Biomedical subjects

D Faulds

Publications and source records attributed to D Faulds.

At least 73 records · Page 4Linked to original sources

PubMed1995

Salmeterol. An appraisal of its quality-of-life benefits and potential pharmacoeconomic positioning in asthma.

Salmeterol is a selective beta 2-receptor agonist with a long duration of action that permits twice daily administration. It is effective in the prophylaxis of asthma symptoms, including nocturnal and exercise-induced asthma, and it has shown clinical benefits in both adults and children. Because of its slow onset of action, salmeterol is not intended for relief of acute symptoms. The addition of salmeterol 50 micrograms twice daily to existing asthma therapy has a positive effect on patient quality of life in the short term (up to 3 months), as assessed by the Living With Asthma Questionnaire and Asthma Quality of Life Questionnaire. This improvement in well-being appears to be greater than that associated with salbutamol (albuterol). Furthermore, in patients with asthma symptoms despite inhaled corticosteroid therapy, a reduced dose of corticosteroid plus salmeterol produced a greater improvement in quality of life as assessed by a daily symptom diary (but not by the Living With Asthma Questionnaire), and was more clinically effective than a higher dose of corticosteroid alone. Evaluation of the effects of salmeterol on quality of life compared with other standard therapies, and extension of these results into the long term are required to consolidate these conclusions. Salmeterol 50 micrograms twice daily was associated with an estimated incremental cost of 736 pounds per symptom-free patient in the final week of 7.5 months' therapy, 648 pounds per patient with improved morning (am) peak expiratory flow rate (PEFR) and 1013 pounds per patient with improved evening (pm) PEFR compared with salbutamol (400 micrograms twice daily) in a cost-effectiveness analysis. However, these results should be tested by sensitivity analyses and compared with the incremental costs of other asthma interventions more applicable to recommended clinical practice. The cost effectiveness of salmeterol relative to other asthma therapies, and the effect of salmeterol on patient quality of life in the long term require further investigation. However, when added to existing asthma therapy, salmeterol improves patient quality of life in the short term (up to 3 months). It may also have some beneficial effects on patient well-being when used to provide a steroid-sparing effect.

Adult↗

PubMed1994

Cyproterone. A review of its pharmacology and therapeutic efficacy in prostate cancer.

Cyproterone (cyproterone acetate) is a steroidal antiandrogenic agent that inhibits the action of adrenal and testicular androgens on prostatic cells. Additionally, its progestogenic activity causes a centrally mediated reduction in testicular secretion of androgens. Studies have demonstrated the effectiveness of cyproterone monotherapy in patients with prostate cancer, and for those in whom orchiectomy is not an acceptable option cyproterone may be a useful alternative. In addition, the drug may be administered in combination with surgical or gonadotrophin-releasing hormone (GnRH) agonist-mediated castration to ensure ablation of adrenal androgens. However, the effectiveness of cyproterone in combination with these forms of testicular androgen deprivation remains to be fully established. Trials to date have not demonstrated prolonged survival in patients receiving the combination therapy. Importantly, however, cyproterone does prevent acute exacerbation of disease during initial treatment with a GnRH agonist. Furthermore, combination therapy tends to be associated with a lower incidence of hot flushes than GnRH agonist-mediated or surgical castration alone. Thus, cyproterone 200 mg/day has proven efficacy in preventing acute flare of disease and reducing the incidence of hot flushes associated with GnRH agonist therapy or orchiectomy. It may also facilitate maximal androgen deprivation in patients receiving GnRH agonist therapy. If this drug is used as monotherapy, dosages of 250 mg/day or greater will probably be required.

Cyproterone↗

PubMed1994

Vinorelbine. A review of its pharmacological properties and clinical use in cancer chemotherapy.

