Biomedical subjects

K L Goa

Publications and source records attributed to K L Goa.

At least 109 records · Page 6Linked to original sources

PubMed1996

Propofol. A pharmacoeconomic appraisal of its use in day case surgery.

Propofol is an intravenous anaesthetic agent that has become widely used in day case surgery. It induces anaesthesia rapidly and 'smoothly', is associated with a quick recovery and has a lower incidence of postoperative nausea and vomiting (PONV) than other agents. In studies comparing propofol with other intravenous anaesthetics (most commonly thiopental sodium) in day case surgery, the use of propofol as induction and/or maintenance anaesthesia was associated with a shorter time to intermediate recovery (street fitness or time to discharge), although the mean time difference was generally less than 1 hour. However, when compared with volatile anaesthetics (particularly desflurane), the differences in time to discharge were smaller. Propofol is also associated with less PONV than barbiturates, volatile anaesthetics or barbiturate/volatile anaesthetic combinations in the immediate postoperative period. The faster recovery time and the decreased incidence of PONV have potential pharmacoeconomic implications. Delayed recovery can increase the use of hospital resources and decrease patient throughput and PONV can incur costs due to an increase in adjunctive medications usage (e.g. antiemetics), nursing time or unintended admissions. The pharmacoeconomic significance of these properties of propofol requires formal evaluation. Pharmacoeconomic investigations, such as cost-effectiveness, cost-benefit and cost-minimisation studies, which include clinical outcome parameters are difficult to conduct in anaesthesia since there are no objective measures of equipotency between anaesthetic agents and because there is no specific health outcome associated with the delivery of anaesthesia. At present, cost-utility studies are not possible because there are no validated instruments for measuring utility in the provision of anaesthesia. To date, pharmacoeconomic analyses of propofol (and other anaesthetic agents) in day case surgery have been restricted to partial cost analyses. Only 2 of these have included the cost of drug wastage, an important consideration since propofol contains no preservative. With 1 exception, these studies have only included drug acquisition costs and propofol was reported to be approximately 1- to 3-fold as costly as other intravenous/inhalational agents. However, these limited analyses have little applicability since they do not include all relevant costs. In addition to drug acquisition costs, pharmacoeconomic studies should also include other direct costs such as the cost of adjunctive medications (including treatment necessary for adverse events), equipment and staff time, indirect costs such as loss of productivity and/or wages and intangible costs such as patient satisfaction and quality of life. A few studies have attempted to quantify some of these factors. Based on differences in recovery time, 2 studies have estimated a decreased demand for nursing staff time associated with the use of propofol compared with thiopental sodium/isoflurane. In addition, informal patient satisfaction assessments show propofol to be equal to or better than other anaesthetic agents. With these broader considerations, it thus remains for future studies to quantify the intangible and indirect costs associated with propofol anaesthesia, to determine whether differences in recovery between propofol and other agents (especially the newer inhalational anaesthetics) are of economic importance, and to identify those instances where propofol use provides the greatest value for available funds.

Ambulatory Surgical Procedures↗

PubMed1996

Enoxaparin. A pharmacoeconomic appraisal of its use in thromboembolic prophylaxis after total hip arthroplasty.

Total hip arthroplasty (THA) is a major orthopaedic procedure with a high risk of postoperative thromboembolism. Increasing demand for this type of surgery, together with its high cost, has led to examination of means by which the cost of THA may be minimised. Current clinical opinion favours the use of suitable pharmacological thromboprophylaxis in patients undergoing THA; such prophylaxis may be provided with subcutaneous standard unfractionated heparin (UFH), oral warfarin or subcutaneous low molecular weight heparin (LMWH). Traditionally, LMWHs have been perceived as being more expensive to use than UFH or warfarin because of their relatively high acquisition cost. However, recent pharmacoeconomic data have shown that cost savings are possible when LMWHs are used. This is attributed mainly to reduced frequency of administration, reductions in costs associated with diagnosis and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and the lack of need for laboratory monitoring of blood coagulation parameters. LMWHs have proportionally less anti-factor IIa (antithrombin) activity relative to anti-factor Xa activity than UFH. Enoxaparin, a LMWH with a mean molecular weight of 4 to 5kD, is reported to have approximately 5 times less activity against thrombin than UFH, for equivalent anti-factor Xa activity. Randomised clinical trials in patients undergoing THA have shown enoxaparin to be at least as effective as UFH in the prevention of DVT and PE, with consistent trends towards a lower incidence of DVT with enoxaparin than with UFH. Similar rates of haemorrhagic complications were reported for enoxaparin and UFH in most trials, although a significantly higher total transfusion requirement was reported for UFH than for enoxaparin in a double-blind study. A significantly higher incidence of bleeding was observed with UFH than with enoxaparin in another study, with similar transfusion requirements for both treatment groups. Cost comparisons in which costs were assigned retrospectively to clinical data have shown cost advantages for LMWHs in general over UFH when costs of administration, hospital bed occupancy and laboratory/radiology procedures are calculated. Cost savings with LMWHs were attributed mainly to reductions in the cost of managing thromboembolic complications in patients receiving these drugs. One meta-analysis showed a saving of $US50 000 (1993 figures) for LMWH over UFH (both subcutaneously twice daily) for every 1000 patients. Subcutaneous enoxaparin at a dosage of 30mg twice daily was shown to be more cost effective than oral warfarin in the prophylaxis of DVT and PE in 2 North American studies in which costs were related to outcomes. One study comprised the application of a decision analysis to a hypothetical group of 10 000 patients; an incremental cost effectiveness of $US12 288 (1993 figures) per death averted was reported for enoxaparin. Enoxaparin was also associated with an overall incremental cost effectiveness of $Can29 140 (1992 figures) per year of life saved (YLS) in the other study, in which costs were applied to clinical data obtained retrospectively from 10 randomised trials. Although no cost-effectiveness analyses have been carried out to compare enoxaparin with UFH, a UK cost comparison reported an overall cost saving of pounds 20 per patient (figures from 1989 to 1990) with enoxaparin 40mg once daily subcutaneously over subcutaneous UFH 5000IU 3 times daily. It has also been suggested that the use of once- or twice-daily enoxaparin in preference to UFH may reduce the overall length of hospital stay; a significant difference emerged in 1 analysis (9.9 or 9.5 vs 11.3 days). Pharmacoeconomic data therefore support the use of enoxaparin as an effective thromboprophylactic treatment with potential cost advantages over warfarin and UFH. Cost-effecti

