Biomedical subjects

C J Dunn

Publications and source records attributed to C J Dunn.

At least 37 records · Page 2Linked to original sources

PubMed1999

Fibrin sealant: a review of its use in surgery and endoscopy.

UNLABELLED: Fibrin sealant (fibrin adhesive; fibrin glue; Beriplast P1) is a haemostatic and wound support product consisting of the blood coagulation factors fibrinogen, factor XIII and thrombin, the antifibrinolytic agent aprotinin and calcium chloride. Fibrin sealant has been used to good effect in a wide variety of surgical and endoscopic procedures. Suture support was provided in series of patients with oesophageal, gastric, colonic or rectal anastomoses, and fibrin sealant was as effective in haemostasis as microcrystalline collagen powder in hepatic surgery. It did not reduce postoperative peritoneal drainage after elective cholecystectomy, however. A 41% reduction (p<0.02) in incidence of air leakage was achieved when fibrin sealant was added to sutures in patients undergoing pulmonary resection in a randomised single-blind study. A high rate of complete remission of malignant pleural effusion has been reported after intrapleural instillation of fibrin sealant, and successful sealing of CSF leaks after trauma or surgery has also been achieved. Attenuation of prolonged or excessive haemorrhage after dental extraction has been achieved in patients on anticoagulant therapy or with haemorrhagic disorders who received fibrin sealant with packing and suturing. Repeated endoscopic injection of fibrin sealant was superior to single injection sclerotherapy with polidocanol 1% in a randomised study in 805 patients with bleeding peptic ulcers. Other data suggest that endoscopic injection of fibrin sealant is associated with lower recurrence of bleeding and need for emergency surgery than thrombin with adrenaline (epinephrine) or hypertonic saline with adrenaline. Similar haemostatic efficacy to laser photocoagulation or sclerotherapy was reported in a retrospective comparison. A statistically significant reduction relative to suturing in the incidence of wound dehiscence was reported after the use of fibrin sealant in cataract surgery, and benefit of the sealant has also been noted in patients receiving skin grafts and in those undergoing transurethral resection of the prostate gland. CONCLUSIONS: Although comparative studies would assist in the clarification of the place of the product discussed with respect to other haemostatic or wound support techniques and to other fibrin sealants, the formulation reviewed here has been shown overall to be effective and well tolerated in a variety of haemostatic and wound healing support roles in numerous types of surgery. Fibrin sealant has also been shown to be useful when administered endoscopically, with superiority over sclerotherapy being shown after repeated application in patients with peptic ulceration. Fibrin sealant can therefore be considered useful in a number of surgical and endoscopic settings.

Animals↗

PubMed1999

Abciximab. A pharmacoeconomic review of its use in percutaneous coronary revascularisation.

UNLABELLED: Abciximab is a monoclonal antibody fragment that inhibits platelet aggregation through antagonism of glycoprotein IIb/IIIa. The drug is used in conjunction with heparin and aspirin to prevent ischaemic complications associated with percutaneous coronary revascularisation in patients with coronary heart disease. Large and well designed clinical studies have shown abciximab, as an adjunct to aspirin and heparin, to reduce by around one-third to one-half the incidence of ischaemic complications within 30 days of percutaneous coronary revascularisation. Use of the drug appears advantageous in patients at high risk, and abciximab also reduces complications in patients undergoing coronary stenting, although the drug does not appear to inhibit restenotic tissue volume within stents. Longer term benefit has also been reported, with emerging 1-year data from a study in patients at all levels of risk showing reductions in a composite end-point of death, myocardial infarction (MI) or urgent repeat revascularisation. Three-year benefit has been reported in high risk patients. Meta-analysis results, and 1-year data from patients receiving stents, have shown reduced mortality with abciximab. Abciximab therapy had an incremental cost over standard therapy from a hospital perspective of $US293 per patient (1991/1992 values) over 6 months in a prospective economic substudy from a major US clinical trial of the drug in high risk patients. Abciximab was cost saving in patients with unstable angina. A mean net cost of hospitalisation of $US476 per patients (1995 costs) has been shown in a further study in patients with a broad range of levels of risk, and observational data indicate reduced duration of hospitalisation with abciximab. Cost-effectiveness data favoured abciximab with aspirin and heparin over a 6-month period in Spanish and Dutch analyses in which data from the above trial were combined with local cost data, but not in an Australian analysis. Subgroup analyses have indicated enhanced cost effectiveness in high risk patients. Available data also show clinical benefit and cost effectiveness of abciximab therapy in conjunction with coronary stent placement. CONCLUSIONS: Data indicate intravenous bolus plus 12-hour infusion regimens of abciximab to be economically viable in patients at high or low risk of ischaemic complications after percutaneous coronary revascularisation. The drug has been shown to be cost effective in patients receiving the drug in conjunction with coronary stents, and subgroup analyses indicate additional cost effectiveness in certain groups of patients at high risk of ischaemic complications (notably those with acute MI and unstable angina).