Vinorelbine is a semisynthetic vinca alkaloid with a broad spectrum of antitumour activity. The drug is effective as a single agent in inoperable/advanced non-small cell lung cancer (NSCLC), producing objective response rates of about 15 to 30%, and as first-line or later chemotherapy for metastatic spread in advanced breast cancer. Combining vinorelbine with standard chemotherapeutic regimens improves response rates in these indications compared with vinorelbine monotherapy: in NSCLC response rates increase to 30 to 50% when vinorelbine is administered with cisplatin. Importantly, survival was prolonged by a further 9 weeks with this combination in a trial in > 600 patients with NSCLC. Comparative trials evaluating vinorelbine in women with advanced breast cancer are few at present. However, results suggest greater efficacy for vinorelbine than for melphalan as second-line chemotherapy, and similar efficacy for vinorelbine plus doxorubicin compared with doxorubicin plus 2 other drugs as first-line chemotherapy. Vinorelbine has tended to yield superior response rates when compared with vindesine, and appears to have greater haematological toxicity (i.e. granulocytopenia) but less neurological toxicity (peripheral neuropathy, constipation, loss of deep tendon reflexes) than this agent. Myelosuppression is the most frequent cause of vinorelbine treatment delay or dose reduction. Other consequences of vinorelbine therapy are those typically seen with antineoplastic agents, such as diarrhoea, nausea and vomiting, and alopecia. However, these are rarely severe. Early clinical investigations indicate that the antitumour effects of vinorelbine in other malignancies including ovarian carcinoma, lymphoma and head and neck cancer warrant further exploration, as does the efficacy of the drug relative to standard approaches and its possible beneficial effects on quality of life of cancer patients. Clarification is also required of the feasibility of an oral dosage form, which in preliminary investigations has shown some efficacy in NSCLC, but a variable response rate and high incidence of gastrointestinal disturbances in women with breast cancer. Thus, vinorelbine as a single agent or combined palliative therapy is effective against advanced NSCLC, and as first- or second-line chemotherapy in advanced breast cancer. This semisynthetic vinca alkaloid has a manageable tolerability profile and potential for use in other malignancies and as an oral formulation. With these attributes, vinorelbine is a valuable option which extends the range of treatments available for these difficult-to-treat malignancies.

Absorption↗

PubMed1994

Cisapride. An updated review of its pharmacology and therapeutic efficacy as a prokinetic agent in gastrointestinal motility disorders.

Cisapride is an orally administered prokinetic agent which facilitates or restores motility throughout the length of the gastrointestinal tract. It is a substituted piperidinyl benzamide, chemically related to metoclopramide, but unlike metoclopramide, cisapride is largely devoid of central depressant or antidopaminergic effects. In placebo-controlled trials, cisapride improved healing rates and symptoms in both adults and children with reflux oesophagitis. Maintenance therapy with cisapride at half the healing dose is effective in reducing the incidence of relapse. Symptoms are also alleviated in patients with functional dyspepsia, and gastric emptying and symptoms are improved in most patients with gastroparesis, an effect which is sustained during long term administration. However, the efficacy of cisapride in end-stage gastroparesis remains less clear. Cisapride increases stool frequency in patients with chronic constipation, and limited data suggest that the drug may also be beneficial in treating chronic intestinal pseudo-obstruction and irritable bowel syndrome. Cisapride demonstrated efficacy comparable with or superior to that of metoclopramide, and was at least as effective as cimetidine and ranitidine in patients with reflux disease. In patients with functional dyspepsia, cisapride has shown at least equal efficacy to domperidone, metoclopramide and ranitidine, and superior efficacy to cimetidine in the small comparative trials conducted to date. Adverse effects in patients receiving cisapride are generally transient and mild, with abdominal cramping, borborygmi, diarrhoea or loose stools most frequently reported. Central nervous system adverse effects are rare. Thus, with its favourable tolerability profile and demonstrated efficacy in a variety of gastrointestinal motility disorders, the position of cisapride as a valuable agent in the management of patients with gastrointestinal motility disorders is strengthening. However, larger well-controlled comparative trials of the drug with other agents are necessary before the relative position of cisapride in therapy can be categorically defined.

Animals↗

PubMed1994

Aciclovir. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy.