Anticoagulants↗

PubMed1996

Streptokinase. A pharmacoeconomic appraisal of its use in the management of acute myocardial infarction.

Thrombolytic therapy with streptokinase and other agents reduces mortality and is now well accepted as the mainstay of revascularisation options for most patients after an acute myocardial infarction. Streptokinase is as efficacious as alteplase (recombinant tissue plasminogen activator; rt-PA) when given as a 3-hour infusion, anistreplase, reteplase and saruplase in reducing mortality. However, in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, an accelerated alteplase regimen (1.5-hour infusion) plus intravenous heparin demonstrated a statistically significant 1% absolute mortality reduction compared with streptokinase plus heparin. Treatment with streptokinase is consistently clinically superior to conventional treatment and is cost effective: the marginal cost per year of life saved (cost/YLS) is less than $US/$Can20,000 (1990 or 1991 currency) assuming 5-year survival. In addition, streptokinase treatment is associated with fewer intensive care days and total days spent in hospital and a decrease in the use of intensive care services compared with conventional therapy. Importantly, the cost/YLS of treating older patients (70 to 80 years) with streptokinase is similar to that in younger patients (approximately $US22,000, 1990 currency). In 1 study, the cost of in-hospital treatment and associated 1-year follow-up costs did not differ significantly regardless of whether patients received streptokinase or anistreplase. In the most comprehensive cost-effectiveness analysis to date, GUSTO investigators determined that the incremental cost/YLS in patients who received the accelerated alteplase regimen instead of streptokinase was $US32,678 (1993 currency); the projected life expectancy was about 15 years. Thrombolytic therapy is generally more cost effective in patients at high risk than in those at low risk. The cost effectiveness of streptokinase is dependent on infarct location and time to treatment, but is more favorable in patients with anterior than inferior infarctions and those treated as soon as possible after symptom onset. There are as yet no comparative data to indicate a clinical benefit for one thrombolytic agent over another in patients treated more than 6 hours after symptom onset; therefore, in all likelihood, streptokinase will be preferred on the basis of cost minimisation. Streptokinase is associated with a slightly higher rate of severe bleeding than alteplase but a lower incidence of stroke. Although quality-of-life information comparing thrombolytics is unavailable, most patients who received streptokinase or alteplase rated their quality of life as high on the basis of results from time trade-off assessments and health surveys. In summary, streptokinase is undeniably cost effective compared with conventional treatment. It is up to individual healthcare systems to determine whether the mortality advantage and cost differential of the accelerated alteplase regimen over streptokinase, as seen in the GUSTO trial, are affordable and justifiable. However, it is important to realise that treatment options may be limited by healthcare resources; thus, streptokinase can be regarded as a cost-effective thrombolytic strategy which is both efficacious and affordable within the constraints of most healthcare budgets.

Aged↗

PubMed1995

Oxybutynin. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in detrusor instability.

Oxybutynin possesses anticholinergic and spasmolytic properties, which together form the basis for its use as a therapeutic option in patients with overactive detrusor function--either idiopathic detrusor instability (DI) or detrusor hyperreflexia. Of the symptoms of detrusor overactivity, urge incontinence is often the most distressing to the patient. Urge incontinence and other subjective parameters (urinary frequency, urgency) improve in tandem with objective (cystometric) measures (maximum detrusor pressure during filling, volume at first desire to void, maximum bladder capacity) in ambulatory, including elderly, patients treated with oxybutynin. However, on the basis of results of limited investigations, the drug appears ineffective in elderly institutionalised individuals. Relative to other anticholinergic drugs, oxybutynin appears at least as effective as propantheline and similar in efficacy to propiverine in small trials, although these results are not definitive. Further investigation of intravesical oxybutynin may lead to this route becoming an option in patients with pre-existing catheters. Adverse effects--dry mouth, constipation, blurred vision--related to the anticholinergic activity of oxybutynin occur frequently and can be sufficiently troublesome to necessitate treatment discontinuation in up to 25% of patients, depending on the dosage. Increases in residual urine volume suggesting urinary retention (undesirable in patients with idiopathic DI), also can develop in some oxybutynin recipients. In summary, oxybutynin is one of the few drugs proven to be beneficial in some patients with overactive detrusor function. Despite the occurrence of unwanted anticholinergic effects in many patients, and apparent lack of efficacy in the elderly institutionalised population, oxybutynin should be considered for the drug of first choice in patients with detrusor overactivity, including the elderly ambulatory population, when pharmacological therapy is indicated.

