0.4% nitroglycerin ointment : in the treatment of chronic anal fissure pain.

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.

Spotlight on gefitinib in non-small-cell lung cancer.

Gefitinib (Iressa), the first commercially available epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor, is indicated in the management of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). However, approved uses differ between countries; in most markets, gefitinib is approved for third-line use only (e.g. the US, Canada and Switzerland), although in some it is approved for both second- and third-line use (e.g. Japan and Australia) and, additionally, in patients considered unsuitable for chemotherapy (e.g. Indonesia and the Philippines). Few third-line treatment options exist for patients with inoperable advanced NSCLC who have failed both docetaxel and platinum-based chemotherapy regimens. Gefitinib represents a significant advance in the treatment of this population; a once-daily oral dosage of 250 mg/day was well tolerated, produced objective tumour responses and disease stabilization, and improved disease-related symptoms and quality of life. It also produced overall survival outcomes that compared favorably with historical outcomes in a similar group of patients treated with three or four different chemotherapy regimens. These findings have been supported by observations from a global compassionate-use program. Ongoing or planned clinical trials are designed to confirm and/or further define the role of the drug in the above and other clinical settings. Preliminary data demonstrate the presence of activating mutations in EGFR-TK among patients whose disease was highly responsive to treatment with gefitinib, although such mutations have not been correlated to all patients who benefit from the drug. Further studies are needed to fully elucidate the clinical implications of EGFR mutations and to identify patients likely to benefit from EGFR-targeted therapy.

Rotigotine: in Parkinson's disease.

Rotigotine is a nonergolinic dopamine D3/D2/D1 receptor agonist delivered via a transdermal system and has been evaluated for the treatment of idiopathic Parkinson's disease. Patients with early Parkinson's disease receiving rotigotine monotherapy experienced significantly greater improvements in parkinsonian symptoms (as measured by Unified Parkinson's Disease Rating Scale scores) compared to placebo in two large, well designed clinical trials. Significant beneficial effects versus placebo were observed with the 30 and 40 cm2 rotigotine patches in both trials.black triangle Patients with advanced Parkinson's disease receiving rotigotine as adjunctive therapy with levodopa experienced clinically significant reductions from baseline in 'off' time in two well designed clinical trials. In one trial, a large placebo effect was observed, therefore, there was no significant difference between placebo and active treatment (20, 40 and 60 cm2) for this primary efficacy variable, However, a recent study found a significant (p < or = 0.003) reduction in 'off' time in rotigotine 40 and 60 cm2 recipients versus that in the placebo group. Rotigotine was generally well tolerated in clinical trials as both monotherapy and when administered with levodopa; adverse events were generally mild or moderate in severity.

Darbepoetin alfa: its use in anemia associated with chronic kidney disease.

Darbepoetin alfa (Aranesp), Nespo) is an amino acid substituted analog of human erythropoietin (EPO) that promotes erythrocyte survival, proliferation, and differentiation. Approved in Europe and the US for the treatment of anemia associated with chronic kidney disease (CKD), it is characterized by delayed clearance and a more prolonged elimination half-life than recombinant human erythropoietin (rhEPO; epoetin alfa and beta), permitting an extended interval between doses. Darbepoetin alfa is generally well tolerated, and clinical trials of 20-52 weeks' duration have demonstrated the efficacy of subcutaneous and intravenous administration at 1- or 2-week intervals in the initial treatment of anemia associated with CKD both in dialysis patients and in patients not yet on dialysis. Trials of up to 52 weeks' duration demonstrated that in the majority of patients with CKD, treatment with darbepoetin alfa at up to 4-week intervals maintained hemoglobin (Hb) levels established by prior erythropoietic treatment, while in patients undergoing dialysis, intravenous or subcutaneous darbepoetin alfa administered at 1- or 2-week intervals was noninferior to rhEPO administered once, twice, or three times per week in maintaining established Hb levels.

Gefitinib: a review of its use in the management of advanced non-small-cell lung cancer.