Aciclovir (acyclovir) is a nucleoside analogue with antiviral activity in vitro against the herpes simplex viruses (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpesvirus 6 (HHV-6). Topical, oral or intravenous aciclovir is well established in the treatment of ophthalmic, mucocutaneous and other HSV infections, with intravenous aciclovir the accepted treatment of choice in herpes simplex encephalitis. The efficacy of aciclovir is increased with early (preferably during the prodromal period) initiation of treatment but, despite significant clinical benefit, viral latency is not eradicated, and pretreatment frequencies of recurrence usually continue after episodic acute treatment is completed. Intravenous administration has also shown benefit in the treatment of severe complications of HSV infection in pregnancy, and neonatal HSV infections. Recurrence of HSV has been completely prevented or significantly reduced during suppressive therapy with oral aciclovir in immunocompetent patients. Use of oral aciclovir is effective but controversial in the treatment of otherwise healthy individuals with varicella (chickenpox), and in some countries it has been recommended for use only in cases which may be potentially severe. The development of rash and pain associated with herpes zoster (shingles) is attenuated with oral or intravenous aciclovir therapy, ocular involvement is prevented, and post-herpetic neuralgia appears to be decreased. Similarly, in a few patients with zoster ophthalmicus, oral aciclovir has reduced the frequency and severity of long term ocular complications and post-herpetic neuralgia, and herpes zoster oticus is improved with intravenous aciclovir. Oral aciclovir has prevented recurrence of HSV genital or orofacial infections during suppressive therapy in > 70% of immunocompetent patients in most clinical trials. Suppression of latent HSV, VZV and CMV infections has been achieved in many immunocompromised patients receiving the oral or intravenous formulations. Aciclovir also appears to offer partial protection from invasive CMV disease in CMV-seropositive bone marrow transplant recipients. The few comparative trials published have shown aciclovir to be at least as effective as other investigated antivirals in the treatment of HSV infections in immunocompetent patients, and more effective than inosine pranobex in the prophylaxis of genital herpes. Similarly, in isolated clinical trials, oral aciclovir appears as effective as topical idoxuridine and oral brivudine in some parameters in immunocompetent patients with VZV infections, and the intravenous formulation appears at least as effective as oral brivudine and intravenous vidarabine in treating these infections in immunocompromised patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Acyclovir↗

PubMed1994

Inhaled fluticasone propionate. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in asthma.

Fluticasone propionate is an androstane carbothioate glucocorticosteroid with almost twice the topical anti-inflammatory potency of beclomethasone dipropionate. Importantly, it is not appreciably absorbed from the gastrointestinal tract. However, the fraction of active drug absorbed from the lungs after inhalation, and therefore total systemic availability, has yet to be determined. Inhaled fluticasone propionate administered at dosages of 1500 micrograms/day for 1 year or 2000 micrograms/day for 6 weeks did not cause clinically significant pituitary-adrenal suppression. Preliminary data from 2 published trials also indicate no significant effect on growth in children. However, wider clinical experience is needed to clarify the effects of long term administration on pituitary-adrenal function, bone metabolism and attainment of adult height in children. In clinical studies, inhaled fluticasone propionate was at least as effective as beclomethasone dipropionate or budesonide when administered at half the dosage of the comparators in patients with mild to moderate or severe asthma. Limited data suggest that fluticasone propionate also has considerable potential in the management of childhood asthma. In trials of up to 1 year in duration, fluticasone propionate appeared to be well tolerated by both adults and children. Whether an improved tolerability profile compared with other corticosteroids is a major clinical benefit of the extremely low oral bioavailability of inhaled fluticasone propionate requires confirmation. Nevertheless, on the basis of available data from initial clinical trials of mostly limited duration, inhaled fluticasone propionate offers an effective treatment option for the management of asthma, with the potential of an enhanced safety profile.

Administration, Inhalation↗

PubMed1994

Parnaparin. A review of its pharmacology, and clinical application in the prevention and treatment of thromboembolic and other vascular disorders.

Parnaparin is a low molecular weight (LMW) heparin which, like other members of its class, apparently demonstrates a greater antithrombotic effect relative to its anticoagulant activity when compared with the unfractionated heparin (heparin) from which it is derived. Moreover, subcutaneous parnaparin has a greater bioavailability and longer half-life than heparin, permitting once-daily administration for the prophylaxis of deep venous thrombosis (DVT) or the treatment of established vascular disorders. Prophylaxis with a 7-day regimen of parnaparin 3200 or 6400 IUaXa/day has consistently been associated with a lower incidence of confirmed DVT compared with usual prophylactic regimens of heparin. This intertreatment difference reached statistical significance in a large multicentre study involving a total of 610 surgical patients (3.2% for parnaparin vs 6.3% for heparin). Thus far, however, comparisons of parnaparin with other LMW heparins for this indication are unavailable. Parnaparin has demonstrated equivalent efficacy to heparin in the treatment of established vascular disorders, including phlebopathies and related syndromes, as well as peripheral arterial occlusive disease. Parnaparin also showed some benefit as an adjunctive therapy in patients with angina pectoris. The risk of general bleeding appears to be similar with parnaparin or heparin, although parnaparin results in fewer haematomas at the site of injection, partly because of the less frequent administration regimen. Parnaparin has also been associated with a lower incidence of pain and/or burning sensation at the injection site compared with heparin. As with other LMW heparins, the possibility that parnaparin will be infrequently associated with thrombocytopenia cannot be excluded. Thus, parnaparin may be preferred over traditional heparin for the prophylaxis of thromboembolic events in surgical patients (particularly those at high risk for DVT), as well as the treatment of established vascular disorders with a thrombotic aetiology. Compared with heparin, parnaparin offers the advantages of a more convenient administration regimen coupled with improved local tolerability. However, the therapeutic advantages of parnaparin relative to other LMW heparins have yet to be established in large scale comparative trials.