Animals↗

PubMed1995

Diclofenac/misoprostol. A review of its pharmacology and therapeutic efficacy in painful inflammatory conditions.

Diclofenac is a well established nonsteroidal anti-inflammatory drug (NSAID) used in the treatment of a variety of painful inflammatory conditions. Although generally well tolerated, diclofenac, like other NSAIDs, is associated with gastrointestinal adverse effects which infrequently can be serious and/or life-threatening. Misoprostol, a prostaglandin E1 analogue, reduces the incidence of NSAID related ulcers, both gastric and duodenal. The lack of conclusive pharmacoeconomic data for misoprostol and the widespread use of NSAIDs makes routine administration of misoprostol difficult to justify for all NSAID users. However, it appears to be an economically warranted approach in the elderly, who are at particularly high risk for NSAID-related gastrointestinal complications. The fixed combination of diclofenac 50mg and misoprostol 200 micrograms administered 2 to 3 times daily for 4 to 12 weeks has shown equivalent therapeutic efficacy to diclofenac (alone or combined with placebo), piroxicam and naproxen, and was slightly more effective than ibuprofen in clinical studies in patients with a variety of painful inflammatory conditions. No significant differences in therapeutic efficacy were noted between elderly (aged > or = 65 years) and younger patients in these studies. Gastrointestinal adverse events are common with diclofenac and misoprostol, administered alone or in combination. Diarrhoea (presumably attributable to the misoprostol component) appears to be more frequent in diclofenac/misoprostol recipients than in those receiving diclofenac alone or combined with placebo. However, diclofenac/misoprostol recipients had significantly fewer gastroduodenal ulcers at the end of treatment relative to patients receiving comparators in clinical trials. In addition, the types and incidences of adverse events are similar in elderly and younger patients. Routine ulcer prophylaxis with misoprostol in all NSAID users is not warranted from a pharmacoeconomic viewpoint. In common with other fixed combination products, dosage flexibility is somewhat compromised with diclofenac/misoprostol. However, once drug dosages are determined in the individual patient, the fixed combination of diclofenac and misoprostol offers the potential for increased patient convenience and possibly patient compliance, and lower drug acquisition costs than those of the individual drugs used together. Thus, it should be considered a useful treatment option in appropriately selected patients with a high risk for serious NSAID-related gastrointestinal complications who require NSAID therapy.

Aged↗

PubMed1995

Enoxaparin. A reappraisal of its pharmacology and clinical applications in the prevention and treatment of thromboembolic disease.

Enoxaparin (enoxaparin sodium) is a low molecular weight derivative of unfractionated heparin which has been evaluated for the treatment and prevention of thromboembolic disease. Since a previous review in Drugs, well controlled clinical trials have confirmed the effectiveness of enoxaparin as prophylaxis in patients with a high risk for deep venous thrombosis (DVT), i.e. those undergoing hip or knee replacement surgery. Enoxaparin 30mg twice daily, initiated postoperatively, offers an overall balance of prophylactic efficacy and haemorrhagic tolerability which is superior to that of unfractionated heparin. In comparative clinical trials, this dosage demonstrated either improved efficacy and a similar haemorrhagic profile, or a similar degree of efficacy with a lower rate of haemorrhagic events, compared with unfractionated heparin 5000IU 3 times daily. Limited data indicate that an enoxaparin regimen of 40mg once daily, starting preoperatively, is more effective than unfractionated heparin in patients undergoing hip replacement and has a comparable haemorrhagic profile. In patients with a moderate risk for DVT, enoxaparin is similar to unfractionated heparin in both efficacy and haemorrhagic profile, while preliminary investigations have demonstrated the utility of enoxaparin in the prevention of DVT in elderly, nonsurgical patients. Enoxaparin may also be useful for the treatment of existing DVT and as an anticoagulant in haemodialysis. Thus, enoxaparin is an effective form of prophylaxis for thromboembolic disease in moderate to high risk surgical situations. Recent evidence for improved efficacy, together with a similar incidence of haemorrhagic complications in most situations, may lead to enoxaparin being preferred to unfractionated heparin for the routine prevention of DVT after high risk surgery. Although detailed comparisons with other low molecular weight heparins and antithrombotic agents are required before its relative clinical utility can be fully assessed, enoxaparin is likely to play a significant role in the prophylaxis of thromboembolic disorders.

Biological Availability↗

PubMed1995

Lenograstim. A review of its pharmacological properties and therapeutic efficacy in neutropenia and related clinical settings.

