozogamicin results in complete remission (CR) or CR with incomplete platelet recovery (CRp) in approximately =25% of adults (including those aged > or =60 years) with CD33-positive AML in first relapse. Preliminary data indicate a potential role for gemtuzumab ozogamicin as a component of induction or consolidation regimens in adults and, based on an early study, in the treatment of children with AML, although randomised, controlled studies are needed. Serious adverse events, notably hepatotoxicity, characterise its tolerability profile, but gemtuzumab ozogamicin is comparatively well tolerated by most patients. Gemtuzumab ozogamicin is a valuable new treatment option for patients aged > or =60 years with CD33-positive AML in first relapse for whom other cytotoxic chemotherapy is not considered appropriate; patients with a first CR (CR1) of >12 months are likely to have the best outcome.
    No preview · Article · Jan 2005 · Drugs
  • Caroline Fenton · Lesley J Scott
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    ABSTRACT: Risperidone (Risperdal) is an atypical antipsychotic with high affinity for 5-hydroxytryptamine (5-HT)2A, dopamine D2 and alpha1- and alpha2-adrenergic receptors. Risperidone is now approved in the UK and the US for use in bipolar mania. Risperidone < or =6 mg/day, as monotherapy or adjunctive therapy with first-line mood stabilisers, significantly improves moderate and severe bipolar mania and improves global functioning over 3 weeks. Improvements in Young Mania Rating Scale (YMRS) scores in double-blind trials were greater with risperidone than with placebo over 3 weeks, and similar to those with haloperidol over 3 and 12 weeks. Risperidone was reasonably well tolerated. Limited data are available on the combination of risperidone and carbamazepine. Risperidone, as monotherapy or combined therapy with lithium or valproate semisodium, is an effective treatment option in bipolar mania.
    No preview · Article · Jan 2005 · CNS Drugs
  • Caroline Fenton · Greg L Plosker
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    ABSTRACT: The two-compound product containing calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g (Dovobet®, Daivobet®) [referred to here as calcipotriol/betamethasone dipropionate], is a topical treatment for psoriasis vulgaris, combining a vitamin D analog and a corticosteroid. For most adult patients with psoriasis vulgaris on the trunk and limbs, up to 4 weeks of therapy with calcipotriol/betamethasone dipropionate provides an effective and well tolerated treatment. In clinical trials, patients with a mean baseline psoriasis area and severity index (PASI) of 9.5–10.9 experienced a mean 65.0–74.4% PASI improvement within 4 weeks, significantly better than improvements with calcipotriol 50 µg/g monotherapy, betamethasone dipropionate 0.5 mg/g monotherapy, or placebo. In addition, in 6.4%–20.1% of patients, lesions cleared. In patients who were subsequently treated with calcipotriol maintenance therapy, benefits were retained for at least 4 weeks. The safety of calcipotriol/betamethasone dipropionate in patients treated for up to 1 year was generally good; fewer than 5% of patients experienced adverse events possibly associated with long-term corticosteroid use. Pharmacologic Properties The different modes of action of the active constituents enables the combination of calcipotriol/betamethasone dipropionate to provide a response to the processes that occur in psoriasis vulgaris. Calcipotriol, a vitamin D analog, binds to the vitamin D3 receptor, regulating cell proliferation and promoting differentiation. Betamethasone dipropionate, a group III corticosteroid, acts via a glucocorticoid receptor and suppresses inflammation and hyperproliferation. Most pharmacologic information is available from studies of calcipotriol and betamethasone dipropionate as monotherapy. In patients with psoriasis vulgaris treated for 4 weeks with calcipotriol/betamethasone dipropionate, keratinocyte differentiation improved to 51.6%, similar to differentiation after betamethasone dipropionate 0.5 mg/g (48.2%), but significantly better than with placebo (unmedicated vehicle) [29.3%]. Calcipotriol 50 µg/g monotherapy (≊32%) was similar to placebo. Proliferation decreased with all active treatments from 11.7–14.1% to 6.8–8.6% and increased (from 10.2% to 13.6%) with placebo. Inflammation (vimentin-positive cells) decreased from 3.2–4.3% to 1.6% with calcipotriol/betamethasone dipropionate, but (unexpectedly) increased with both monotherapies and placebo. Statistically significant skin thinning occurred in 30 healthy adults who applied calcipotriol/betamethasone dipropionate twice daily for 4 weeks (maximum 12.9%, similar to that with betamethasone monotherapy [14.0%]). In patients with psoriasis vulgaris, calcipotriol 50 µg/g monotherapy generally improved cell differentiation and hyperproliferation within 4 weeks, and dermal inflammation after 8 weeks. At high doses in some studies, calcipotriol had dose-dependent effects on calcium metabolism in patients with extensive psoriasis vulgaris. The activity of betamethasone dipropionate 0.05% (0.5 mg/g) as measured by skin blanching, was similar in monotherapy and two-compound product formulations. Less than 1% of calcipotriol/betamethasone