Gefitinib (Iressa), the first commercially available epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor, is indicated in the management of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). However, approved uses differ between countries; in most markets, gefitinib is approved for third-line use only (e.g. the US, Canada and Switzerland), although in some it is approved for both second- and third-line use (e.g. Japan and Australia) and, additionally, in patients considered unsuitable for chemotherapy (e.g. Indonesia and the Philippines). Few third-line treatment options exist for patients with inoperable advanced NSCLC who have failed both platinum-based and docetaxel chemotherapies. Gefitinib represents a significant advance in the treatment of this population; a once-daily, oral dosage of 250 mg/day was well tolerated, produced objective tumour responses and disease stabilisation, and improved disease-related symptoms and quality of life. It also produced overall survival outcomes that compared favourably with historical outcomes in a similar group of patients treated with three or four different chemotherapy regimens. These findings have been supported by observations from a global compassionate-use programme. Ongoing or planned clinical trials are designed to confirm and/or further define the role of the drug in the above and other clinical settings.

Transdermal buprenorphine.

Buprenorphine is a low molecular weight, lipophilic, opioid analgesic. Recently, a transdermal matrix patch formulation of buprenorphine has become available in three dosage strengths designed to release buprenorphine at 35, 52.5 and 70 micro g/h over a 72-hour period. At least satisfactory analgesia with minimal requirement for rescue medication (50% of patients treated with transdermal buprenorphine, in two trials. Furthermore, despite the availability of rescue medication to all patients, those receiving transdermal buprenorphine tended to experience greater pain relief, reduced pain intensity and longer pain-free sleep. Transdermal buprenorphine was generally well tolerated. Systemic adverse events were typical of opioid treatment or were attributable to the underlying disease.

Candesartan cilexetil: an update of its use in essential hypertension.

UNLABELLED: Candesartan cilexetil is converted to the angiotensin II receptor antagonist candesartan during absorption from the gastrointestinal tract. The selective and competitive binding of candesartan to the angiotensin II type 1 (AT(1)) receptor prevents binding of angiotensin II, a key mediator in the renin-angiotensin system. Significant reductions in systolic BP and diastolic BP are achieved with a once-daily dosage of candesartan cilexetil 2 to 32 mg/day in patients with mild to moderate hypertension. In randomised studies, candesartan cilexetil 8 to 16 mg/day was at least as effective as therapeutic dosages of losartan or other angiotensin II receptor antagonists. At a dosage of up to 32 mg/day candesartan cilexetil demonstrated greater antihypertensive efficacy than losartan 50 or 100 mg/day. In comparative trials, candesartan cilexetil demonstrated similar or greater antihypertensive efficacy compared with enalapril or hydrochlorothiazide and equivalent efficacy compared with amlodipine. The efficacy of candesartan cilexetil is not affected by age, and the drug provided significant BP reductions in Black patients and in those with severe hypertension. Long-term clinical studies to assess the effects of treatment with candesartan cilexetil on cardiovascular morbidity and mortality are ongoing. Regression of left ventricular hypertrophy has been seen with candesartan cilexetil treatment in patients with hypertension. Furthermore, the drug has favourable effects on renal function in patients with hypertension with or without coexisting diabetes mellitus. Renal vascular resistance and albumin excretion were reduced following treatment with candesartan cilexetil. Glucose homeostasis and lipid metabolism were not affected by treatment in patients with type 2 diabetes mellitus. Candesartan cilexetil is well tolerated and is not associated with cough, a common adverse effect of angiotensin converting enzyme inhibitor treatment. A pooled analysis of clinical trials found that the tolerability profile of candesartan cilexetil is not significantly different from that of placebo. Adverse events are not dose-related and are generally of mild to moderate severity. CONCLUSIONS: Candesartan cilexetil is an effective antihypertensive agent with a tolerability profile similar to that of placebo. Comparative data indicate that candesartan cilexetil has antihypertensive efficacy equivalent to that of other major classes of antihypertensive agents and has a long duration of action. Therefore, candesartan cilexetil is a useful therapeutic option in the management of patients with hypertension.

Polyethylene glycol-liposomal doxorubicin: a review of its use in the management of solid and haematological malignancies and AIDS-related Kaposi's sarcoma.