Abciximab↗

PubMed1998

Anti-inflammatory/antiarthritic ketonic bisphosphonic acid esters.

Bisphosphonate ester 2 is an inhibitor of inflammation, but is devoid of antiarthritic effects. SAR studies on a series of related bisphosphonate esters resulted in compounds 6e, 6i, 6j, and 6m, which exhibited excellent inhibition of an arthritis model, in addition to potent anti-inflammatory effects.

Animals↗

PubMed1998

Role of PECAM-1 (CD31) in neutrophil transmigration in murine models of liver and peritoneal inflammation.

Platelet endothelial cell adhesion molecule-1 (PECAM-1) is thought to be critical for transendothelial migration of leukocytes, including neutrophils. Because neutrophil-mediated liver injury during endotoxemia is dependent on transmigration, we investigated the role of PECAM-1 in the pathophysiology of endotoxin-induced liver injury. Male C3Heb/FeJ mice were treated with galactosamine (Gal) and endotoxin (ET) (700 mg/kg Gal/100 micrograms/kg ET), and liver sections were stained for PECAM-1 expression. Control livers showed the presence of PECAM-1 on endothelial cells of large vessels but not in sinusoids. Gal/ET treatment did not change the expression pattern of PECAM-1. Gal/ET-induced liver injury (area of necrosis: 38 +/- 3%) was not attenuated by treatment with 3 mg/kg of the antimurine PECAM-1 antibody 2H8. The antibody had no effect on sequestration and transmigration of neutrophils in sinusoids or the margination of neutrophils in large vessels. In contrast, 2H8 inhibited glycogen-induced neutrophil migration into the peritoneum by 74%; this effect correlated with PECAM-1 expression in the intestinal vasculature. Thus PECAM-1 is neither expressed nor inducible in hepatic sinusoids and is consequently not involved in neutrophil transmigration in the liver during endotoxemia. On the other hand, expression of PECAM-1 in mesenteric veins is critical for peritoneal neutrophil accumulation.

Animals↗

PubMed1998

Involvement of intercellular adhesion molecule-1 in the antigen-induced infiltration of eosinophils and lymphocytes into the airways in a murine model of pulmonary inflammation.

