Biomedical subjects

L R Wiseman

Publications and source records attributed to L R Wiseman.

At least 19 recordsLinked to original sources

PubMed2000

Docetaxel: an update of its use in advanced breast cancer.

UNLABELLED: Docetaxel, a semisynthetic member of the taxoid class of antineoplastic agents, is effective in the treatment of patients with advanced (locally advanced or metastatic) breast cancer. Reported objective response rates for docetaxel 100 mg/m2 ranged from 54 to 69% and 53 to 82% as first-line monotherapy or combination therapy, respectively. Objective response rates of 23 to 65% and 30 to 81% have been reported for docetaxel as second-line monotherapy or combination therapy, respectively. In Japanese studies, second-line docetaxel 60 mg/m2 produced objective response rates of 42 to 55%. At the recommended dose of 100 mg/m2 given as a 1-hour intravenous (i.v.) infusion every 3 weeks, docetaxel had significantly greater efficacy than doxorubicin, mitomycin plus vinblastine and methotrexate plus fluorouracil, and similar efficacy to fluorouracil plus vinorelbine in pretreated patients with advanced breast cancer. In chemotherapy-naive patients, first-line combined therapy with docetaxel and doxorubicin had significantly greater efficacy than doxorubicin plus cyclophosphamide. Promising results have been achieved in phase I/II trials of a weekly regimen of docetaxel (generally 30 to 45 mg/m2). Preliminary data indicate a potential role for docetaxel in the neoadjuvant therapy of early breast cancer. The major dose-limiting adverse event associated with docetaxel is neutropenia. Although other adverse events are common, the tolerability profile of docetaxel is generally acceptable in the majority of patients, particularly in comparison with other antineoplastic regimens. CONCLUSIONS: Although no single standard regimen has been identified as optimal for the treatment of advanced breast cancer, phase III trials have shown that docetaxel has improved efficacy over doxorubicin alone (considered one of the current gold standards), methotrexate/fluorouracil and mitomycin/vinblastine in second-line therapy. In combination with doxorubicin, docetaxel has demonstrated better efficacy than doxorubicin/cyclophosphamide in first-line therapy. These results provide a basis for therapy choice in advanced breast cancer. Clinical trials comparing docetaxel monotherapy versus paclitaxel monotherapy and versus docetaxel combination therapy are warranted. The role of docetaxel in the adjuvant and neoadjuvant treatment of early breast cancer is being evaluated.

Antineoplastic Agents, Phytogenic↗

PubMed2000

Oxaliplatin. A review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies.

UNLABELLED: Oxaliplatin is a platinum compound that inhibits DNA synthesis, primarily by causing intrastrand cross-links in DNA. Oxaliplatin has a broad spectrum of antineoplastic activity and has demonstrated a lack of cross-resistance with other platinum compounds. In patients with metastatic colorectal cancer, intravenous oxaliplatin has been trialled as a monotherapy and in combination with other agents. The highest response rates were achieved when oxaliplatin was used in combination with fluorouracil/folinic acid (leucovorin; calcium folinate), typically > or = 50% in the first-line setting and 13 to 45% as a second-line therapy. First-line triple therapy with oxaliplatin and fuorouracil/folinic acid achieved significantly higher response rates and longer median progression-free survival than fluorouracil/folinic acid therapy alone. However, no significant difference in the median duration of overall survival was found. This may be a consequence of the subsequent use of oxaliplatin and/or surgery after disease progression in patients who relapsed after fluorouracil/folinic acid therapy alone. Neoadjuvant therapy with oxaliplatin/fluorouracil/folinic acid has proven beneficial in enabling surgical removal of previously unresectable liver metastases. In 2 studies, surgery with curative intent was performed in 16 and 51% of patients with initially unresectable liver metastases following oxaliplatin/fluorouracil/folinic acid therapy; the 5-year survival rates were 40 and 50%, respectively. In patients with advanced ovarian cancer, first-line therapy with oxaliplatin/cyclophosphamide achieved an objective response rate which did not differ significantly from that of cisplatin/cyclophosphamide (33 vs 42%). In addition, oxaliplatin has shown efficacy in patients with platinum-pretreated ovarian cancer and achieved objective response rates similar to paclitaxel in this setting (16 vs 17%). Promising results have also been found with oxaliplatin in patients with non-Hodgkin's lymphoma, breast cancer, mesothelioma and non-small cell lung cancer. Reversible, cumulative, peripheral sensory neuropathy is the principle dose-limiting factor of oxaliplatin therapy. Haematological and gastrointestinal toxicities occur frequently but are generally mild to moderate in intensity. CONCLUSION: Oxaliplatin in combination with fluorouracil/folinic acid is an effective treatment option for patients with metastatic colorectal cancer, both as a first-line therapy and in patients refractory to previous chemotherapy. Although preliminary results failed to show any overall survival advantage of this regimen over fluorouracil/folinic acid alone, this may be a consequence of trial design and requires further examination. Additional clinical investigation of oxaliplatin in patients with other cancers is warranted given the promising results achieved in early trials, most notably in patients with platinum-pretreated ovarian cancer.