Lenograstim is a recombinant glycosylated human granulocyte colony-stimulating factor (rHuG-CSF) which principally regulates the formation and function of neutrophils. Like other colony-stimulating factors (CSFs), lenograstim has been developed for the prevention and treatment of iatrogenic and disease-related neutropenic conditions. In phase III clinical studies, prophylactic administration of lenograstim shortened the duration of chemotherapy-induced neutropenia in patients with nonmyelogenous cancers who received standard-dose chemotherapy or myeloablative regimens followed by bone marrow transplantation (BMT). A decrease in the incidence of infection after standard regimens and fewer days with infectious and febrile neutropenic episodes during recovery from BMT occurred concomitantly with the amelioration of neutropenia. In each setting, the decrease in morbidity was associated with shorter hospitalisation times and reduced administration of parenteral antibacterial agents. As with another rHuG-CSF, filgrastim, bone pain (non-serious) was the most common adverse reaction to lenograstim therapy. This occurred in 13% of lenograstim recipients and 5% of placebo recipients treated for chemotherapy-induced neutropenia with standard regimens. Lenograstim may facilitate dose optimisation and permit limited dose intensification of standard chemotherapy. Furthermore, the drug, used alone or in combination with chemotherapy, is effective in mobilising peripheral blood progenitor cells (PBPCs) for subsequent reinfusion. The latter is a promising technique which may supplement or ultimately replace BMT for stem cell rescue after myeloablative chemotherapy. However, it has yet to be established whether the dose intensification achievable with lenograstim and/or stem cell rescue has a material effect on relapse-free and survival times. Preliminary data suggest that lenograstim is effective in increasing the neutrophil count in patients with severe chronic neutropenia (Kostmann's syndrome), as well as patients with AIDS or AIDS-related complex with zidovudine-induced neutropenia. Thus, lenograstim, like other CSFs, is a valuable adjunct to cytotoxic chemotherapy for the treatment of nonmyelogenous cancers, including myeloablative regimens followed by stem cell rescue with BMT and/or PBPC infusion. Future clinical experience is likely to confirm the usefulness of the drug in the management of disease-related neutropenia, myeloid disorders and neutropenia in patients with AIDS.

Amino Acid Sequence↗

PubMed1995

Alteplase. A reappraisal of its pharmacological properties and therapeutic use in acute myocardial infarction.

Alteplase (recombinant tissue-type plasminogen activator) stimulates the fibrinolysis of blood clots by converting plasminogen to plasmin. The efficacy of intravenous alteplase in the early treatment of patients with acute myocardial infarction has been unequivocally proven, and recent results from the GUSTO trial indicate a significant advantage in 30-day survival for alteplase in an accelerated dosage regimen (< or = 100mg infused over 90 minutes rather than 3 hours) over streptokinase. The advantage of the accelerated alteplase dosage regimen seems to be maintained for at least 1 year. The role of heparin as adjunctive therapy to thrombolysis remains to be fully defined but heparin administration appears to be more important in conjunction with alteplase than with streptokinase. Ideally, patients should receive alteplase as soon as possible after the onset of symptoms of acute myocardial infarction and, while therapy is most beneficial when administered early, survival is improved when the drug is administered up to 12 hours after symptom onset. The accelerated regimen of alteplase used in the GUSTO trial demonstrated a survival advantage in patients < or = 75 as well as those > 75 years of age which was at least as great as that seen with streptokinase. Similarly, alteplase reduces mortality in patients with both anterior and inferior infarctions; however, those with anterior wall infarctions show an improved outcome over those with inferior infarcts. On the basis of pharmacoeconomic analysis of GUSTO data, the accelerated alteplase regimen cost an estimated additional $US32,678 per year of life saved compared with a conventional streptokinase regimen. Cumulative 1-year costs were greater in patients who received the accelerated alteplase regimen but survival was significantly greater than in patients who received streptokinase. No difference in quality of life was evident in patients who received either treatment. The incidence of major haemorrhage associated with alteplase therapy appears to be similar to that seen with other fibrinolytic agents, increasing with increasing dose; however, the risk of stroke, particularly haemorrhagic stroke, is higher with alteplase than with streptokinase. Thus, alteplase has become firmly established as a first-line option in the management of acute myocardial infarction. On the basis of accumulated evidence, the greatest risk reduction with alteplase therapy may be in certain high risk groups, such as those with anterior infarcts, selected elderly patients and those who present late after symptom onset.

Aged↗

PubMed1995

Transnasal butorphanol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute pain management.

Butorphanol is a synthetic opioid agonist-antagonist analgesic with a pharmacological and therapeutic profile that has been well established since its launch as a parenteral formulation in 1978. The introduction of a transnasal formulation of butorphanol represents a new and noninvasive presentation of an analgesic for moderate to severe pain. This route of administration bypasses the gastrointestinal tract, and this is an advantage for a drug such as butorphanol that undergoes significant first-pass metabolism after oral administration. The onset of action and systemic bioavailability of butorphanol following transnasal delivery are similar to those after parenteral administration. The analgesic efficacy of transnasal butorphanol was generally superior to that of placebo in clinical trials in patients with moderate to severe postoperative pain or migraine headache. Results from single trials indicate that transnasal butorphanol provides pain relief comparable to that of intramuscular pethidine (meperidine) in postsurgical pain and comparable to or greater than intramuscular methadone in migraine headache. Moderate to severe musculoskeletal pain also appears to be responsive to transnasal butorphanol on the basis of results from 1 small noncomparative study. Tolerability of transnasal butorphanol parallels that of the injectable form, with somnolence, dizziness, nausea and/or vomiting reported most frequently. Thus, transnasal butorphanol is a novel formulation of an established analgesic which appears suitable for the short term treatment of moderate to severe pain, especially in an ambulatory setting. Transnasal butorphanol is likely to provide an alternative to oral opioid analgesics, particularly in the presence of nausea or vomiting, or to parenteral opioids when the oral route of administration is not appropriate.