dipropionate (2.5g 12-hourly dosage) is absorbed through normal skin. After topical application, elimination from the depot created by dermal application occurs over several days. Although 5–6% of radiolabeled 3H-calcipotriol 2.5g (monotherapy) was absorbed, no calcipotriol or active metabolites were detected over 21 days, suggesting fast transformation to inactive metabolites. There was a linear increase in the stratum corneum concentration of betamethasone dipropionate at treatment durations of up to 2 hours; concentrations also increased significantly as drug concentration increased from 0.02% to 0.05%. Therapeutic Efficacy Six large, randomized trials (n = 501–1603) have assessed the efficacy of calcipotriol/betamethasone dipropionate in adults with psoriasis vulgaris. Five were double-blind trials; calcipotriol/betamethasone dipropionate once or twice daily for up to 4 weeks improved the PASI by 65.0–74.4% from mean baseline scores of 9.5–10.9. This was significantly better than seen with placebo (22.7–28.8%) or once- or twice-daily monotherapy with calcipotriol 50 µg/g (46.1–58.8%), betamethasone dipropionate 0.5 mg/g (57.2–63.1%), and tacalcitol 4 µg/g (once daily only, 33.3%) [comparators varied between trials, but all differences were significant]. There was no significant difference between once- and twice-daily calcipotriol/betamethasone dipropionate. Over 4 weeks or less, there were significantly more investigator-assessed responders (with a marked improvement or clearance of, or absent/very mild, disease) among recipients of two-compound product therapy (56.3–76.1%) than placebo (7.5–10.2%), or calcipotriol 50 µg/g (22.3–50.7%), betamethasone dipropionate 0.5 mg/g (37.0–55.8%) or tacalcitol 4 µg/g monotherapy (17.0%). The percentage of patients achieving complete clearance of lesions within 4 weeks with calcipotriol/betamethasone dipropionate was 6.4% and 14.0% (once daily) and 20.1% (twice daily), versus 9.7% with twice-daily calcipotriol, 1.2% with once-daily tacalcitol and 0% with placebo; no statistical analysis was reported. One double-blind trial continued for 8 weeks: PASI improvements were significantly better with up to 4 weeks of calcipotriol/betamethasone dipropionate therapy followed by 4 weeks of calcipotriol monotherapy than with 8 weeks of tacalcitol (all once daily). A 4-week double-blind trial of two-compound product versus monotherapy continued with a 4-week open-label extension phase of treatment with twice-daily calcipotriol; at the end of this phase, PASI improvements were similar irrespective of treatment received in weeks 1–4. In the sixth, partly blinded trial, treatment with the two-compound product formulation once daily for 8 weeks was also better than either 8 weeks’ treatment with twice-daily calcipotriol monotherapy or once-daily two-compound product therapy (up to 4 weeks) followed by two-compound product formulation at weekends and calcipotriol monotherapy on weekdays (once daily for 4 weeks). Tolerability In six large clinical trials, calcipotriol/betamethasone dipropionate was generally well tolerated, with only one serious possibly drug-related adverse event (a patient with extensive psoriasis vulgaris developed facial edema, which resolved when treatment was discontinued). Lesional/perilesional drug reactions (most commonly pruritus) occurred in up to 10.6% of recipients of calcipotriol/betamethasone dipropionate, with no significant difference between once- or twice-daily administration. This was significantly better than with calcipotriol 50 µg/g (11.4–19.8%), similar to betamethasone dipropionate 0.5 mg/g (4.7–8.6%), and, in one trial, significantly better than placebo (12.5–15.7%). Pruritus affected 2.6–5.1% of calcipotriol/betamethasone dipropionate recipients, and 2.6–14.3% of patients overall. Mild or moderate skin atrophy was reported for seven patients in three trials; in recipients of two-compound product therapy (three patients), calcipotriol 50 µg/g monotherapy (one patient), betamethasone dipropionate 0.5 mg/g monotherapy (two patients) and placebo (one patient). Fewer than 1% of calcipotriol/betamethasone dipropionate recipients and ≊1% of betamethasone recipients withdrew from short-term clinical trials because of adverse events, versus 1.0–7.6% of recipients of other monotherapies and placebo. Over 8 weeks, all-cause adverse events affected 24.3–38.3% of active treatment recipients and 31.5–34.4% of placebo recipients; the incidence was no higher with the two-compound product than with monotherapy. In a large 1-year safety trial, significantly fewer recipients of calcipotriol/betamethasone dipropionate were affected by adverse drug reactions than recipients of 4 weeks of two-compound product therapy followed by 48 weeks of calcipotriol monotherapy (21.7% vs 37.9%); 29.6% of recipients of alternating 4-weekly cycles of two-compound product and calcipotriol monotherapy experienced adverse reactions. Skin atrophy affected seven patients in the trial, including four who received the two-compound product daily, as required, throughout the study period. No recipients of calcipotriol/betamethasone dipropionate for ≤1 year experienced adrenal suppression and fewer than 5% experienced adverse events possibly associated with long-term corticosteroid use.