Animals↗

PubMed1999

Oxaliplatin: a review of its use in the management of metastatic colorectal cancer.

UNLABELLED: Oxaliplatin is a cytotoxic agent which, like other platinum compounds, acts primarily by causing inter- and intra-strand cross-links in DNA, thereby inhibiting DNA synthesis. Oxaliplatin has a bulky carrier ligand which is thought to enhance cytotoxicity and abolish cross-resistance between oxaliplatin and other platinum compounds. Phase II and III clinical trials have found oxaliplatin combined with fluorouracil/calcium folinate (leucovorin/folinic acid) to be an effective first- and second-line treatment for patients with metastatic colorectal cancer. First-line triple therapy with oxaliplatin and fluorouracil/calcium folinate achieved significantly higher response rates than fluorouracil/calcium folinate alone in 2 phase III studies (objective response rates 59 vs 23% and 50.7 vs 22.3%). In addition, median progression-free survival was longer with triple therapy in both studies (8.9 vs 5.2 and 8.75 vs 6.0 months). However, there was no significant difference in median duration of survival between treatment groups, although this may be a consequence of the subsequent use of oxaliplatin and/or surgery in patients who relapsed during therapy with fluorouracil/calcium folinate alone. About 30 to 45% of patients (whose disease progressed during or after fluorouracil-based therapy) responded to second-line combination therapy with oxaliplatin and fluorouracil/calcium folinate. Median progression-free survival ranged from 7 to 10 months and the median duration of survival from 10 to 17 months. Objective responses were achieved in 20 and 24% of patients in 2 small trials of first-line oxaliplatin monotherapy and in about 10% of patients given the drug as a second-line option. Peripheral sensory neuropathy is the dose-limiting toxicity associated with oxaliplatin. Severe neurotoxicity has been estimated to occur in 10% of patients after 6 treatment cycles and in 50% after 9 cycles of an oxaliplatin dosage of 130 mg/m2 once every 3 weeks. It is cumulative, but reversible on discontinuation of therapy. Nausea, vomiting and diarrhoea are common, but are usually mild to moderate. Myelosuppression is also observed, but is usually mild. CONCLUSION: oxaliplatin is a promising treatment option for patients with metastatic colorectal cancer. It appears to be particularly advantageous (in terms of response rate and duration of progression-free survival) when used in combination with fluorouracil/calcium folinate as both a first- and second-line option, although preliminary studies have failed to show any survival advantage over fluorouracil/calcium folinate alone. Promising results have been found in studies of the drug as monotherapy, and oxaliplatin may also prove useful in the neoadjuvant setting in patients with unresectable liver metastases; however, data are limited at present.

Animals↗

PubMed1999

Epirubicin: a review of its intravesical use in superficial bladder cancer.