We investigated the effects of in vivo intraperitoneal treatment with the rat monoclonal antibody (mAb), YN1.7.4 (YN1) against intercellular adhesion molecule-1 (ICAM-1) on the ovalbumin (OA)-inhalation-induced infiltration of leukocytes into the airways of OA-sensitized mice. YN1 (100 to 400 microg) given over a period of 72 h dose-dependently reduced the influx of lymphocytes and eosinophils into the bronchial lumen by > 60% and > or = 70%, respectively, when compared with saline or purified rat IgG-treated controls. Alveolar macrophages (AM) in the bronchoalveolar lavage fluid (BALF) were also decreased by > 50%. Lung tissue inflammation as determined by histopathologic examination was reduced. The number of neutrophils in the blood of OA-sensitized mice 3 days after challenge was significantly increased by treatment with YN1. However, at 24 h and 72 h after OA-challenge, the numbers of eosinophils and mononuclear cells in the bone marrow were reduced by YN1 treatment. Additionally, at 72 h after OA-challenge, the numbers of bone-marrow neutrophils were depressed. BALF levels of interleukin-5 (IL-5) and of IgA were lower for YN1-treated mice than for controls. With increasing doses of YN1, the levels of anti-ICAM-1 mAb in the plasma were proportionally increased. To correlate these results with YN1 treatment, blood and BALF T cells and BALF eosinophils were examined with flow cytometry. Blood T cells from YN1-treated mice were unable to bind phycoerythrin (PE)-labeled anti-ICAM- mAb ex vivo. These results implied that ICAM-1 on these cells was bound (occupied) by YN1 administered in vivo. Dose-related decreases were observed in the percentage and mean channel fluorescence (MCF) values of ICAM-1+ BALF T cells and eosinophils. The percentages of CD11a+ or CD49d+ eosinophils were also suppressed. Our data suggest that ICAM-1 is an important molecule involved in the recruitment of leukocytes into the airways of sensitized mice after pulmonary challenge.

Animals↗

PubMed1997

Neutrophil margination and extravasation in sinusoids and venules of liver during endotoxin-induced injury.

Neutrophils contribute to liver damage during endotoxin shock. The objective of this investigation was to document where neutrophils localize in the hepatic vasculature and whether they migrate out of sinusoids or postsinusoidal venules. A well-characterized model of galactosamine and endotoxin shock and immunostaining for neutrophil-associated migration inhibition factor-related protein complex 8/14 S100 calcium-binding proteins were used. Treatment of C3Heb/FeJ mice with 100 micrograms/kg Salmonella abortus equi endotoxin alone or in combination with 700 mg/kg galactosamine induced a time-dependent increase of neutrophil margination in sinusoids and postsinusoidal venules at 4 h. The number of venular neutrophils decreased in both groups at later time points without evidence for transmigration. Extravasation of neutrophils was only observed from sinusoids in galactosamine plus endotoxin-treated animals between 4 and 7 h, which correlated with parenchymal cell injury. After endotoxin alone, large numbers of neutrophils remained sequestered in sinusoids without injury. These data suggest that neutrophils cause hepatocellular injury during endotoxemia after extravasation and are less likely to cause damage when sequestered in the vasculature. In the liver, neutrophils migrate out of sinusoids and not out of postsinusoidal venules.

Animals↗

PubMed1997

Carvedilol. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders.

Carvedilol competitively blocks beta 1, beta 2 and alpha 1 receptors. The drug lacks sympathomimetic activity and has vasodilating properties that are exerted primarily through alpha 1-blockade. Animal models indicate that carvedilol confers protection against myocardial necrosis, arrhythmia and cell damage caused by oxidising free radicals, and the drug has no adverse effects on plasma lipid profiles. Recent data have confirmed the antihypertensive efficacy of carvedilol in patients with mild to moderate essential hypertension. Carvedilol has similar efficacy to other beta-blocking agents, calcium antagonists, ACE inhibitors and hydrochlorothiazide. Carvedilol also improves exercise tolerance and ischaemic symptoms in patients with stable angina pectoris. Significant reductions in serious cardiac events after acute myocardial infarction and in frequency and severity of ischaemic events in patients with unstable angina have also been demonstrated. Interest in the use of carvedilol in patients with congestive heart failure (CHF) has culminated in the publication of a cumulative analysis of data from 1094 patients with mild to severe CHF who participated in the US Carvedilol Heart Failure Study Program (4 trials). After a median follow-up of 6.5 months, a significant overall reduction in mortality relative to placebo (3.2 vs 7.8%) was revealed in patients who had received carvedilol 6.25 to 50 mg twice daily (plus diuretics and ACE inhibitors). All-cause mortality, risk of hospitalisation for cardiovascular reasons and hospitalisation costs were also reduced significantly (by 65, 28% and 62%, respectively) in these trials. In addition, the Australia and New Zealand Heart Failure Research Collaborative Group showed a 26% reduction in the combined risk of death or hospitalisation with carvedilol 12.5 to 50 mg/day relative to placebo after a mean 19-month follow-up period in 415 patients with CHF (relative risk 0.74). Adverse events with carvedilol appear to be less frequent than with other beta-blocking agents, are dosage-related and are usually seen early in therapy. Events most commonly reported are related to the vasodilating (postural hypotension, dizziness and headaches) and the beta-blocking (dyspnoea, bronchospasm, bradycardia, malaise and asthenia) properties of the drug. Carvedilol appears to date to have little effect on the incidence of worsening heart failure. Concomitant administration of carvedilol with some medications requires monitoring. Carvedilol is therefore likely to have a beneficial role in the management of controlled CHF, but further clinical studies are required to show the place of beta-adrenoceptor blocking therapy in general in this indication, and the position of carvedilol relative to other similar agents. Carvedilol is also confirmed as effective in the management of mild to moderate hypertension and ischaemic heart disease.