Absorption↗

PubMed1994

Tiapride. A review of its pharmacology and therapeutic potential in the management of alcohol dependence syndrome.

Tiapride, an atypical neuroleptic agent, is a selective dopamine D2-receptor antagonist with little propensity for causing catalepsy and sedation. It shows preferential activity at receptors previously sensitised to dopamine and those located extrastriatally. Tiapride demonstrates antidyskinetic activity reflecting antidopaminergic actions, and also anxiolytic activity mediated by mechanisms that are poorly understood. Unlike the benzodiazepines, tiapride does not affect vigilance and has a low potential for interaction with alcohol (ethanol), and possibly for abuse. Tiapride facilitates management of alcohol withdrawal, but its use in patients at risk of severe reactions in acute withdrawal should be accompanied by adjunct therapy for hallucinosis and seizures. Since it may prove difficult to identify such patients and there is also a small risk of neuroleptic malignant syndrome (particularly with parenteral administration), the usefulness of tiapride in this setting is likely to be limited. Nevertheless, relative freedom from the complications associated with benzodiazepine therapy suggest a possible role for the drug in the treatment of individuals suitable for alcohol detoxification as outpatients. Preliminary clinical studies in alcoholic patients following detoxification have shown that tiapride ameliorates psychological distress, improves abstinence, and reduces drinking behaviour, and in the short term facilitates reintegration within society. These benefits were associated with reduced consumption of health care resources. However, the potential risk of tardive dyskinesia at the dosage employed (300 mg/day) requires evaluation and necessitates medical supervision. Thus, with its lack of adverse effects on vigilance and low propensity for interaction with alcohol and possibly for abuse, tiapride will probably find particular use in the management of alcoholic patients suitable for detoxification in an outpatient setting; and, if initial findings are confirmed in large well-designed trials, in the short term (< or = 6 months) therapy of reformed alcoholic patients under medical supervision.

Administration, Oral↗

PubMed1994

Roxithromycin. An update of its antimicrobial activity, pharmacokinetic properties and therapeutic use.

Roxithromycin is a derivative of the macrolide antibacterial erythromycin with in vitro antibacterial activity resembling that of the parent compound. The drug has activity against some Staphylococcus spp., many Streptococcus spp., Moraxella (Branhamella) catarrhalis, Mycoplasma pneumoniae, Legionella pneumophila and Chlamydia trachomatis as well as many less common organisms. Measured using recently proposed guidelines, roxithromycin has in vitro activity against Haemophilus influenzae. In comparison with that of its parent compound, the pharmacokinetic profile of roxithromycin is characterised by high plasma, tissue and body fluid concentrations and a long half-life permitting an extended dosage interval. Roxithromycin has proven clinical efficacy in upper and lower respiratory infections, skin and soft tissue infections, urogenital infections and orodental infections, and appears to be as effective as more established treatments including erythromycin, amoxicillin/clavulanic acid and cefaclor. The drug has also shown promise in a variety of more specialised indications including opportunistic infections in human immunodeficiency virus (HIV)-positive patients and as part of a Helicobacter pylori eradication regimen. Roxithromycin is very well tolerated with an overall incidence of adverse events of approximately 4%. Thus, roxithromycin is an attractive therapeutic alternative in its established indications, especially when the option of once-daily administration is considered.

Absorption↗

PubMed1994

Lansoprazole. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy in acid-related disorders.