UNLABELLED: The anthracycline epirubicin has been investigated for intravesical use in patients with superficial bladder cancer. In multicentre, randomised trials, prophylaxis with intravesical epirubicin 30 to 80 mg after transurethral resection (TUR) was more effective than no prophylaxis in the prevention of disease recurrence. Intravesical prophylaxis with epirubicin was as effective as that with equivalent dosages of doxorubicin after TUR. Data are conflicting concerning the relative efficacy of intravesical epirubicin and bacillus Calmette-Guerin (BCG) in patients at intermediate risk of recurrence after TUR, but epirubicin was less effective than BCG in those at high risk. The efficacy and tolerability of prophylaxis with epirubicin relative to that with mitomycin is not yet established. The efficacy of epirubicin as prophylaxis after TUR in combination with BCG or interferon-alpha-2b, or as treatment in patients with superficial bladder cancer has been evaluated in small, noncomparative trials, but requires clarification. Adverse events associated with intravesical epirubicin were generally mild and transient. The most common adverse events were localised to the bladder (cystitis, haematuria and urinary tract infection). Systemic adverse events (cardiac, haematological or related to hypersensitivity) were not reported in many trials of intravesical epirubicin, and when reported generally occurred in < or =5% of patients who received the drug. Intravesical epirubicin was generally tolerated as well as intravesical doxorubicin and was associated with a lower incidence of mild chemical cystitis in 1 clinical trial. The incidence of adverse events associated with intravesical epirubicin was markedly lower than that associated with intravesical BCG. CONCLUSIONS: Intravesical epirubicin has shown efficacy in preventing disease recurrence after TUR of superficial bladder cancer. In comparison with equivalent dosages of doxorubicin, the efficacy of epirubicin for this indication is generally similar, and the tolerability profile may be more favourable. Epirubicin is less effective than BCG as intravesical prophylaxis in patients at high risk of recurrence after TUR; the relative efficacy of epirubicin and BCG after TUR in patients at intermediate risk is not yet clear. Intravesical epirubicin is generally tolerated better than BCG. Intravesical epirubicin may be used as prophylaxis after TUR in patients who are at low or intermediate risk of recurrence of superficial bladder cancer.

Antibiotics, Antineoplastic↗

PubMed1999

Basiliximab.

The chimaeric monoclonal antibody basiliximab specifically binds the alpha subunit of the interleukin-2 (IL-2) receptor on activated T lymphocytes. Through competitive antagonism of IL-2, basiliximab supplements standard immunosuppressive therapy after renal transplantation. < or =24 Hours after a single intravenous dose of basiliximab 2.5 to 25 mg, approximately 90% of available IL-2 receptors on T lymphocytes were complexed with the drug. This level of basiliximab binding was maintained for 4 to 6 weeks when renal transplant patients received basiliximab 20 mg 2 hours before and then 4 days after transplantation surgery. In 2 large, well-designed trials, the percentage of patients with biopsy-confirmed acute rejection episodes after renal transplantation was significantly lower with basiliximab 20 mg (administered 2 hours before and then 4 days after transplantation surgery; 30 or 33%, respectively) than placebo (44 or 46%) at 6 months after surgery. Basiliximab was well tolerated during clinical trials. The incidence of infections (including active cytomegalovirus infection) and post-transplant lymphoproliferative disorders was similar with basiliximab and placebo. Cytokine release syndrome was not observed in patients who received basiliximab.

Animals↗

PubMed1999

Moxifloxacin.

Moxilloxacin is a new fluoroquinolone antibacterial agent with a broad spectrum of activity, encompassing gram-negative and gram-positive bacteria. It has improved activity against gram-positive species (including staphylococci, streptococci, enterococci) and anaerobes compared with ciprofloxacin. This is offset by slightly lower activity against pseudomonal species and Enterobacteriaceae. In common with other fluoroquinolones, moxifloxacin attains good penetration into respiratory tissues and fluids and its bioavailability is substantially reduced by coadministration with an antacid or iron preparation. However, moxifloxacin does not interact with theophylline or warfarin. In clinical trials in patients with community-acquired pneumococcal pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB) or acute sinusitis, moxifloxacin 400 mg once daily achieved bacteriological and/or clinical success rates of approximately 90% or higher. Moxifloxacin was as effective as amoxicillin 1 g 3 times daily and clarithromycin 500 mg twice daily in CAP and as effective as clarithromycin in AECB. In patients with sinusitis, a 7-day course of moxifloxacin 400mg once daily was as effective as a 10-day course of cefuroxime axetil 250mg twice daily. In contrast to some other fluoroquinolones, moxifloxacin appears to have a low propensity for causing phototoxic and CNS excitatory effects. The most common adverse events are gastrointestinal disturbances.

Anti-Infective Agents↗

PubMed1999

Terbinafine. An update of its use in superficial mycoses.