Adrenergic beta-Antagonists↗

PubMed1996

ICAM-1 mediates leukocyte-endothelium adhesive interactions in the reversed passive Arthus reaction.

A murine anti-rat intercellular adhesion molecule 1 (ICAM-1) monoclonal antibody (mAb), 1A29, was used to investigate the importance of blood leukocyte-associated beta 2-integrin (CD11/CD18) vascular endothelium-associated ICAM-1 adhesive interactions in the reversed passive Arthus reaction (RPAR) in rats. An Arthus pleurisy reaction (4 h) was employed in these studies because it permits the accurate quantitation of polymorphonuclear neutrophil (PMN) influx into the pleural space and fluid accumulation. 1A29, which localized within Arthus lung lesions, caused a dose-dependent (0.5-2.0 mg/kg, i.v.) inhibition of PMN influx (19-56%) and exudate volume (9-55%) in the Arthus pleurisy reaction. P7 (2 mg/kg, i.v.), a murine anti-human P-selectin mAb used as an isotype-matched control for 1A29, did not localize at the lung lesion site and was inactive. Immunohistochemical analysis of lung tissue from 1A29-treated rats demonstrated increased granulocyte accumulation in the alveolar capillaries compared with more extensive granulocyte emigration into the lung tissue and pleural space in P7-treated rats and Arthus control rats; however, quantitative image analysis revealed increased numbers of lung granulocytes in 1A29-treated rats compared with controls. Neither ICAM-1 mRNA nor expression, assessed by immunocytochemistry, was increased above control levels in rats during the pleural Arthus reaction. Neutropenia was not observed in either 1A29- or P7-treated rats.

Animals↗

PubMed1996

The inflammatory potential of IL-2: local induction of a specific chronic granulomatous lesion in mice.

Subcutaneous injection of recombinant human interleukin-2 (rhuIL-2) at 10(2)-10(4) U/mouse induced delayed (48 h) accumulation of mononuclear leukocytes with diffuse granulocytes, including eosinophils. Subcutaneous local infusion of rhuIL-2 or recombinant murine IL-2 (10(2)-10(4) U/mouse) via implanted Alzet miniosmotic pumps in mice induced chronic inflammatory lesions characterized by infiltration of large vacuolated mononuclear leukocytes, lymphoid cells, and eosinophil foci; neovascularization, with high endothelial-like cells, was prominent, exhibiting intravascular trapping and migration of large mononuclear leukocytes. Leukocyte infiltrates comprised T lymphocytes (CD4+; CD8+), B lymphocytes, and macrophages. Control infusions of bovine serum albumin (BSA) induced weak fibrotic lesions with sparse macrophage infiltration and minimal accumulation of lymphocytes; VLA4+ and ICAM-1+ leukocyte infiltrates were significantly greater in IL-2-induced lesions compared with BSA-induced lesions. Quantitative image analysis showed significantly increased lesion size in the IL-2-induced lesions compared with those induced by BSA infusion. The vascularity of IL-2-induced lesions assessed by immunostaining for platelet-endothelial cell adhesion molecule was increased compared with control, BSA-induced lesions mainly due to neovascularization. ICAM-1 and VCAM-1 expression was significantly enhanced in IL-2 lesions. No systemic pathological changes were observed following IL-2 infusion. We conclude that local slow-release of IL-2 causes the evolution and maintenance of a specific chronic inflammatory lesion.