Lansoprazole is a benzimidazole derivative that effectively decreases gastric acid secretion, regardless of the primary stimulus, via inhibition of gastric H+,K(+)-adenosine triphosphatase (ATPase). It provides effective symptom relief and healing of peptic ulcer and reflux oesophagitis after 4 to 8 weeks of therapy and appears to prevent recurrence of lesions when administered as maintenance therapy. When administered at therapeutic dosages, lansoprazole produced higher healing rates than ranitidine or famotidine in patients with duodenal and gastric ulcers. Lansoprazole heals duodenal ulcers more rapidly than ranitidine or famotidine. Relief of ulcer symptoms in lansoprazole recipients is at least equivalent to, and tends to be more rapid than, that in patients receiving histamine H2-receptor antagonists. In comparisons with omeprazole 20 mg/day, lansoprazole 30 mg/day produced duodenal ulcer healing more rapidly and reduced ulcer pain to a greater extent at 2 weeks, but overall healing rates were similar after 4 weeks of therapy. At therapeutic dosages, lansoprazole produces superior healing and symptom relief of reflux oesophagitis in comparison with ranitidine, and it tends to relieve heartburn more effectively than omeprazole, although both agents produce equivalent healing. Healing of peptic ulcers or reflux oesophagitis refractory to histamine H2-receptor antagonists occurs after 8 weeks in the majority of patients treated with lansoprazole, and lansoprazole and omeprazole demonstrate similar efficacy in patients with refractory peptic ulcers. In patients with Zollinger-Ellison syndrome, lansoprazole effectively controls mean basal gastric acid output. Lansoprazole is generally well tolerated in clinical trials. The incidence of adverse effects is similar to that of omeprazole, ranitidine and famotidine in comparative studies. Combination therapy with lansoprazole and antibacterial agents such as amoxicillin, tinidazole, roxithromycin and/or metronidazole appears to eradicate Helicobacter pylori in 22 to 80% of patients with this organism. Limited data also suggest that lansoprazole may have superior activity against H. pylori in comparison with omeprazole, although the clinical relevance of this preliminary finding requires further confirmation. Thus, lansoprazole may be considered as alternative to existing antisecretory agents available for the treatment of acid-related disorders, particularly because it may provide more rapid healing and relief of symptoms.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1994

Nimesulide. An update of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy.

Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID) administered orally or rectally twice daily for a variety of inflammatory and pain states. In mostly short term studies (up to 4 weeks), it was effective in reducing pain associated with osteoarthritis, cancer, thrombophlebitis, oral surgery and dysmenorrhoea in adults, reducing pain associated with general surgery in adults and children, and pain, fever and inflammation accompanying respiratory tract infections, otorhinolaryngological diseases and traumatic injury in adults and children. Nimesulide appeared to be at least as effective as other NSAIDs in all of these indications. Nimesulide has been well tolerated by adult, elderly and paediatric patients in clinical trials and large postmarketing surveillance studies. In general qualitative terms nimesulide exhibits the usual adverse events associated with NSAIDs (gastrointestinal, dermatological and neurological). However, it has a pharmacodynamic profile suggestive of a possibly reduced propensity to cause adverse gastrointestinal effects, although this has not been conclusively demonstrated in comparative clinical trials, many of which showed a similar incidence of such effects for nimesulide and the comparator agent. Additionally, nimesulide has been well tolerated by most aspirin (acetylsalicylic acid)- and/or NSAID-intolerant patients and in patients with asthma. Thus, available evidence indicates that nimesulide is an effective and well tolerated alternative to other NSAIDs in the short term treatment of pain and inflammation of osteoarthritis and various other causes.

Animals↗

PubMed1994

Abciximab (c7E3 Fab). A review of its pharmacology and therapeutic potential in ischaemic heart disease.

Abciximab (c7E3 Fab) is a chimaeric human-murine monoclonal antibody Fab (fragment antigen binding) fragment. It binds to the platelet glycoprotein IIb/IIIa receptor and inhibits platelet aggregation. In two double-blind placebo-controlled trials, abciximab therapy reduced the incidence of ischaemic complications during the initial postoperative period (30 days or until hospital discharge) in high-risk patients undergoing percutaneous coronary angioplasty or directional atherectomy. It also reduced the incidence of clinical restenosis compared with placebo during longer term (6 months) follow-up of these patients. Although abciximab delayed the need for coronary artery bypass graft surgery, it did not reduce the proportion of patients ultimately requiring this procedure. The drug was generally well tolerated in clinical trials, with bleeding complications being the major adverse event. Abciximab is at an early stage of its clinical introduction and, not surprisingly, some aspects of its use remain to be further assessed. Nevertheless, results show the addition of abciximab to standard aspirin plus heparin therapy during coronary angioplasty or directional atherectomy improves the outcome of the revascularisation procedure in patients with a high risk of subsequent acute ischaemic complications. The results of further trials defining the optimum dosage of heparin when administered with abciximab, and evaluating the role of abciximab in a wider range of patients, are eagerly awaited.