    No preview · Article · Dec 2004 · American Journal of Clinical Dermatology
  • Article: Daptomycin
    Caroline Fenton · GM Keating · MP Curran
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    ABSTRACT: Daptomycin is a lipopeptide antibacterial with rapid in vitro activity against Gram-positive cocci. It is approved for use in patients with complicated skin and skin structure infections (cSSSIs) caused by specified Gram-positive cocci. In vitro, daptomycin was active against Staphylococcus aureus (including meticillin-resistant strains), Streptococcus pyogenes, S. agalactiae, group C and G beta-haemolytic streptococci and vancomycin-susceptible Enterococcus faecalis. Bactericidal activity in vitro was rapid and concentration dependent. In two randomised, investigator-blinded, multicentre trials in patients with cSSSIs, intravenous daptomycin 4 mg/kg once daily was as effective as standard therapy (intravenous semi-synthetic penicillin 4-12 g/day or vancomycin 1g 12-hourly). Clinical success rates assessed 6-20 days after treatment end were 82.1% in daptomycin recipients and 82.9% in recipients of standard therapy (pooled data). In patients with cSSSIs, the adverse event profiles of daptomycin and vancomycin were similar. Creatine phosphokinase (CPK) levels increased in 2.8% of daptomycin recipients and 1.8% of patients who received standard therapy; only one daptomycin recipient (0.2%) experienced increased CPK levels and muscle symptoms that were not associated with any comorbid factors.
    No preview · Article · Sep 2004 · Drugs
  • Article: Valdecoxib
    Caroline Fenton · Gillian M. Keating · Antona J. Wagstaff
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    ABSTRACT: Valdecoxib is an orally administered, highly selective cyclo-oxygenase (C0X)-2 inhibitor with anti-inflammatory and analgesic properties. In well designed trials, valdecoxib demonstrated efficacy versus placebo in patients with osteoarthritis (OA), rheumatoid arthritis (RA), primary dysmenor-rhoea and postoperative pain. Initial results in patients with migraine headache were promising. The efficacy of valdecoxib appears dose dependent up to 40 mg/ day. Valdecoxib 10 mg/day was as effective as naproxen and rofecoxib in improving signs and symptoms of OA. The American College of Rheumatology 20% response rate was similar in recipients of valdecoxib, naproxen and diclofenac in patients with RA. In patients with dysmenorrhoea, valdecoxib 20 or 40mg up to twice daily provided as effective pain relief as naproxen sodium 550mg twice daily. In acute post-surgical pain, single-dose valdecoxib 40mg had a rapid onset of action, provided similar analgesia to oxycodone 10mg plus paracetamol (acetaminophen) 1000mg and provided a longer time to rescue medication than rofecoxib or oxycodone/paracetamol after oral surgery. Pre-emptive administration of valdecoxib 10–80mg was particularly effective in dental pain. Valdecoxib had opioid-sparing effects after hip or knee arthroplasty and reduced pain after laparoscopic cholecystectomy. Valdecoxib is generally well tolerated. The incidence of gastroduodenal ulcers was generally lower than with nonselective NSAIDs (i.e. NSAIDs not specifically developed as selective COX-2 inhibitors). With concomitant aspirin, the ulcer rate in valdecoxib recipients increased significantly, but was still lower than that in recipients of aspirin plus nonselective NSAIDs. In conclusion, valdecoxib, a COX-2-selective inhibitor, is as efficacious in pain relief as nonselective NSAIDs, with better gastrointestinal tolerability. It was as effective in RA, OA and primary dysmenorrhoea (the approved indications) as nonselective NSAIDs and as effective as rofecoxib in RA flare. In acute post-surgical pain, valdecoxib provided similar pain relief to oxycodone/paracetamol, had a long duration of action, a rapid onset of analgesia and was opioid-sparing. Valdecoxib provides a valuable alternative in the treatment of chronic arthritis pain and acute pain. Pharmacodynamic Properties Valdecoxib (a ‘coxib’) is a highly selective inhibitor of cyclo-oxygenäse (C0X)-2 with anti-inflammatory and analgesic properties. This selectivity is the likely mechanism conferring the better gastrointestinal (GI) tolerability profile of coxibs relative to NSAIDs not specifically developed as selective COX-2 inhibitors (referred to here