Animals↗

PubMed1996

Increased ventilation in runners during running as compared to walking at similar metabolic rates.

At similar levels of carbon dioxide production (VCO2) and oxygen consumption (VO2), runners have been shown to have a greater minute ventilation (VE) during running as compared to walking. The mechanism responsible for these differences has yet to be identified. To determine if these differences are a result of differences in acid-base status, potassium (K+), norepinephrine and/or epinephrine levels, seven well-trained runners completed walk and run tests at similar VO2 and VCO2 levels. The occurrence of entrainment of the breathing and stride frequencies during both walking and running was also determined. VE was significantly greater during the run as compared to the walk, 73.7 (2.2) versus 68.6 (2.0) l.min-1, respectively, despite the similarity in VO2 and VCO2 levels. Alveolar ventilation was not significantly different between the run and the walk, 60.4 (4.7) versus 59.6 (4.4) l.min-1, respectively. Dead space ventilation was found to be significantly greater during running as compared to walking, 13.3 (3.2) versus 9.0 (4.7) l.min-1, respectively. The increases in VE were due to increases in breathing frequency and decreases in tidal volume during the run as compared to the walk. Arterial partial pressures of CO2 (PaCO2) were not significantly different when comparing walking and running to rest values nor when comparing walking and running. Arterial pH was significantly lower during walking as compared to rest and running. Bicarbonate levels were significantly lower during walking as compared to rest. Lactate was significantly greater during walking as compared to rest and to running. K+ levels were significantly higher during walking and running as compared to rest. Epinephrine and norepinephrine levels were not significantly different between running and walking. During the walk, six of the seven subjects entrained their breathing frequency to the stride frequency, and during the run three of the seven subjects demonstrated entrainment. Results from this investigation do not support mediation of VE under the present experimental conditions by changes in arterial levels of humoral factors previously shown to influence VE.

Acid-Base Equilibrium↗

PubMed1996

Aspergillus fumigatus infection of an automatic internal cardiac defibrillator.

We report a patient without immune compromise with infection of an automatic internal cardiac defibrillator patch due to Aspergillus fumigatus presenting 8 years after implantation. The mechanism of infection was unknown, but symptoms began 1 month after laser uvulopalatopharyngoplasty was performed for sleep apnea. The patches were surgically removed and the patient was treated sequentially with amphotericin B and itraconazole. He remains without evidence of infection 12 months after the completion of therapy.

Aged↗

PubMed1996

Mitoxantrone: a review of its pharmacological properties and use in acute nonlymphoblastic leukaemia.