Abciximab↗

PubMed1994

Filgrastim. A review of its pharmacological properties and therapeutic efficacy in neutropenia.

Filgrastim, a recombinant human granulocyte colony-stimulating factor (G-CSF), has identical biological activity to that of endogenous human G-CSF, but differs in that it contains an N-terminal methionine residue and is not glycosylated. It principally stimulates activation, proliferation and differentiation of neutrophil progenitor cells and has been evaluated in the treatment of patients with various neutropenic conditions, both iatrogenic and disease-related. Two comparative studies have demonstrated that prophylactic administration of filgrastim 230 micrograms/m2/day significantly reduces the incidence, duration and severity of neutropenia in patients with previously untreated small-cell lung cancer receiving standard-dose chemotherapy with CDE (cyclophosphamide, doxorubicin plus etoposide). Concomitant with the amelioration of neutropenia, the incidence of febrile neutropenia was significantly reduced by 50% and there were 35 and 50% decreases in hospitalisation rates and intravenous antibiotic requirements. Since not all patients receiving standard-dose chemotherapy are at risk of infectious complications, prophylactic filgrastim use may be reserved for those patients who have developed febrile neutropenia during a previous cycle of the same regimen. This strategy may prove less costly, although potential savings must be weighed against a greater risk of patient morbidity and reduced quality of life. When combined with standard intravenous antibiotic therapy, filgrastim further decreases morbidity in patients with established febrile neutropenia and may have a positive impact on overall treatment costs by shortening the length of hospitalisation. Attention is focused on the use of haematopoietic growth factors to support dose-intensification of chemotherapy with a view to improving treatment outcomes in patients with chemo-responsive tumours. Filgrastim, used alone, permits modest increases in dose-intensity and/or dose-escalation of some standard-dose chemotherapy regimens. Moreover, the drug has proven useful as an adjunct to myeloablative chemotherapy followed by stem cell rescue with autologous bone marrow transplantation and/or peripheral blood progenitor cells. However, the impact of these dose-intensification approaches on survival remains to be determined in well-controlled clinical studies. Filgrastim is effective in increasing the neutrophil count and decreasing morbidity in patients with severe chronic neutropenia, including Kostmann's syndrome, and in idiopathic and cyclic neutropenia. In addition, filgrastim has accelerated neutrophil recovery in patients with idiosyncratic drug-induced agranulocytosis. Available data indicate that filgrastim is generally well tolerated. The most frequent adverse reaction is mild to moderate medullary bone pain, reported by approximately 20% of patients, although this can generally be controlled using simple analgesics without the need to discontinue treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Paclitaxel. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of cancer.

Paclitaxel is a new anticancer agent with a novel mechanism of action. It promotes polymerisation of tubulin dimers to form microtubules and stabilises microtubules by preventing depolymerisation. In noncomparative trials, continuous infusion of paclitaxel 110 to 300 mg/m2 over 3 to 96 hours every 3 to 4 weeks produced a complete or partial response in 16 to 48% of patients with ovarian cancer and 25 to 61.5% of patients with metastatic breast cancer, many of whom were refractory to treatment with cisplatin or doxorubicin, respectively. 23 to 100% of patients with ovarian cancer achieved complete or partial responses with paclitaxel in combination with cisplatin, carboplatin, cyclophosphamide, altretamine and/or doxorubicin. Similarly, response rates of 30 to 100% were observed with paclitaxel plus doxorubicin, cisplatin, mitoxantrone and/or cyclophosphamide in patients with metastatic breast cancer. Comparative trials in patients with advanced ovarian cancer showed paclitaxel therapy to produce greater response rates than treatment with parenteral hydroxyurea (71 vs 0%) or cyclophosphamide (when both agents were combined with cisplatin) [79 vs 63%]. Paclitaxel was also more effective than mitomycin in 50 patients with previously untreated breast cancer (partial response in 20 vs 4% of patients). Paclitaxel therapy also produced promising results in patients with advanced squamous cell carcinoma of the head and neck, malignant melanoma, advanced non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), germ cell cancer, urothelial cancer, oesophageal cancer, non-Hodgkin's lymphoma or multiple myeloma, and was successfully combined with cisplatin, carboplatin and/or etoposide in patients with NSCLC, SCLC or advanced squamous cell carcinoma of the head and neck. Hypersensitivity reactions were initially a concern with administration of paclitaxel, although current dosage regimens have reduced the incidence of these events to less than 5%. The major dose-limiting adverse effects of paclitaxel are leucopenia (neutropenia) and peripheral neuropathy. Other haematological toxicity was generally mild. Cardiac toxicity was reported in small numbers of patients and most patients developed total alopecia. Several aspects of paclitaxel use remain to be clarified, including the optimal treatment schedule and infusion time, confirmation of the tolerability profile and efficacy of combination regimens in an expanded range of malignancies. Long term follow-up of paclitaxel recipients will also allow the effects of the drug on patient survival to be determined. Nevertheless, paclitaxel is a promising addition to the current therapies available, with significant activity reported in patients with advanced ovarian or breast cancer or other types of tumors.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Hepatitis B vaccine: a pharmacoeconomic evaluation of its use in the prevention of hepatitis B virus infection.