UNLABELLED: Terbinafine is an allylamine antifungal agent which has fungicidal activity against a wide variety of dermatophytes, moulds and certain dimorphic fungi, and fungistatic activity against Candida albicans. Oral terbinafine 250 mg/day is effective in the treatment of superficial dermatophyte infections such as onychomycosis, tinea pedis and tinea corporis/cruris, generally achieving mycological cure in > 80% of patients. The drug is also effective in children with tinea capitis when administered orally in the dosage range 62.5 to 250 mg/day for 4 weeks. Comparative data indicate that oral terbinafine is more effective than continuous or intermittent intraconazole in dermatophyte onychomycosis, and is as effective as itraconazole 400 mg/day in tinea pedis. The drug has shown greater efficacy than griseofulvin in dermatophyte onychomycosis, tinea pedis and tinea corporis/cruris, and comparable efficacy in children with tinea capitis. Additionally, oral terbinafine is more effective than ketoconazole 200 mg/day in tinea corporis/cruris. Topical terbinafine 1% formulations are effective when applied once or twice daily for up to 2 weeks, achieving mycological cure in > 80% of patients with tinea pedis, tinea corporis/cruris, cutaneous candidiasis and pityriasis versicolor. Its formulations are at least as effective as miconazole 2% cream and naftifine 1% gel in tinea pedis, and more effective than clotrimazole 1% cream, bifonazole 1% cream and oxiconazole 1% lotion. Mycological cure rates achieved with terbinafine generally improve after treatment cessation, reflecting the drug's fungicidal mechanism of action and its residual effect in tissue. Terbinafine is well tolerated after oral or topical administration and has a relatively low potential for drug interactions. Pharmacoeconomic data support the use of terbinafine in dermatophyte infections of the skin or nails. CONCLUSIONS: Evidence suggests that oral terbinafine is the treatment of choice for dermatophyte onychomycosis, as it achieves high rates of mycological and clinical cure, is generally well tolerated and has a relatively low potential for drug interactions. It must also be considered a first-line treatment option, along with itraconazole, in cutaneous mycoses which warrant systemic treatment; topical terbinafine is a treatment of choice in less extensive mycoses. The use of terbinafine in non-dermatophyte or mixed infections has not been fully defined.

Animals↗

PubMed1999

Exemestane.

Exemestane is a steroidal agent which causes inactivation of the aromatase enzyme by binding irreversibly to the substrate binding site. Oral exemestane 25 mg/day inactivates peripheral aromatase activity (approximately 98% inactivation) and reduces basal plasma estrone, estradiol and estrone sulphate levels by 85 to 95% in postmenopausal women with advanced breast cancer. Phase II trials indicate that oral exemestane 25 mg/day is an effective second- or third-line agent in the treatment of postmenopausal women with advanced breast cancer (achieving an objective response in up to 28 and 26% of patients, respectively). Results from a phase III trial indicate that exemestane achieves a similar objective response rate to megestrol as a second-line therapy; however, exemestane achieved a significantly longer duration of overall success, time to disease progression and survival time. Exemestane is at least as well tolerated as megestrol, but is associated with significantly fewer bodyweight changes, mainly bodyweight gain (> or = 10%). Other common adverse events are hot flushes, nausea and fatigue.

Androstadienes↗

PubMed1999

Daclizumab: a review of its use in the prevention of acute rejection in renal transplant recipients.

UNLABELLED: The humanised monoclonal antibody daclizumab is an immunosuppressive agent that reduces acute rejection in renal transplant recipients. It is specific for the alpha subunit (Tac/CD25) of the interleukin-2 (IL-2) receptor on activated T cells and achieves immunosuppression by competitive antagonism of IL-2-induced T cell proliferation. Daclizumab has advantages over murine antibodies to the IL-2 receptor, including improved effector function, a low potential for immunogenicity and long elimination half-life. When added to standard cyclosporin-based immunosuppressive therapy with or without azathioprine, daclizumab (1 mg/kg prior to surgery and once every 2 weeks thereafter for a total of 5 doses) significantly reduced the 6-month rate of acute rejection compared with placebo in 2 phase III studies. The mean number of rejection episodes was significantly reduced and the time to first acute rejection significantly increased in daclizumab versus placebo recipients. Patient survival at 1 year after transplantation was significantly higher with daclizumab than placebo in 1 study and showed a trend in favour of the drug in the other study. The 1-year graft survival rate tended to be greater in daclizumab than in placebo recipients in both studies, In a phase II study, acute rejection rates in patients treated with both daclizumab and mycophenolate mofetil (plus standard cyclosporin-based immunosuppression) were lower than those achieved with mycophenolate mofetil alone. Preliminary results indicate that daclizumab is also a useful agent in paediatric renal transplant recipients. Further investigation of the efficacy and tolerability of the drug in this patient group is clearly warranted. Daclizumab does not increase the incidence of adverse events when added to standard cyclosporin-based therapy. The incidence of opportunistic infections, lymphoproliferative disorders and malignancies was not increased above that seen with placebo. CONCLUSIONS: Although the effects of daclizumab on long term graft and patient survival require further investigation, available data indicate that daclizumab is an important advance in renal transplant immunosuppression, reducing acute graft rejection without affecting the tolerability of standard cyclosporin-based immunosuppression.