Administration, Intranasal↗

PubMed1995

Atovaquone. A review of its pharmacological properties and therapeutic efficacy in opportunistic infections.

Atovaquone has been investigated as an alternative agent for oral use in the treatment of both mild to moderate Pneumocystis carinii pneumonia (PCP) and toxoplasmosis, opportunistic infections commonly experienced by patients with AIDS. In patients with mild to moderate PCP, a dosage of 750mg 3 times daily (administered in tablet form) has similar overall therapeutic efficacy (defined as clinical response without a treatment-limiting adverse event) to the conventional therapies oral cotrimoxazole (trimethoprim-sulfamethoxazole) and intravenous pentamidine, respectively. Response rates to atovaquone are lower than those achieved with cotrimoxazole, but atovaquone has superior tolerability. Atovaquone recipients experienced significantly fewer treatment-limiting adverse effects than patients treated with cotrimoxazole (7 vs 20%) or pentamidine (4 vs 36%). Mortality rates were higher among atovaquone-treated patients than in cotrimoxazole recipients (7 vs 0.6%) 4 weeks after completion of therapy in a large comparative trial, although most deaths were caused by bacterial infections. However, a similar rate of mortality was reported for atovaquone- and pentamidine-treated patients (16 vs 17% 8 weeks after discontinuation of therapy) in another study. In predominantly small numbers of patients with toxoplasmosis, of whom most were unresponsive to conventional agents, atovaquone 750mg 4 times daily (administered as tablets) produced a complete or partial radiological response rate of 37 to 87.5% 52% of patients achieved a complete or partial clinical response after 6 weeks of treatment in the largest trial (n = 87), although the incidence of toxoplasmosis-related death was 24% 18 weeks after therapy was initiated. Thus, atovaquone will be a useful option for the treatment of patients with mild to moderate PCP who are intolerant or unresponsive to cotrimoxazole, especially if the increased plasma drug concentrations observed with the suspension further improve response rates. Atovaquone should also be considered a promising agent for the treatment of toxoplasmosis.

AIDS-Related Opportunistic Infections↗

PubMed1995

Alteplase. A reappraisal of its pharmacology and therapeutic use in vascular disorders other than acute myocardial infarction.

Alteplase is the product of recombinant DNA technology and is chemically identical to endogenous tissue-type plasminogen activator: Plasminogen is converted to plasmin by alteplase, and fibrinolysis of blood thrombi is subsequently stimulated. Alteplase is now firmly established as a treatment of choice in the management of acute myocardial infarction. The efficacy of intravenous alteplase in the treatment of pulmonary thromboembolism has also been established and appears to be similar to that of streptokinase and urokinase in this indication and in arterial thrombotic occlusion. However, its use in this latter indication and in other vascular disorders has not been as extensively documented. Although trials demonstrating the efficacy of intravenous alteplase in patients with deep vein thrombosis and intra-arterial alteplase in patients with arterial thrombotic occlusion exist, reliable data on the efficacy of the fibrinolytic in ischaemic stroke and intracranial haemorrhage are scarce. Little clinical benefit is apparent in patients with unstable angina, although careful use may be warranted in those with definite pretreatment coronary thrombi. Of concern, there is a suggestion that general use of alteplase in patients with unstable angina may be associated with increased incidence of myocardial infarction. The incidence of major haemorrhage associated with alteplase therapy increases with increasing dose and appears to be similar to that seen with other fibrinolytic agents. Thus, further well-designed studies of the use of alteplase in ischaemic stroke and cerebral haemorrhage are required. However, a small subset of patients with unstable angina and definite pretreatment coronary thrombi may benefit from alteplase therapy. Further, preliminary data suggest efficacy in the therapy of deep vein thrombosis and arterial thrombotic occlusion, and alteplase has a proven place in the fibrinolytic treatment of pulmonary thromboembolism.

Administration, Oral↗

PubMed1995

Fluconazole. An update of its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients.