UNLABELLED: Polyethylene glycol (PEG)-liposomal doxorubicin is a formulation of the anthracycline doxorubicin in which the drug is encapsulated in PEG-coated liposomes. This alters the pharmacokinetic properties of doxorubicin, prolonging circulation time and enhancing localisation to tumours. In a large randomised trial, intravenous PEG-liposomal doxorubicin was at least as effective as topotecan in patients with ovarian cancer refractory or sensitive to first-line platinum-based chemotherapy. Overall response rates of patients with ovarian cancer refractory to platinum- and paclitaxel-based chemotherapy who received the drug ranged from 18.3 to 27.6% in noncomparative clinical trials. PEG-liposomal doxorubicin also has antitumour activity in patients with metastatic breast cancer pretreated with other chemotherapeutic agents. Overall response rates were similar in patients with pretreated metastatic breast cancer who had received PEG-liposomal doxorubicin or two comparator salvage chemotherapy regimens (vinorelbine or mitomycin C plus vinblastine) in an interim analysis of a large randomised study. In patients with advanced AIDS-related Kaposi's sarcoma, PEG-liposomal doxorubicin monotherapy produced overall response rates ranging from 46 to 77% in randomised trials. The drug was significantly more effective than bleomycin plus vincristine alone or in combination with standard doxorubicin, as measured by tumour response. As a replacement for standard doxorubicin in commonly used combination therapies, PEG-liposomal doxorubicin has shown activity in multiple myeloma and aggressive non-Hodgkin's lymphoma in small, preliminary trials. The most common adverse events associated with PEG-liposomal doxorubicin are myelosuppression, palmar-plantar erythrodysaesthesia, stomatitis and nausea. These can be managed by delaying or reducing dosages. Although preliminary trials are promising, the relative cardiotoxicity of PEG-liposomal doxorubicin compared with the standard formulation has not been clearly established. CONCLUSIONS: Monotherapy with PEG-liposomal doxorubicin is effective as a second-line chemotherapy in patients with platinum-refractory ovarian cancer and in patients with metastatic breast cancer. However, as with all chemotherapeutic agents, the benefits of treatment need to be weighed against the agent's tolerability profile. Strong comparative data have helped to establish PEG-liposomal doxorubicin as the first-line treatment option in patients with advanced Kaposi's sarcoma. Anticancer activity has also been observed in studies conducted in small numbers of patients with multiple myeloma or non-Hodgkin's lymphoma receiving PEG-liposomal doxorubicin instead of standard doxorubicin in combination regimens, although further data are needed to confirm the clinical relevance of these findings.

Botulinum toxin A (Botox Cosmetic): a review of its use in the treatment of glabellar frown lines.

Botox Cosmetic (Botox) is a formulation of the neuromuscular blocking agent botulinum toxin type A (BTX-A). When injected into hyperactive corrugator superciliaris and/or procerus muscles of the face that predominantly control frowning, Botox produces a transient (3- to 6-month), dose-dependent localized muscle weakness, resulting in a temporary improvement in glabellar frown lines ('brow furrows'). After a decade of successful 'off-label' use, the efficacy and tolerability of Botox (total dose 20 biological units) in the treatment of glabellar frown lines have been demonstrated in two identical, large, multicenter, randomized, double-blind, placebo-controlled pivotal trials in a total of 537 subjects, mostly women, with moderate or severe glabellar lines during facial animation. Based both on subjects' and physicians' assessments, the improvement in glabellar lines with Botox was superior to that with placebo at each visit during the 120-day post-injection follow-up period, beginning on day 7 post-injection. The peak effect was seen on day 30 post-injection when 80% of subjects in the two studies combined had the severity of their lines at maximum frown reduced to mild or none, as assessed by their physician, and 89% had at least a moderate (> or =50%) improvement in the appearance of their glabellar lines, as rated by themselves. In a noncomparative extension of these trials, there was a tendency for a higher proportion of subjects to respond to Botox injections after a second and third treatment session. Botox injections for glabellar lines are well tolerated. Headache, the most common adverse event, occurred with a similar frequency to placebo in the two pivotal studies (13% vs 18%). Temporary blepharoptosis occurred in 3.2% of Botox recipients; however, the incidence of this adverse event tended to decrease with repeated treatment sessions. In summary, Botox injections offer a convenient, effective, and well tolerated treatment for improving glabellar frown lines. Repeated injections are necessary to maintain a long-term effect; however, this technique clearly represents an attractive option for individuals who wish to avoid a more major procedure.

Transdermal ethinylestradiol/norelgestromin: a review of its use in hormonal contraception.