Acute Disease↗

PubMed1998

Midodrine. A review of its therapeutic use in the management of orthostatic hypotension.

Midodrine is a prodrug which undergoes enzymatic hydrolysis to the selective alpha 1-adrenoceptor agonist desglymidodrine after oral administration. Oral midodrine significantly increases 1-minute standing systolic blood pressure compared with placebo. The drug also improves standing time and energy level and clinical symptoms of orthostatic hypotension including dizziness, light-headedness and syncope. Comparative studies have shown midodrine to have similar efficacy to dihydroergotamine mesylate, norfenefrine, fludrocortisone and etilefrine, and to be more effective than dimetofrine and ephedrine in patients with orthostatic hypotension. Midodrine is well tolerated, with the most commonly reported adverse events being piloerection, pruritus, paraesthesias, urinary retention and chills. The risk of supine hypertension, which is associated with midodrine therapy in up to 25% of patients, can be reduced by taking the final daily dose at least 4 hours before bedtime. Thus, oral midodrine is an effective therapeutic option for the management of various forms of orthostatic hypotension. This well-tolerated agent is likely to be useful in conjunction with standard nonpharmacological care.

Adrenergic alpha-Agonists↗

PubMed1998

Propionyl-L-carnitine.

Propionyl-L-carnitine stimulates energy production in ischaemic muscles by increasing citric acid cycle flux and stimulating pyruvate dehydrogenase activity. The free radical scavenging activity of the drug may also be beneficial. Propionyl-L-carnitine improves coagulative fibrinolytic homeostasis in vasal endothelium and positively affects blood viscosity. Improvements in maximum walking distance (MWD) correlated positively with increased mitochondrial oxidative adenosine triphosphate (ATP) synthesis in a study in patients with peripheral arterial disease. Oral propionyl-L-carnitine 1 to 3 g/day significantly improved mean MWD compared with placebo in patients with peripheral arterial obstructive disease (Fontaine Leriche stage II) in double-blind multicentre phase III studies (mean improvements ranged from 21 to 50% with placebo and from 33 to 73% with propionyl-L-carnitine). In one phase III study, propionyl-L-carnitine 1 to 3 g/day significantly improved mean MWD (measured by treadmill) compared with placebo (by 73 vs 46% after 24 weeks) in patients with intermittent claudication. Oral propionyl-L-carnitine therapy was associated with significant improvements in quality of life compared with placebo in patients with a baseline MWD < 250m. Propionyl-L-carnitine appears to be well tolerated, showing a similar incidence of adverse events to that reported in placebo recipients.

Aged↗

PubMed1998

Paclitaxel. An update of its use in the treatment of metastatic breast cancer and ovarian and other gynaecological cancers.

UNLABELLED: The antitumour agent paclitaxel has proved to be effective for the treatment of patients with metastatic breast or ovarian cancer, and limited data also indicate its clinical potential in patients with cervical or endometrial cancer. The regimen of paclitaxel administration has varied in clinical trials, the most common including a dosage of between 135 and 250 mg/m2 administered over an infusion period of 3 or 24 hours once every 3 weeks. Promising results have been achieved in phase I/II trials of a weekly regimen of paclitaxel (60 to 175 mg/m2). The objective response rate in patients with metastatic breast cancer (either pretreated or chemotherapy-naive) is generally between 20 and 35% with paclitaxel monotherapy, which compares well with that of other current treatment options including the anthracycline doxorubicin. Combination therapy with paclitaxel plus doxorubicin appears superior to treatment with either agent alone in terms of objective response rate and median duration of response. However, whether combination therapy also provides a survival advantage remains unclear; recent results of a phase III study indicate that it does not. Paclitaxel is also a useful second-line option in some patients with anthracycline-resistant disease. Combination therapy with paclitaxel and cisplatin has proved highly effective as first-line therapy for patients with advanced ovarian cancer, showing superior efficacy to cyclophosphamide/cisplatin in terms of progression-free survival time and median duration of survival. Combination therapy with paclitaxel and carboplatin has also shown promising results. Paclitaxel monotherapy is a useful second-line option for patients with platinum-refractory metastatic ovarian cancer (objective response rates have ranged from 15 to 48%). The major dose-limiting adverse events associated with paclitaxel include myelotoxicity and peripheral neuropathy. Paclitaxel has acceptable tolerability in most patients, although adverse events are common. CONCLUSION: Paclitaxel generally appears to be as effective as other antineoplastic agents used in the treatment of metastatic breast cancer, including doxorubicin. Importantly, it is a useful second-line option for some patients with anthracycline-resistant disease. Combination therapy with both paclitaxel and doxorubicin is a highly effective first-line option for metastatic breast cancer; however, recent results indicate no survival advantage versus monotherapy. Paclitaxel is a valuable agent for second-line treatment of patients with platinum-refractory metastatic ovarian cancer and, when combined with cisplatin or carboplatin, is recommended as first-line therapy for this disease.