Fluconazole is a triazole antifungal agent which is now an established part of therapy in patients with immune deficiencies. It is effective against oropharyngeal/oesophageal candidiasis (candidosis) when used orally once daily either as treatment or secondary prophylaxis in patients with AIDS or as treatment or primary prophylaxis in neutropenia associated with cancer therapy. Fluconazole also resolves symptoms in up to 60% of patients with cryptococcal meningitis and AIDS. However, in this infection its efficacy as treatment relative to that of amphotericin B is equivocal, and its major role is as the drug of choice for maintenance therapy following amphotericin B induction. In this regard, fluconazole has been proven superior to amphotericin B and to itraconazole 200 mg/day. Comparisons with other drugs used for the treatment of mucosal candidiasis in patients with AIDS show fluconazole to be superior to nystatin, similar to itraconazole and at least as effective as clotrimazole and ketoconazole; it was more so than the latter azole in 1 study. In patients undergoing chemotherapy or bone marrow transplantation, fluconazole as primary prophylaxis has produced greater clinical benefit than a clotrimazole regimen. The incidence of adverse events appears to be somewhat higher in patients with AIDS compared with HIV-negative cohorts, but the qualitative pattern of events is similar. The most frequent events are gastrointestinal complaints, headache and skin rash: rare exfoliative skin reactions and isolated instances of clinically overt hepatic dysfunction have occurred in patients with AIDS. Issues yet to be clarified include: the use of fluconazole in children with AIDS, in whom results have been promising; its efficacy against other fungal infections encountered in immunocompromised patients; whether the drug influences mortality, as has been suggested by one placebo-controlled trial in patients undergoing bone marrow transplant; and the appropriateness of its potential for use as primary prophylaxis against cryptococcal meningitis in patients with AIDS, where it shows efficacy but there is concern over increasing risk of development of secondary resistance. Notwithstanding these undefined aspects of its clinical profile, fluconazole is now confirmed as an important antifungal drug in the management of fungal infections in patients with immune deficiencies. In patients with AIDS it is the present drug of choice as maintenance therapy against cryptococcal meningitis and is a preferred agent for secondary prophylaxis against candidal infections; it is also a favoured agent for primary prophylaxis in patients at risk because of neutropenia associated with chemotherapy or bone marrow transplantation .

AIDS-Related Opportunistic Infections↗

PubMed1995

Lamotrigine. An update of its pharmacology and therapeutic use in epilepsy.

Lamotrigine is an antiepileptic agent which blocks voltage-dependent sodium channels, thereby preventing excitatory neurotransmitter release. Clinical evidence indicates that lamotrigine is effective against partial and secondarily generalised tonic-clonic seizures, as well as idiopathic (primary) generalised epilepsy. As monotherapy, lamotrigine 100 to 300 mg/day has similar medium term (30 to 48 weeks) efficacy to carbamazepine 300 to 1400 mg/day and phenytoin 300 mg/day against partial onset seizures and idiopathic generalised tonic-clonic seizures in adults with newly diagnosed epilepsy, and appears to be better tolerated than the older agents. As adjunctive therapy, lamotrigine (50 to 500 mg/day) has shown efficacy in short term ( < or = 6-months) placebo-controlled studies in adults with refractory partial epilepsy, reducing total seizure frequency (by < or = 60%) and producing improvement ( > or = 50% reduction in seizure frequency) in < or = 67% of patients. Both simple and complex partial seizures and secondarily generalised tonic-clonic seizures are reduced by lamotrigine, with generalised seizures (particularly absence seizures, atonic seizures and Lennox-Gastaut syndrome) tending to be more responsive than partial seizures. This reduction in seizure frequency is sustained on long term ( < or = 3 years) therapy and is reportedly accompanied by an improvement in psychological well-being. In children with refractory multiple seizure types, lamotrigine ( < or = 15 mg/kg/day; 400 mg/day) has proved effective as add-on therapy, with approximately equal to 40% of patients showing > or = 50% reductions in seizure frequency and approximately equal to 10 % achieving abolition of seizures after 3 months' treatment. Generalised seizures, including atypical and typical absence seizures, atonic and tonic seizures and Lennox-Gastaut syndrome are most responsive. The most common adverse events associated with lamotrigine are primarily neurological, gastrointestinal and dermatological. Maculopapular or erythematous skin rash, occasionally severe, occurs in approximately equal to 10% of patients and is the most common cause of treatment withdrawal. The risk of rash can, however, be minimised through adoption of a low, slow dosage titration schedule on initiating therapy. As monotherapy, lamotrigine produces less drowsiness than carbamazepine or phenytoin, and less asthenia and ataxia than phenytoin. Clinical experience would therefore suggest that lamotrigine is a particularly effective and generally well tolerated broad-spectrum agent for adjunctive treatment of both partial epilepsy and idiopathic generalised epilepsy in adults and children. Initial indications point to the drug filling an increasingly important future role in the monotherapy of newly diagnosed epilepsy.

Adult↗

PubMed1995

Desflurane. A review of its pharmacodynamic and pharmacokinetic properties and its efficacy in general anaesthesia.