Acute nonlymphoblastic leukaemia (ANLL) is a malignant condition strongly associated with advancing age. Of adult acute leukaemias, 80 to 85% are classified as ANLL, with more than half of all patients being aged over 60 years. Although advancing age has been reported to be a poor prognostic factor in ANLL, recent clinical trials have shown good results in patients aged 60 years and over after coadministration of the anthracenedione antineoplastic agent mitoxantrone with cytarabine. In 1 study in particular, which involved patients aged 60 to 81 years, no correlation was found between increasing age and response rate. However results of a major clinical trial showed age greater than 60 years to be associated with poorer outcomes. Mitoxantrone as initial induction treatment is at least as effective as daunorubicin when either drug is given in combination with cytarabine to patients with previously untreated ANLL. Complete response rates in randomised comparative trials were 53 to 67% after mitoxantrone with cytarabine and 37 to 70% after daunorubicin with cytarabine. In a major US study, significantly more patients achieved a complete response after 1 treatment cycle of mitoxantrone and cytarabine than after daunorubicin and cytarabine. Mitoxantrone has also been effective in inducing complete remissions in patients with relapsed or refractory ANLL, mainly in combination with other antineoplastic agents. Overall survival appears similar after treatment with regimens containing either mitoxantrone or daunorubicin in patients with ANLL, although there have been reports of trends towards increased survival rates with mitoxantrone. The incidence of cardiotoxicity appears low in patients with ANLL who have received mitoxantrone. Lower cardiotoxicity of mitoxantrone relative to daunorubicin has not been conclusively demonstrated in patients with ANLL, although trials in patients with breast cancer have shown mitoxantrone to cause fewer cardiac adverse effects than doxorubicin. This is of particular interest in the elderly, as this group of patients is especially susceptible to the effects of anthracycline-induced cardiac toxicity. Thus, mitoxantrone is a suitable first-line agent for the induction of remission in patients with ANLL, with clearly demonstrated efficacy in patients aged 60 years and over.

Adult↗

PubMed1996

Epoetin beta. A review of its pharmacological properties and clinical use in the management of anaemia associated with chronic renal failure.

Epoetin beta is a recombinant form of erythropoietin, the hormone responsible for the maintenance of erythropoiesis. The drug binds to and activates receptors on erythroid progenitor cells which then develop into mature erythrocytes. Epoetin beta increases reticulocyte counts, haemoglobin levels and haematocrit in a dose-proportional manner. These changes are accompanied by beneficial cardiovascular effects, including decreased cardiac output, resting heart rate and left ventricular hypertrophy in patients with chronic renal failure (CRF). Increases of 15 to 54% in haemoglobin levels and 17 to 60% in haematocrit were reported after subcutaneous or intravenous epoetin beta therapy in studies of 8 weeks' to 12 months' duration. Two multicentre clinical trials demonstrated clearly the superior efficacy of epoetin beta over placebo in 229 patients with CRF undergoing haemodialysis. Reduction or elimination of transfusion requirements was reported in studies where this parameter was measured. Comparative data indicate that dosage reductions of approximately 30% compared with intravenous therapy are possible when subcutaneous administration of epoetin beta is used. Haematocrit increased more rapidly in 5 multicentre studies in patients who received epoetin beta subcutaneously than in those who received the same dosage intravenously. Correction of anaemia with epoetin beta is associated with significant improvements in quality of life in patients with CRF. Available data indicate greatest cost-effectiveness in patients who are severely incapacitated by anaemia before treatment. The cost of administration of the drug may also be reduced by the use of the subcutaneous route. Hypertension may occur in patients who receive epoetin beta but may be minimised by avoiding rapid increases in haematocrit (> 0.5%/week), and is managed in most cases with control of fluid status and antihypertensive medication. Although clotting of the vascular access has not been conclusively linked to epoetin beta, caution is recommended in patients undergoing haemodialysis. Increased heparinisation is recommended to prevent clotting in dialysis equipment. Epoetin beta is more effective and/or better tolerated than alternative treatments (e.g. androgenic steroids) for anaemia associated with CRF. It also causes significant improvements in quality of life, exercise capacity and overall well-being. Results of clinical studies indicate that subcutaneous administration is desirable where possible in the majority of patients. Thus, epoetin beta has become established as an effective treatment for anaemia associated with CRF.

Anemia↗

PubMed1996

Azithromycin. A review of its pharmacological properties and use as 3-day therapy in respiratory tract infections.