Animals↗

PubMed1998

Anastrozole. A review of its use in the management of postmenopausal women with advanced breast cancer.

UNLABELLED: Anastrozole is a new oral nonsteroidal aromatase inhibitor indicated for the second-line endocrine treatment of postmenopausal women with advanced breast cancer. In postmenopausal women, anastrozole significantly reduces plasma estrogen levels; maximal suppression is achieved at dosages > or = 1 mg/day and levels remain suppressed during long term therapy. In two phase III clinical trials, anastrozole 1 or 10 mg/day showed similar clinical efficacy to that of oral megestrol (megestrol acetate) 160 mg/day in postmenopausal women with advanced breast cancer. Primary end-points [including time to disease progression (120 to 170 days) and overall response rates (complete and partial response and stable disease lasting > or = 24 weeks: 29 to 37%)] and secondary end-points [time to treatment failure (115 to 168 days) and duration of response (257 to 261 days)] did not differ significantly between treatment groups. However, a significant survival advantage was observed in patients treated with anastrozole 1 mg/day compared with megestrol in a follow-up combined analysis of patients enrolled in both studies (median time to death 26.7 vs 22.5 months). Quality of life parameters were generally improved to a similar extent in all treatment groups. Anastrozole is generally well tolerated in the majority of patients, the most common adverse events being gastrointestinal (GI) disturbances (incidence 29 to 33%). These events are generally mild or moderate and transient. Other adverse events reported with anastrozole include headache (< or = 18%), asthenia (< or = 16%), pain (< or = 15%), hot flushes and bone pain (both < or = 12%), back pain and dyspnoea (both < or = 11%) and peripheral oedema (< or = 9%). GI disturbance tended to be more common with anastrozole than megestrol, particularly at the 10 mg/day dosage; however, compared with megestrol, anastrozole is less frequently associated with weight gain. CONCLUSIONS: Anastrozole, with its apparent survival advantage versus megestrol (demonstrated in a combined analysis of phase III studies), convenient once daily oral administration and acceptable short term tolerability profile, is a second-line treatment option for postmenopausal patients with tamoxifenrefractory advanced breast cancer. The results of ongoing comparative trials with tamoxifen will determine the relative efficacy of anastrozole as first-line endocrine therapy for advanced breast cancer and as adjuvant therapy for early disease. In addition, direct comparative studies are required to determine the efficacy of anastrozole relative to that of other oral aromatase inhibitors such as letrozole and vorozole.

Anastrozole↗

PubMed1998

Cerivastatin.

Cerivastatin is a synthetic HMG-CoA reductase inhibitor with high liver selectivity, which lowers plasma cholesterol levels by inhibiting endogenous cholesterol synthesis. In vitro, the affinity of cerivastatin for HMG-CoA reductase was higher than that of lovastatin, simvastatin and pravastatin. This higher enzyme affinity was reflected in vivo, with a lower ED50 (dose causing 50% inhibition) for cerivastatin in rats and beagle dogs compared with lovastatin. Cerivastatin 0.2 mg/day significantly reduced low density lipoprotein (LDL)-cholesterol, total cholesterol and triglyceride levels, and increased high density lipoprotein (HDL)-cholesterol levels, in patients with type IIa hypercholesterolaemia. Available data indicate that cerivastatin has a tolerability profile similar to that of other HMG-CoA reductase inhibitors. No drug interactions were observed when cerivastatin was coadministered with digoxin, warfarin, cimetidine or the antacid magnesium/aluminium hydroxide.