as nonselective NSAIDs). In an in vitro study, the valdecoxib concentration required to inhibit 50% of enzyme activity was 0.005 μmol/L for COX-2, but was 140 μmol/L for COX-1. Binding of valdecoxib to COX-2 is reversible and inhibited by nonselective NSAIDs. An in vitro study found valdecoxib only weakly antagonised the anti-platelet effect of aspirin. Pharmacokinetic Properties In healthy male volunteers, valdecoxib 10 mg/day was rapidly absorbed, reaching a steady-state mean maximum plasma concentration (Cmax) of 161 ng/mL after a mean 2.25 hours (tmax). A single dose of valdecoxib 50mg reached a mean Cmax of 1040 ng/mL at a tmax of 1.7 hours. Absorption may be delayed by up to 2 hours by food. The elimination half-life of valdecoxib was ≈7–8 hours; this increased in elderly patients, with overall exposure to valdecoxib increasing by 30–40%. In patients with moderate hepatic impairment, exposure to valdecoxib is increased by 130%. Valdecoxib is extensively metabolised via cytochrome P450 (CYP) isoenzymes, especially CYP3A4 and CYP2C9, and interacts with some drugs metabolised by CYP isoenzymes (e.g. fluconazole, dextromethorphan and omeprazole). Excretion is mainly renal (76% of a radiolabelled valdecoxib dose) and metabolites are mostly excreted via the kidney. In healthy volunteers, coadministration of valdecoxib and warfarin significantly increased the international normalised ratio and its variability. Exposure to lithium, or ethinylestradiol/norethisterone (norethindrone) 35μg/1μg increased with coadministration of valdecoxib. Therapeutic Efficacy Oral valdecoxib was more effective than placebo (p < 0.05) and similar in efficacy to nonselective NSAIDs in patients with osteoarthritis (OA), rheumatoid arthritis (RA), primary dysmenorrhoea, acute postoperative pain and migraine headache in randomised, double-blind trials. ]In 12-week studies in patients with OA of the hip or knee, valdecoxib 10 or 20 mg/day generally improved global assessments (e.g. composite arthritis index scores) by 27–37% from baseline and pain assessments (e.g. patient’s perception of arthritis pain) by 26–45%, to a significantly greater extent than placebo (10–30% and 12–36%, respectively). Valdecoxib 10 or 20 mg/day had similar efficacy to naproxen 500mg twice daily (stable OA) and valdecoxib 10 mg/day was similar to rofecoxib 25 mg/day in reducing pain intensity in a 2-week study in patients with a flare of OA of the knee. In patients with stable RA, American College of Rheumatology 20% (ACR-20) response rates and improvements in ACR-20 components were similar (32–36%) in patients receiving valdecoxib 20 or 40 mg/day or diclofenac slow release 75mg twice daily for 26 weeks. In patients experiencing an RA flare, valdecoxib 10–40 mg/day had similar efficacy to naproxen 500mg twice daily for 12 weeks and resulted in significantly better outcomes, including ACR-20 response rates (46–49%), than placebo (32%). Valdecoxib 20 or 40mg twice daily as required for 3 days provided significant pain relief and reduced pain intensity (time weighted total of pain relief [TOTPAR] and time weighted sum of pain intensity difference) compared with placebo 8 and 12 hours after the first dose in patients with primary dysmenor-rhoea, with some dose-dependent effects evident. Naproxen sodium 550mg had similar efficacy. In postoperative dental pain, valdecoxib 20 or 40mg (mostly single doses) was significantly better than placebo, based on onset of analgesia, 6- and 24-hour TOTPAR scores and time to rescue medication. Preoperative valdecoxib administration was particularly effective. Postoperative pain intensity was significantly reduced versus placebo with valdecoxib 40 and 80mg administered before bunionectomy, and with parecoxib administered before laparoscopic cholecystectomy. Use of opioids reduced by 16–43% relative to placebo, and pain intensity significantly reduced in patients receiving valdecoxib 20 or 40mg twice daily following knee or hip arthroplasty. Valdecoxib 40mg showed some advantages over rofecoxib 50mg; in one study, valdecoxib recipients had a faster onset of analgesia (<30 minutes) and, in another, had significantly higher TOTPAR scores and a significantly longer time to rescue medication. In two studies, valdecoxib 40mg was associated with significantly higher 24-hour TOTPAR scores and a significantly longer time to rescue