The azalide antibacterial agent azithromycin is a semisynthetic acid-stable erythromycin derivative with an expanded spectrum of activity and improved tissue pharmacokinetic characteristics relative to erythromycin. The drug is noted for its activity against some Gram-negative organisms associated with respiratory tract infections, particularly Haemophilus influenzae. Azithromycin has similar activity to other macrolides against Streptococcus pneumoniae and Moraxella catarrhalis, and is active against atypical pathogens such as Legionella pneumophila, Chlamydia pneumoniae and Mycoplasma pneumoniae. Once-daily administration of azithromycin is made possible by the long elimination half-life of the drug from tissue. Azithromycin is rapidly and highly concentrated in a number of cell types after absorption, including leucocytes, monocytes and macrophages. It undergoes extensive distribution into tissue, from where it is subsequently eliminated slowly. A 3-day oral regimen of once-daily azithromycin has been shown to be as effective as 5- to 10-day courses of other more frequently administered antibacterial agents [such as erythromycin, amoxicillin-clavulanic acid and phenoxymethylpenicillin (penicillin V)] in patients with acute exacerbations of chronic bronchitis, pneumonia, sinusitis, pharyngitis, tonsillitis and otitis media. Adverse effects of azithromycin are mainly gastrointestinal in nature and occur less frequently than with erythromycin. Azithromycin is likely to prove most useful as a 3-day regimen in the empirical management of respiratory tract infections in the community. Its ease of administration and 3-day duration of therapy, together with its good gastrointestinal tolerability, should optimise patient compliance (the highest level of which is achieved with once-daily regimens). Azithromycin is also likely to be useful in the hospital setting, particularly for outpatients and for those unable to tolerate erythromycin.

Anti-Bacterial Agents↗

PubMed1996

Dalteparin sodium. A review of its pharmacology and clinical use in the prevention and treatment of thromboembolic disorders.

The low molecular weight heparin (LMWH) dalteparin sodium is notable for its improved pharmacokinetic characteristics (chiefly increased bioavailability and plasma elimination half-life) compared with unfractionated heparin (UFH). These properties enable the drug to be given subcutaneously as a single daily dose, compared with the 8- to 12-hourly regimens necessary with UFH. Dalteparin sodium also appears to exert a greater inhibitory effect than UFH on plasma activity of coagulation factor Xa relative to its effects on clotting times [usually expressed as activated partial thromboplastin time (APTT)] and activity of factor IIa. It is not associated with any clinically significant effects on the fibrinolytic system and may have less lipolytic activity than UFH. Extensive clinical studies have been conducted to compare the antithrombotic efficacy of dalteparin sodium with that of UFH in surgical thromboprophylaxis, treatment of established deep vein thrombosis (DVT) and the anticoagulation of patients undergoing haemodialysis and haemofiltration. The majority of trails of patients receiving thromboprophylactic heparin perioperatively have shown similar efficacy of dalteparin sodium and UFH in the prevention of DVT and pulmonary embolism (PE), although 2 groups of investigators reported superior antithrombotic potency for dalteparin sodium. The two types of heparin appear similarly effective in the management of established DVT and the maintenance of the extracorporeal circulation in haemodialysis circuits. Dalteparin sodium has also shown clinical benefit in the management of patients with unstable angina or non-Q-wave myocardial infarction. The overall incidence of haemorrhagic complications observed with daltparin sodium therapy is no greater than that associated with UFH, and data suggest that perioperative transfusion requirements and frequency of bleeding are lower after dalteparin sodium. The antithrombotic efficacy of dalteparin sodium is at least equivalent to that of UFH, although further clinical comparisons with other LMWHs are required. Further studies are also needed to clearly define any advantages of dalteparin sodium over UFH (and other antithrombotics) with regard to the incidence of haemorrhagic complications. The drug has also shown clinical efficacy in the prevention of myocardial infarction and death in patients with unstable coronary artery disease. In addition, there may be cost advantages attached to the once-daily subcutaneous regimen of dalteparin sodium, but this requires further examination. Thus, dalteparin sodium is an effective antithrombotic agent for perioperative thromboprophylaxis, the management of established DVT, and the anticoagulation of patients undergoing haemodialysis.

Anticoagulants↗

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↗

PubMed1995

Epoetin alfa. A review of its clinical efficacy in the management of anaemia associated with renal failure and chronic disease and its use in surgical patients.