Animals↗

PubMed1998

Moexipril. A review of its use in the management of essential hypertension.

UNLABELLED: Moexipril is a prodrug which is hydrolysed after oral administration to its active metabolite moexiprilat, an inhibitor of the angiotensin converting enzyme (ACE). Once daily administration of moexipril 7.5 or 15 mg effectively reduces blood pressure in patients with essential hypertension (including the elderly and postmenopausal women with this condition). In double-blind randomised comparative studies, moexipril 7.5 to 15 mg once daily showed similar efficacy to other antihypertensive agents, including captopril, hydrochlorothiazide, atenolol, metoprolol, sustained release verapamil and nitrendipine. Combined therapy with hydrochlorothiazide and moexipril had a significantly greater antihypertensive effect than either agent alone. Moexipril is well tolerated by the majority of patients and compares well in this respect with other antihypertensive agents. Its tolerability profile appears to be characteristic of ACE inhibitors as a class (the most common adverse events being headache, symptoms of upper respiratory tract infection and cough). Moexipril generally had no clinically significant effect on lipid, glucose or electrolyte metabolism or haematological parameters, and, in particular, it was not associated with any significant changes in lipid or glucose metabolism in postmenopausal women (with or without hormone replacement therapy). CONCLUSIONS: Once daily moexipril is a useful agent for the treatment of essential hypertension, which compares well with currently available options in terms of clinical efficacy and tolerability. In addition, clinical experience to date supports its use in postmenopausal women.

Age Factors↗

PubMed1998

Intranasal azelastine. A review of its efficacy in the management of allergic rhinitis.

UNLABELLED: Azelastine, a phthalazinone compound, is a second generation histamine H1 receptor antagonist which has shown clinical efficacy in relieving the symptoms of allergic rhinitis when administered as either an oral or intranasal formulation. It is thought to improve both the early and late phase symptoms of rhinitis through a combination of antihistaminic, antiallergic and anti-inflammatory mechanisms. Symptom improvements are evident as early as 30 minutes, after intranasal administration of azelastine [2 puffs per nostril (0.56mg)] and are apparent for up to 12 hours in patients with seasonal allergic rhinitis (SAR). The effect on nasal blockage is variable: in some studies objective and/or subjective assessment showed a reduction in blockage, whereas in other studies there was no improvement. Intranasal azelastine 1 puff per nostril twice daily is generally as effective as standard doses of other antihistamine agents including intranasal levocabastine and oral cetirizine, ebastine, loratadine and terfenadine at reducing the overall symptoms of rhinitis. The relative efficacies of azelastine and intranasal corticosteroids (beclomethasone and budesonide) remain unclear. However, overall, the corticosteroids tended to improve rhinitis symptoms to a greater extent than the antihistamine. Azelastine was well tolerated in clinical trials and postmarketing surveys. The most frequently reported adverse events were bitter taste, application site irritation and rhinitis. The incidence of sedation did not differ significantly between azelastine and placebo recipients and preliminary report showed cardiovascular parameters were not significantly altered in patients with perennial allergic rhinitis (PAR). CONCLUSION: Twice-daily intranasal azelastine offers an effective and well tolerated alternative to other antihistamine agents currently recommended for the symptomatic relief of mild to severe SAR and PAR in adults and children (aged > or = 12 years in the US; aged > or = 6 years in some European countries including the UK). The rapid onset, confined topical activity and reduced sedation demonstrated by the intranasal formulation of azelastine may offer an advantage over other antihistamine agents, although this has yet to be confirmed.

Administration, Intranasal↗

PubMed1998

Dexrazoxane. A review of its use as a cardioprotective agent in patients receiving anthracycline-based chemotherapy.