UNLABELLED: Ethinylestradiol 20 microg/day plus norelgestromin 150 microg/day have been formulated into a transdermal patch for hormonal contraception. The predominant mechanism of action for transdermal ethinylestradiol/norelgestromin (Ortho Evra, Evra) is inhibition of ovulation by suppression of gonadotropins. It suppresses follicular development, induces changes to the endometrium that reduce the probability of implantation, and increases the viscosity of cervical mucus, which may prevent sperm penetration into the uterus. Two large randomized, nonblind efficacy studies demonstrated that transdermal ethinylestradiol/norelgestromin was as efficacious in preventing pregnancy as oral triphasic ethinylestradiol/levonorgestrel or oral ethinylestradiol/desogestrel. A large, noncomparative study also showed transdermal ethinylestradiol/norelgestromin to have good contraceptive efficacy. Moreover, in the two comparative trials, women using transdermal ethinylestradiol/norelgestromin had higher rates of perfect compliance than women using oral contraception. Age did not affect the rate of perfect compliance in women using the transdermal ethinylestradiol/norelgestromin patch, whereas the rate of compliance reduced with younger age in oral contraceptive users. Pooled results from three efficacy studies found that 1.8% of patches were replaced as a result of complete detachment and 2.9% because of partial detachment. Physical exercise, water immersion, and living in a humid climate did not affect patch adhesion. Transdermal ethinylestradiol/norelgestromin was generally well tolerated in clinical trials. The most common menstrual disturbances were breakthrough bleeding/spotting and dysmenorrhea. The incidence of discontinuation of treatment because of an adverse event was < or = 3.2%, with the most common reason being application-site reactions. CONCLUSIONS: Transdermal ethinylestradiol/norelgestromin offers a well tolerated, effective, reversible, and easy-to-use method of hormonal contraception with an increased likelihood of compliance relative to oral contraceptives.

Topical bimatoprost: a review of its use in open-angle glaucoma and ocular hypertension.

Bimatoprost, a synthetic prostamide analogue, is a new ocular hypotensive agent indicated for the second-line treatment of open-angle glaucoma and ocular hypertension. The drug is formulated as a 0.03% ophthalmic solution. Bimatoprost lowers intraocular pressure (IOP) by increasing aqueous humour outflow. When applied topically once daily in patients with ocular hypertension or glaucoma, bimatoprost 0.03% significantly reduced IOP. Mean IOP was reduced by approximately 7.5 to 9.2mm Hg 12 hours after drug administration in randomised clinical trials. The reduction in IOP was maintained throughout the 24-hour dosage interval. Once-daily treatment with bimatoprost 0.03% was found to be significantly more effective than timolol 0.5% (administered twice daily as an ophthalmic solution or once daily as a gel-forming solution) in randomised comparative trials in patients with ocular hypertension and glaucoma. Furthermore, after 1 to 6 months' treatment, the percentage of patients reaching a target IOP of < or =17mm Hg was significantly greater in the bimatoprost-treated groups than in those receiving timolol. Bimatoprost 0.03% ophthalmic solution was found to be at least as effective as topical latanoprost 0.005% administered once daily in two clinical trials. Reductions in IOP 16 and 20 hours postdose were greater in patients treated with bimatoprost, indicating superior control of IOP at timepoints throughout the dosage interval. In patients refractory to beta-blocker therapy, treatment with bimatoprost 0.03% produced greater reductions in diurnal IOP measurements than combination therapy with topical dorzolamide 2%/timolol 0.5%; approximately twice as many bimatoprost 0.03% recipients achieved an IOP of < or =16mm Hg. The most commonly reported adverse effect during clinical trials of once-daily bimatoprost 0.03% was conjunctival hyperaemia which occurred in 42 to 46% of patients treated. However, most cases were mild and only 1 to 4% of patients withdrew from treatment as a result. Overall withdrawal rates as a result of adverse events during clinical trials ranged from 2.6 to 7%. Bimatoprost has been reported to cause changes in the pigmentation of the periorbital skin, eyelashes and iris, and increase eyelash growth. The long-term consequences of these effects are unknown. Cardiopulmonary adverse effects, which have been associated with the use of beta-blockers such as timolol, were not reported in clinical trials of bimatoprost. Thus, in clinical trials of up to 1-year duration, bimatoprost 0.03% has been found to be effective in significantly lowering IOP and is generally well tolerated. It provides an alternative treatment option for patients in whom beta-blockers are contraindicated. Furthermore, bimatoprost provides an effective second-line treatment option in patients who do not achieve target IOP with other topical ocular hypotensive agents, or who experience unacceptable adverse effects. Wider clinical use of this drug will establish the place of bimatoprost in the treatment of open-angle glaucoma and ocular hypertension.

Vardenafil.