Epoetin alfa is a recombinant form of erythropoietin, a glycoprotein hormone which stimulates red blood cell production by stimulating the activity of erythroid progenitor cells. This review discusses the use of the drug in the management of anaemia in diseases often associated with advancing age [renal failure, cancer, rheumatoid arthritis (RA) and other chronic diseases, and the myelodysplastic syndromes (MDS)] and in surgical patients. Intravenous and subcutaneous therapy with epoetin alfa raises haematocrit and haemoglobin levels, and reduces transfusion requirements, in anaemic patients with end-stage renal failure undergoing haemodialysis or peritoneal dialysis. The drug is also effective in the correction of anaemia in patients with chronic renal failure not yet requiring dialysis and does not appear to affect renal haemodynamics adversely or to precipitate the onset of end-stage renal failure. Response rates of 32 to 82% with epoetin alfa therapy have been reported in patients with anaemia associated with cancer or cytotoxic chemotherapy. Limited data in patients with anaemia associated with RA show correction of anaemia after epoetin alfa treatment. Response rates to the drug of 0 to 56% have been noted in patients with MDS. Epoetin alfa also reduces anaemia, increases the capacity for autologous blood donation and reduces the need for allogeneic blood transfusion in patients scheduled to undergo surgery. Hypertension occurs in 30 to 35% of patients with end-stage renal failure who receive epoetin alfa, but this can be managed successfully with correction of fluid status and antihypertensive medication where necessary, and is minimised by avoiding rapid increases in haematocrit. Although vascular access thrombosis has not been conclusively linked to therapy with the drug, increased heparinisation may be required when it is administered to patients on haemodialysis. Epoetin alfa does not appear to exert any direct cerebrovascular adverse effects. Thus, epoetin alfa is a well established and effective therapy for the management of anaemia associated with renal failure. It also improves haematocrit and quality of life in patients with anaemia associated with cancer or chemotherapy. Epoetin alfa increases the capacity for blood donation and reduces the decrease in haematocrit seen in patients donating autologous blood prior to surgery. It also reduces, but may not eliminate, the need for allogeneic blood transfusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1995

Celiprolol. An evaluation of its pharmacological properties and clinical efficacy in the management of hypertension and angina pectoris.

Celiprolol is a beta 1-selective adrenoceptor antagonist (beta-blocker) which acts as a weak agonist at beta 2-adrenoceptors. The drug demonstrates vasodilator properties and does not depress heart rate to the same extent as propranolol, atenolol or metoprolol. Celiprolol has shown equivalent antihypertensive efficacy to other beta-blockers, notably propranolol, atenolol, metoprolol and pindolol, in patients aged 18 to 75 years with mild to moderate essential hypertension. The drug has also shown similar antihypertensive efficacy to the angiotensin converting enzyme inhibitor enalapril and to combination diuretic therapy with hydrochlorothiazide and amiloride. Celiprolol was equally effective in adult patients of all ages, although no data are available for patients aged over 75 years. Data from a small number of clinical trials indicate celiprolol to be as effective as both propranolol and atenolol in improving work capacity and reducing the frequency of anginal attacks in patients with stable effort angina. However, the drug has not yet been evaluated in postmyocardial infarction patients. Celiprolol offers advantages over other beta-blockers, including reduction of peripheral vascular resistance and maintenance of resting heart rate, cardiac output and renal perfusion. The drug is also associated with improvements in plasma lipid profiles and does not appear to adversely affect carbohydrate metabolism or lung function, although its use in patients with reversible obstructive pulmonary disease is not recommended. Celiprolol is therefore a highly cardioselective beta-blocker with ancillary characteristics which are potentially useful in patients with hypertension and angina complicated by other conditions commonly associated with advanced age. These include impaired glucose tolerance or diabetes mellitus, peripheral vascular disease and hyperlipidaemia. The drug may also be preferred to other beta-blockers in patients in whom a reduction in heart rate would be particularly undesirable. Further long term (> 12 months) clinical trials and pharmacoeconomic data are now required to confirm the clinical relevance of the pharmacodynamic advantages of celiprolol therapy.

Administration, Oral↗