Desflurane is a halogenated ether inhalation general anaesthetic agent with low solubility in blood and body tissues, and approximately one-fifth the potency of isoflurane. The pharmacodynamic properties of desflurane generally resemble those of isoflurane; thus, it produces dose-dependent depression of the central nervous and cardiorespiratory systems, and tetanic fade at the neuromuscular junction. The alveolar equilibration of desflurane is rapid (90% complete at 30 minutes compared with 73% for isoflurane). Both desflurane and isoflurane are distributed to various tissues to a similar extent. Desflurane is resistant to chemical degradation and undergoes negligible metabolism (approximately equal to 10% of that seen with isoflurane). Desflurane 'wash-out' is approximately equal to 2 to 2.5 times faster than that of isoflurane in the first 2 hours after discontinuation of anaesthesia. The low solubility of desflurane facilitates a rapid induction of anaesthesia and precise control of the depth of anaesthesia (during maintenance). Results from a few clinical studies indicate that emergence from desflurane is significantly earlier (by approximately equal to 2 to 6 minutes) than that from propofol anaesthesia, whereas other studies do not concur. In comparison with isoflurane, emergence from desflurane anaesthesia is significantly earlier (by 5 minutes) after ambulatory and approximately equal to 50% earlier (also significant) after nonambulatory surgical procedures. Limited comparative studies with halothane or sevoflurane also suggest an earlier time of emergence from desflurane anaesthesia. Comparative studies of desflurane and propofol, and other inhalation agents, indicate that the times to toleration of oral fluids, sitting and discharge from recovery room are similar, regardless of the general anaesthetic agent administered. However, some limited data in elderly patients (aged > 65 years) suggest that this patient group spends a significantly shorter time in the postanaesthesia care unit after desflurane than after isoflurane anaesthesia. Differences, if any, in the recovery of cognitive and psychomotor functions after desflurane or propofol anaesthesia remain unclear. However, in comparison with isoflurane anaesthesia, recovery of these functions (up to 45 minutes post-operatively) occurs earlier after desflurane. Significantly fewer patients are subjectively impaired (i.e. drowsy, clumsy, fatigued or confused) upon recovery from desflurane than from isoflurane anaesthesia. Likewise, significantly fewer adult patients are delirious when recovering from desflurane than from isoflurane anaesthesia, though in paediatric patients delirium is more likely when recovering from desflurane than from halothane anaesthesia. Haemodynamic stability during coronary artery surgery is as well maintained with desflurane as with isoflurane, and the drug does not worsen the adverse postoperative outcomes.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1995

Tretinoin. A review of its pharmacodynamic and pharmacokinetic properties and use in the management of acute promyelocytic leukaemia.

Tretinoin (all-trans retinoic acid), a vitamin A derivative, induces cellular differentiation in several haematological precursor cell lines and cells from patients with acute promyelocytic leukaemia. Drug treatment with tretinoin is associated with morphological and functional maturation of leukaemic promyelocytes and a progressive reduction in the occurrence of the characteristic t(15;17) chromosomal translocation. Recent therapeutic trials indicate that tretinoin induces remission in 64 to 100% of patients with acute promyelocytic leukaemia. In newly diagnosed patients, remission induction treatment with tretinoin followed by intensive chemotherapy resulted in a significant reduction in relapse rate and prolongation of event-free and overall survival compared with chemotherapy alone in 1 comparative trial. Tretinoin alone does not totally eradicate the leukaemic clone and consolidation chemotherapy is recommended as follow-up. The use of reverse transcription polymerase chain reaction (RT-PCR) provides a sensitive and specific technique to assist in prediction and monitoring of a patient's response to treatment and to help detect the presence of residual or recurrent disease. The use of tretinoin is potentially limited by the rapid and almost universal development of drug resistance and occurrence of the often severe retinoic acid syndrome. Useful strategies have been described to manage these effects but current and future efforts must be directed at elucidating the mechanisms involved and determining the optimum therapeutic management. In summary, results to date indicate that the combination of tretinoin and intensive chemotherapy is more effective than chemotherapy alone and appears to improve the prognosis of newly diagnosed patients with acute promyelocytic leukaemia. Further information on the relative efficacy of various induction and post-remission strategies in subsets of patients will help determine optimum use of this promising agent in the management of acute promyelocytic leukaemia.

Animals↗

PubMed1995

Amifostine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as a radioprotector and cytotoxic chemoprotector.

Amifostine (WR-2721) was originally developed as a radioprotective agent. In animals, it protects normal tissues from the damaging effects of irradiation and, as shown in more recent studies, of several cytotoxic agents. Protection of tumours is generally reduced compared with that of normal tissues in animals, suggesting that amifostine may increase the therapeutic window of cytotoxic therapies. Clinical data concerning amifostine suggest that cytotoxic chemotherapy-induced haematological toxicity and cisplatin-induced neurotoxicity, nephrotoxicity and ototoxicity are decreased upon administration of amifostine prior to cytotoxic drugs. Similarly, amifostine reduces damage to normal tissues caused by radiotherapy. Available data show that this protection is achieved without adversely affecting tumour response or patient survival. In 1 large trial, the reduction in cyclophosphamide- and cisplatin-related toxicities manifested as a decrease in the incidence and severity of neutropenia-related fever and sepsis and in the number of patients with ovarian cancer who discontinue therapy before completion of treatment, thus improving the tolerability of this antineoplastic regimen. In addition, the incidences of cisplatin-induced nephro- and neurotoxicity were reduced. Increased doses of cytotoxic therapy have also been administered when amifostine was given prior to therapy, which may increase tumour response. The predominant adverse effect associated with amifostine are hypotension, nausea and vomiting, somnolence and sneezing. Thus, amifostine is likely to be a useful adjuvant to the treatment of patients with malignancy, particularly those receiving cyclophosphamide plus cisplatin. discontinued therapy before completion of treatment, thus improving the tolerability of this antineoplastic regimen. In addition, the incidences of cisplatin-induced.

Amifostine↗

PubMed1995

Alglucerase. A pharmacoeconomic appraisal of its use in the treatment of Gaucher's disease.