Worldwide, hepatitis B virus (HBV) infection is a major cause of acute and chronic hepatitis, cirrhosis and hepatocellular cancer. Infants and children are at the greatest risk of becoming chronically infected with HBV, and therefore at the greatest risk of developing long term sequelae. Immunisation against HBV represents an important means of controlling the disease. Hepatitis B vaccines are effective in preventing HBV infection and are well tolerated. In addition, they are suitable for integration into mass neonatal vaccination programmes. While there are considerable economic data concerning hepatitis B vaccination, differing methodologies and end-points present a challenge in reviewing these studies for consistent findings. Immunisation strategies should be implemented in accordance with local area disease incidence and patterns of HBV transmission, and will be influenced by regional budgetary constraints. In conclusion, universal neonatal vaccination is both cost effective and appropriate for control of HBV infection in regions of medium or high endemicity. In low endemicity areas, selective vaccination of high-risk groups is cost effective, but its impact on the incidence of HBV infection will depend on the ability to reach these groups. Expanded vaccination strategies may be appropriate where local conditions prohibit efficient access to high-risk groups.

Adolescent↗

PubMed1994

Hormone replacement therapy: I. A pharmacoeconomic appraisal of its therapeutic use in menopausal symptoms and urogenital estrogen deficiency.

Menopause and the accompanying reduction in estrogen production may cause a number of symptoms in women which include hot flushes, sweating, mood and sleep disturbances, fatigue and urogenital dysfunction. The effectiveness of estrogen-based hormone replacement therapy (HRT) in ameliorating these symptoms, and in preventing long term sequelae such as osteoporosis, is well established. Comparative trials indicate that oral conjugated estrogens 0.625mg, oral ethinyl estradiol 0.02mg and transdermal estradiol 0.05mg have equivalent efficacy in relief of mild to moderate menopausal symptoms and prevention of bone mineral loss. Concomitant progestogen therapy is usually prescribed for women with intact uteri to protect against endometrial hyperplasia and carcinoma. The addition of progestogen maintains and may even enhance the bone-conserving effects of estrogen, and continuous regimens appear to reduce the incidence of irregular menses. Adverse reactions are predominantly local skin irritation with transdermal preparations (14% of patients) and systemic effects common to most forms of HRT including breast tenderness, flushing, headache and irregular bleeding, occurring in less than or equal to 2% of patients. Data concerning the effect of HRT on quality of life are limited, but most analyses have assigned utility values of 0.99 for mild and 0.95 for severe menopausal symptoms. However, recent clinical data suggest that these utility values may underestimate the impact of menopausal symptoms on quality of life. The cost benefit and cost effectiveness of HRT in the treatment of menopausal symptoms have not been fully researched, although preliminary results suggest that conjugated estrogens and transdermal estradiol compare well with alternative therapies such as veralipride and Chinese medicines. A Swedish study using a prevalence-based approach estimated that estriol treatment in all women with urinary incontinence aged greater than or equal to 65 years resulted in monetary savings compared with treating 20% of women. Cost-utility data indicated that the change in quality-adjusted life years (QALYs) with HRT was always positive, but the degree of change was determined by the baseline assumptions. Estimated changes in QALYs with HRT ranged from 0.006 for 5 years of treatment with unopposed estrogen in women with intact uteri, to 0.5 for 10 years of the same treatment in women with severe menopausal symptoms following hysterectomy. Compliance with HRT is suboptimal as 5 to 50% of women withdraw from therapy, thereby increasing costs per year of life saved.(ABSTRACT TRUNCATED AT 400 WORDS)