medication than oxycodone/paracetamol. Preliminary reports found a single dose of valdecoxib 40mg to be better than placebo in patients with moderate-to-severe migraine headache pain (resulting in mild or no pain in 48% vs 30% and relief of associated symptoms like nausea and phonophobia at 2 hours postdose). Valdecoxib 40–60mg was effective in up to three consecutive headaches and valdecoxib 20mg also significantly improved migraine pain and some other symptoms relative to placebo. Tolerability Valdecoxib was generally well tolerated in clinical trials. The incidence of headache, dizziness and fever was generally similar in recipients of valdecoxib and placebo. GI symptoms other than ulcers had a similar incidence in valdecoxib and placebo recipients in most large, well designed trials, and the incidence of individual and total GI symptoms was similar in valdecoxib and placebo groups in a large pooled analysis. Exceptions were a higher incidence of total GI symptoms with valdecoxib 10 (but not 20) mg/day, ibuprofen and diclofenac than with placebo in a trial in patients with OA and, in patients with RA receiving a supratherapeutic dose of valdecoxib 40 mg/day for 12 weeks, significantly more dyspepsia than in those receiving placebo. In patients with OA or RA, the incidence of endoscopically-proven gastric and gastroduodenal ulcers was significantly lower with valdecoxib 5–40 mg/day than with diclofenac, ibuprofen or naproxen (although in one trial there was no significant difference between valdecoxib 20 mg/day and naproxen). The incidence of duodenal ulcers was significantly lower with valdecoxib 20 and 40 mg/day than with diclofenac 75mg twice daily in two studies, although no significant differences were seen between valdecoxib and other nonselective NSAIDs in the incidence of duodenal ulcers. The incidence of gastroduodenal ulcers was significantly greater in valdecoxib recipients who also used aspirin than in those who did not, although the incidence in valdecoxib plus aspirin recipients was still lower than that in nonselective NSAID plus aspirin recipients. In a pooled analysis of eight 12- to 26-week trials in patients with OA or RA, the incidence of ulcer complications (perforation, obstruction or bleeding) was significantly lower with valdecoxib 5–80 mg/day than with nonselective NSAIDs. In individual trials, no renal adverse effects occurred significantly more frequently in valdecoxib recipients than in other treatment groups or placebo recipients. However, a pooled analysis of almost 1000 patients with arthritis found a significantly increased incidence of renal events (mostly oedema or deterioration in blood pressure control) in patients receiving valdecoxib 10 mg/day (3%, similar to that with nonselective NSAIDs, vs 1% with placebo). Pooled analyses of 6- to 52-week trials in >7900 arthritic patients found no difference in the incidence of thrombotic events between recipients of valdecoxib, other NSAIDs (ibuprofen, diclofenac or naproxen) and placebo. Dosage and Administration Valdecoxib is approved in the US and some countries in the EU for the treatment of the signs and symptoms of OA and adult RA and for primary dysmenorrhoea. Dosage recommendations, contraindications and cautions differ between the EU and the US. In the US, the approved dosage of oral valdecoxib for the treatment of arthritis is 10mg once daily, with no dosage adjustment required in patients aged >65 years. For primary dysmenorrhoea, the approved dosage is 20mg twice daily as required. In the EU countries in which valdecoxib is approved, the dosage for arthritis is 10mg once daily up to 20mg once daily if needed; treatment should be initiated at the lower dosage in patients aged >65 years. For primary dysmenorrhoea, the approved dosage is 40mg up to twice daily on day 1 and once daily on subsequent days. p ]Clinically significant drug interactions have occurred with drugs which are metabolised by CYP isoenzymes, including CYP2D6. Caution is recommended with concomitant administration of valdecoxib and other CYP2D6 substrates that have a narrow therapeutic index (e.g. flecainide, propafenone and metoprolol). Interactions with ACE inhibitors, reducing their antihypertensive effects, and with furosemide and thiazide diuretics, reducing their natriuretic effect, may also occur.
    No preview · Article · Jun 2004 · Drugs