Alglucerase is a modified form of human placental glucocerebrosidase used as enzyme replacement therapy for patients with Gaucher's disease, in whom functional glucocerebrosidase is deficient. Alglucerase has provided a breakthrough in treatment for patients with this relatively rare disease. With alglucerase infusions typical disease manifestations are ameliorated or normalised: hepatosplenomegaly is reduced, haematological parameters improve, and patients experience an increased quality of life usually within 4 to 6 months of treatment. Parameters of bone disease also respond, but generally over a longer period of treatment. Alglucerase is well tolerated by children and adults, with few adverse effects reported. Seroconversion occurs in approximately 15% of patients on high-dose therapy, but does not appear to affect the efficacy of treatment. Several dosage regimens have been used to deliver alglucerase, and the comparative benefits of these remain controversial. High-dose regimens of 60 IU/kg bodyweight administered every 2 weeks are clearly effective; however, smaller dosages given more frequently are also effective and incur a greatly reduced acquisition cost. Patient responses are variable, and the dosage regimen should be tailored to individual needs. Dosage regimens may be considerably reduced for the maintenance phase of treatment, but clinical experience is as yet insufficient to establish the minimum dosages required in the long term. Acquisition cost of alglucerase is $US3.70 per unit (1994 US dollars); thus, a dosage regimen of 60 IU/kg bodyweight administered every 2 weeks for a patient weighing 70kg costs $US404,040 per year. The minimal costs per quality-adjusted life year saved (QALY) have been estimated for 3 dosage regimens over a 10-year period. Cost per QALY was $US147,000 for 60 IU/kg bodyweight administered every 2 weeks, $US75,000 for 30 IU/kg every 2 weeks, and $US49,000 for 2.3 IU/kg administered 3 times per week. These costs were calculated assuming immediate death with no treatment, which suggests that the actual costs per QALY for most patients with type 1 or 3 disease are likely to be much higher. Drug administration costs may become a significant part of the cost during maintenance therapy; in addition, possible cost savings due to increased patient productivity and reduced palliative treatments remain unresolved. Although some patients may obtain increased benefit from high-dosage regimens, the very high cost may preclude general use of these regimens. Healthcare resources consumed by alglucerase therapy represent a large opportunity cost for other therapeutic areas.(ABSTRACT TRUNCATED AT 400 WORDS)

Cost-Benefit Analysis↗

PubMed1995

Alteplase: a pharmacoeconomic evaluation of its use in the management of myocardial infarction.

Alteplase (recombinant tissue plasminogen activator; rt-PA) is a thrombolytic agent that when given in an accelerated regimen with intravenous heparin has survival advantages compared with streptokinase in the treatment of acute myocardial infarction, as shown by the results of the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial. Although alteplase is more fibrin-specific than streptokinase, alteplase therapy is associated with a small relative increase in the incidence of haemorrhagic stroke, but appears to cause a small relative decrease in the incidence of major bleeding. Because alteplase has a higher acquisition cost than alternative thrombolytic agents, analyses have been undertaken to assess whether administration of alteplase after myocardial infarction is a cost-effective use of healthcare resources. In retrospective analyses undertaken before completion of the GUSTO trial, it was generally assumed, on the basis of better 90-minute patency rates, that alteplase would provide survival advantages compared with streptokinase or conventional nonthrombolytic therapy. Alteplase had acceptable cost-effectiveness ratios compared with conventional therapy and streptokinase therapy from both third-party payer and hospital perspectives. Subgroup analyses demonstrated that alteplase was more cost effective when given early after symptom onset and when given to patients with large infarcts. Prospective evaluations of the cost effectiveness of alteplase in 3-hour and accelerated regimens have similarly demonstrated that alteplase therapy after myocardial infarction improves survival at an 'acceptable' cost. The largest prospective evaluation undertaken to date was performed in conjunction with the GUSTO trial. Primary analysis, on the basis of the clinical findings of the GUSTO trial and prospective collection of cost data from US patients, revealed that the cost-effectiveness ratio for accelerated alteplase therapy compared with streptokinase was $US32,687 (1993 dollars) per year of life saved (YLS). This value is most relevant for US patients and lies within the definition of 'cost effective' if $US50,000/YLS is the benchmark for acceptable use of resources. The cost-effectiveness ratio for alteplase was most sensitive to assumptions regarding long term survival and cost differences after the first year following treatment. In subgroup analyses, alteplase was a cost-effective treatment option for all elderly patients (> 60 years of age) and all patients > 40 years of age with anterior infarction. Alteplase therapy appears to have in-hospital costs/charges similar to those for primary percutaneous transluminal coronary angioplasty (PTCA), mainly because PTCA appears to have a favourable effect on duration of hospitalisation. Given the technical expertise and facilities required for PTCA, it is likely that thrombolytic therapy will remain the management option of choice in most centres. In conclusion, under the conditions of the GUSTO study, accelerated alteplase in combination with intravenous heparin confers survival advantages compared with streptokinase therapy. While decision-makers must choose how best to use their available healthcare resources, pharmacoeconomic evaluations have confirmed that, on the basis of accepted benchmark values, alteplase therapy is a cost-effective therapeutic option for the treatment of acute myocardial infarction, especially in elderly patients with either anterior or inferior infarcts and nearly all patients with anterior myocardial infarction. Thus, on the basis of clinical and economic data, predominantly provided by the GUSTO trial, alteplase is a cost-effective first-line management option for acute myocardial infarction.

Economics, Pharmaceutical↗