Climacteric↗

PubMed1994

Hormone replacement therapy: II. A pharmacoeconomic appraisal of its role in the prevention of postmenopausal osteoporosis and ischaemic heart disease.

The reduction in estrogen production that occurs at menopause is associated with several long term sequelae. There is an accelerated decrease in bone mineral density leading to an increased risk of osteoporotic fracture. Furthermore, changes in plasma lipid profiles and other cardiovascular parameters increase the risk of cardiovascular and cerebrovascular pathology. These effects are additional to the menopausal symptoms experienced by many women. The effectiveness of estrogen-based hormone replacement therapy (HRT) is well established in preventing bone mineral loss and also in ameliorating menopausal symptoms, with the addition of progestogen maintaining or possibly enhancing the bone-conserving effects. However, prolonged therapy appears to be necessary to conserve bone mineral density and prevent osteoporotic fracture, particularly in women aged greater than or equal to 75 years, and compliance with long term therapy is likely to be poor. Estrogen favourably alters plasma lipid profiles, improves coronary blood flow and inhibits the central distribution of body fat. Effects on haemostatic mechanisms and coronary vasomotor response to acetylcholine have also been suggested as mechanisms for the beneficial effects of estrogen on ischaemic heart disease. The effects of concomitant progestogens on plasma lipids are variable, and may depend on the type, dosage regimen and duration of therapy. Pharmacoeconomic analyses of HRT have used a variety of risk assumptions. Relative risk rates of osteoporotic fracture and mortality from myocardial infarction are assumed to reduce to 0.5 after greater than 5 years' therapy. Long term HRT is associated with a relative risk of approximately 1.3 for breast cancer, whereas the relative risk of endometrial cancer is 4.0 to 8.0 in women with intact uteri receiving prolonged unopposed estrogen therapy. HRT that includes progestogens is assumed to incur no added risk of endometrial cancer, and this treatment is generally recommended for women with intact uteri. Data concerning the effect of HRT on quality of life are limited and utility values for hip fracture of 0.95 to 0.36 have been assigned, depending on assumptions of disability. Cost-benefit, cost-effectiveness and cost-utility studies evaluating HRT in the prevention of osteoporotic fracture have differed widely in methodology, making comparison of results difficult. HRT appears to be most economically useful in the prevention of fracture if used in women who have undergone hysterectomy, in women with high risk of osteoporotic fracture or ischaemic heart disease, and/or in women with menopausal symptoms.(ABSTRACT TRUNCATED AT 400 WORDS)

Breast Neoplasms↗

PubMed1993

Mifepristone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential.

Mifepristone is a potent oral antiprogestogen which acts at the level of the receptor, having a high affinity for the progesterone receptor. Most of the clinical trials have studied its efficacy in the termination of early pregnancy when used in conjunction with a low dosage of a prostaglandin analogue. In these studies, mifepristone 100 to 600mg administered as a single dose or over 3 or 4 days, 36 to 48 hours before a prostaglandin analogue given vaginally, intramuscularly or orally, induced complete abortion in about 95% of women. Used alone, mifepristone is an effective cervical priming agent prior to termination of first trimester pregnancy by vacuum aspiration, and facilitates termination of second trimester pregnancy by prostaglandin by reducing the interval between the start of prostaglandin treatment and termination, the cumulative prostaglandin dosage, and the adverse effects associated with these drugs. Mifepristone can also be used to induce labour in cases of intrauterine fetal death. Mifepristone has been shown to be an effective postcoital contraceptive with a likely emergency role, since its repeated use modifies the menstrual cycle. Pilot studies have been performed in unresectable meningioma and metastatic breast cancer, and in Cushing's syndrome. Mifepristone is generally well tolerated, and thus is an effective, appropriate, medical alternative to surgical termination of early pregnancy. It has as yet unexplored potential as a postcoital contraceptive and in oncology.

Contraceptives, Postcoital↗