UNLABELLED: Dexrazoxane has been used successfully to reduce cardiac toxicity in patients receiving anthracycline-based chemotherapy for cancer (predominantly women with advanced breast cancer). The drug is thought to reduce the cardiotoxic effects of anthracyclines by binding to free and bound iron, thereby reducing the formation of anthracycline-iron complexes and the subsequent generation of reactive oxygen species which are toxic to surrounding cardiac tissue. Clinical trials in women with advanced breast cancer have found that patients given dexrazoxane (about 30 minutes prior to anthracycline therapy; dexrazoxane to doxorubicin dosage ratio 20:1 or 10:1) have a significantly lower overall incidence of cardiac events than placebo recipients (14 or 15% vs 31%) when the drug is initiated at the same time as doxorubicin. Cardiac events included congestive heart failure (CHF), a significant reduction in left ventricular ejection fraction and/or a > or = 2-point increase in the Billingham biopsy score. These results are supported by the findings of studies which used control groups (patients who received only chemotherapy) for comparison. The drug appears to offer cardiac protection irrespective of pre-existing cardiac risk factors. In addition, cardiac protection has been shown in patients given the drug after receiving a cumulative doxorubicin dose > or = 300 mg/m2. It remains to be confirmed that dexrazoxane does not affect the antitumour activity of doxorubicin: although most studies found that clinical end-points (including tumour response rates, time to disease progression and survival duration) did not differ significantly between treatment groups, the largest study did show a significant reduction in response rates in dexrazoxane versus placebo recipients. Dexrazoxane permits the administration of doxorubicin beyond standard cumulative doses; however, it is unclear whether this will translate into prolonged survival. Preliminary results (from small nonblind studies) indicate that dexrazoxane reduces cardiac toxicity in children and adolescents receiving anthracycline-based therapy for a range of malignancies. The long term benefits with regard to prevention of late-onset cardiac toxicity remain unclear. With the exception of severe leucopenia [Eastern Cooperative Oncology Group (ECOG) grade 3/4 toxicity], the incidence of haematological and nonhaematological adverse events appears similar in patients given dexrazoxane to that in placebo recipients undergoing anthracycline-based chemotherapy. Although preliminary pharmacoeconomic analyses have shown dexrazoxane to be a cost-effective agent in women with advanced breast cancer, they require confirmation. CONCLUSIONS: Dexrazoxane is a valuable drug for protecting against cardiac toxicity in patients receiving anthracycline-based chemotherapy. Whether it offers protection against late-onset cardiac toxicity in patients who received anthracycline-based chemotherapy in childhood or adolescence remains to be determined. Further clinical experience is required to confirm that it does not adversely affect clinical outcome, that it is a cost-effective option, and to determine the optimal treatment regimen.

Animals↗

PubMed1998

Abciximab. An updated review of its use in ischaemic heart disease.

UNLABELLED: Abciximab is a glycoprotein IIb/IIIa receptor antagonist that has proven to be of significant clinical value in improving patient outcome after percutaneous coronary revascularisation. Primarily, the drug inhibits platelet aggregation, but it may also have anticoagulant activity and other beneficial effects, such as inhibiting migration and promoting apoptosis of smooth muscle cells. Large well designed studies have found administration of abciximab (as an adjunct to heparin and aspirin) during percutaneous coronary revascularisation to significantly reduce the incidence of ischaemic complications occurring in the 30 days after the procedure. Significant benefit, particularly on the incidence of myocardial infarction, was still evident after 6 months in 2 of 4 major trials. Abciximab provides particular benefit in patients with unstable angina or myocardial infarction who are undergoing percutaneous coronary revascularisation. The benefits of the drug are additive to those achieved with coronary stenting. Very preliminary data suggest that abciximab may improve coronary blood flow after myocardial infarction and allow reperfusion to be achieved with reduced thrombolytic doses. Caution is required to minimise the risk of bleeding complications with the use of abciximab in combination with heparin and aspirin. Careful patient selection, use of an appropriate heparin regimen, early vascular sheath removal and meticulous femoral artery access site care are recommended. Thrombocytopenia can occur with abciximab treatment, but severe cases are uncommon (< 2% of patients) and can be treated with platelet transfusions. The high acquisition cost of abciximab may be partly or fully offset by the costs averted by the reduced incidence of ischaemic complications and need for urgent and/or repeat revascularisation in high risk patients who receive the drug. However, if bleeding complications occur, this adds to treatment costs. Cost effectiveness analyses generally support the use of abciximab in high risk patients. CONCLUSIONS: Abciximab can be recommended for the prevention of acute ischaemic events in most patients undergoing percutaneous coronary revascularisation, but careful patient selection and strict adherence to the recommended treatment protocol are required to reduce the risk of bleeding complications and thrombocytopenia. Its use in high risk patients is largely supported by pharmacoeconomic data. Further pharmacoeconomic information is needed to establish the drug as a standard of care for all patient groups. The indications for abciximab are likely to expand as more data on its use in acute coronary syndromes become available.

Abciximab↗