Vardenafil selectively inhibits phosphodiesterase type 5 (PDE5), an enzyme which hydrolyses cyclic guanosine monophosphate in the cavernosum tissue of the penis. Inhibition of PDE5 results in increased arterial blood flow leading to enlargement of the corpus cavernosum. Because of the increased tumescence, veins are compressed between the corpus cavernosum and the tunica albuginea, resulting in an erection. Vardenafil has a high bioavailabilty and is rapidly absorbed. An erection of >60% rigidity was maintained for approximately twice as long following visual stimulation in patients treated with vardenafil 10 or 20mg than in recipients of placebo. In a large, placebo-controlled trial in patients with mild to severe erectile dysfunction (ED), vardenafil 5, 10 or 20mg taken as needed over a 12-week period significantly improved the scores in questions 3 and 4 of the International Index of Erectile Function (IIEF). The rate of successful attempts at intercourse with ejaculation was also significantly higher with vardenafil (71 to 75%) than in the placebo group (39.5%), and significantly more patients treated with vardenafil than placebo responded 'yes' to a Global Assessment Question (GAQ) asking if treatment had improved erections. In a 26-week trial in 736 men with ED of varied aetiologies and severity patients receiving vardenafil 5, 10 or 20mg experienced significantly improved erections with 85% of vardenafil 20mg recipients reporting improved erectile function (assessed using the GAQ) compared with 28% of placebo recipients. Treatment with vardenafil also significantly improved scores in response to questions 3 and 4 of the IIEF compared with placebo. A 12-week trial in 452 men with ED associated with diabetes mellitus demonstrated that treatment with vardenafil 20mg compared with placebo significantly improved IIEF erectile function domain scores and the rate of positive responders to the erectile improvement GAQ. Similar results were reported in a placebo-controlled trial of vardenafil 10 to 20mg involving 440 patients with ED after radical prostatectomy. Adverse events associated with vardenafil were those commonly associated with PDE5 inhibitors: headache, flushing, dyspepsia and rhinitis. These were mostly dose-dependent and mild to moderate in intensity.

Transdermal oxybutynin: for overactive bladder.

Oxybutynin binds to the M(3) muscarinic receptors on the detrusor muscle of the bladder, preventing acetylcholinergic activation and relaxing the muscle. The transdermal system delivers oxybutynin over a 3- to 4-day period after application to intact skin. Peak plasma concentrations of oxybutynin and the major active metabolite, N-desethyloxybutynin, are reached 24 - 48 hours after a single application and therapeutic concentrations are maintained throughout the dosage interval. In a large, randomised, double-blind trial, transdermal oxybutynin 3.9 mg/day significantly decreased the median number of incontinence episodes per week compared with placebo (-19 vs -15, p = 0.0165) in patients with overactive bladder. In addition, the micturition frequency was reduced and average voided volume was increased by transdermal oxybutynin treatment. Significant reductions in incontinence episodes following transdermal oxybutynin treatment were also observed in two further studies and the clinical efficacy was similar to that of oral tolterodine or oral oxybutynin. Transdermal oxybutynin was well tolerated in clinical trials. Application site reactions were the most common adverse effect; however, the majority were mild to moderate in severity. Adverse events associated with anticholinergic drugs (e.g. dry mouth) were less frequently reported in patients treated with transdermal oxybutynin than in those receiving orally administered oxybutynin or tolterodine.

Formoterol delivered by Turbuhaler: in pediatric asthma.

Formoterol is an inhaled long-acting beta(2)-adrenoceptor agonist, with a rapid onset of action and a bronchodilator effect that lasts for at least 12 hours. As add-on therapy to anti-inflammatory medication (e.g. corticosteroids), formoterol 4.5 and 9 microg twice daily delivered by Turbuhaler for 3 months significantly improved lung function (change from baseline in forced expiratory volume in 1 second and/or peak expiratory flow) compared with placebo in randomised, double-blind trials in pediatric patients (aged 6-17 years). In addition, formoterol 9 microg twice daily for 12 weeks reduced the use of rescue medication compared with salmeterol 50 microg twice daily in a nonblind trial in pediatric patients (aged 7-16 years). Single-dose formoterol 4.5 or 9 microg delivered by Turbuhaler provided significant prophylaxis against exercise-induced bronchoconstriction compared with placebo, and demonstrated a longer duration of effect than terbutaline, in a randomized, double-blind, crossover trial in pediatric patients (aged 8-17 years). Formoterol delivered by Turbuhaler was well tolerated in pediatric patients, with respiratory infection being the most commonly reported adverse event.