less clear. Quinagolide is not licensed for lactation suppres­sion in the UK. However, in patients with hyperprolactinaemia who are hypersensitive to ergot derivatives, quinagolide offers an alternative option.

References 1. Rains CP, Bryson HM, Fitton A. Cabergoline: a review of its

pharmacological properties and therapeutic potential in the treatment of hyperprolactinaemia and inhibition of lactation. Drugs 1995 Feb; 49(2): 255-79

2. Ho KY, Thorner MO. Therapeutic applications of bromocriptine in endocrine and neurological diseases. Drugs 1988; 36: 67-82

3. Serri O. Progress in the management of hyperprolactinamia [editorial]. New Eng J Med 1994 Oct 6; 331(14): 942-4

4. Sandoz withdrawing Parlodel postpartum lactation suppression indication. FDC Report - Pink Sheet 1994 Aug 22; T&G I

5. Parlodel indication withdrawn in Italy. Scrip 1995 May 5; (2022): 23

Doxazosin: long-acting a-blocker for hypertension and prostatic hypertrophy

Doxazosin appears to have a valuable role in the management of patients \\ ith hypertension and/or benign prostatic hypertrophy.

In patient. with hypertcn,ion. doxal.o~in appear to be particularly appropriate fOrlhose with other cardiovascular risk fa tors such a hyper holcstcrolaemia and diabetes mellitus.

In bcnign prostatic hypertrophy, doxazosin may bc mo~t u ·cful in patients with trouble ome symptoms who are unable or unwilling to undergo invasive procedure ·. but who require rapid symptomati relief. The drug is not ·uitable for those patient with urinary retention.

Role in hypertension explored

Compared with other a-blockers

Doxazosin t is a selective al-adrenoceptor antagonist, and as such is a member of a drug class widely recom­mended as a suitable first-line option for the management of mild to moderate hypertension.[l-3]

Compared with other agents of its class, doxazosin has a more prolonged elimination half-life (16 to 22 hours, vs 2.5 to 2.9 hours forprazosin and 8 to 13 hours forterazosin»)4] Doxazosin and terazosin are both administered once daily, whereas prazosin is administered 2 or 3 times daily)5]

Doxazosin 0.5 to 16 mg/day was generally as effective as terazosin 1 to 20 mg/day and prazosin 1 to 20 mg/day in double-blind, parallel trials in patients with mild to moderate essential hypertension)4]

In addition, the tolerability profile of doxazosin is as expected for a member of this drug class. Dizziness, head­ache, fatigue and somnolence are the most frequently reported adverse effects in hypertensive patients treated with the drug)6]

Orthostatic hypotension may occur with a-blockers, and may have serious consequencesP] This effect is particularly prominent with the first dose of the drug, and may be minimised by gradual dosage titration, administration before

1172-0360/95/00017-005/$01.00 ©Adis International Limited. All rights reserved

6. British National Formulary No. 29. London: The Pharmaceutical Press, 1995;307-8

7. New Ethicals Compendium. 5th Ed. Auckland: Adis International Ltd, 1994; 551-3

8. Clinical Pharmacokinetics: drug data handbook 1990. Auckland: Adis Press Ltd, 1990; 21

9. Webster J, Piscitelli G, Polli A, et al. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med 1994 Oct 6; 331(14): 904-9

10. Giusti M, Porcella A, Carraro M, et al. A cross-over study with the two novel dopaminergic drugs cabergoline and quinagolide in hyperprolactinemic patients. J Endocrinol Invest 1994; 17: 51-7

11. European Multicentre Study Group for Cabergoline in Lactation Inhibition. Single dose cabergoline versus bromocriptine in inhibition of puerperal lactation: randomised, double blind multicentre study. BMJ 1991 Jun 8; 302: 1367-71

12. Giorda G, Devincentiis S, Motta T, et al. Cabergoline versus bromocriptine in suppression of lactation after cesarean delivery. Gynecol Obstet Invest 1991; 31(2): 93-6

retiring to bed and attention to nondrug measures, such as fluid balance)7]

In the US, the acquisition costs of doxazosin are lower than those of terazosin but higher than those of prazosin for the lowest recommended dosages)8] In Canada, prazosin has lower acquisition costs than either terazosin or doxazosin.

Compared with other antihypertensive drug classes

The results of several double-blind trials indicate that doxazosin generally has antihypertensive efficacy comparable with that of alternative agents, including:

• ACE inhibitors (captopril and enalapril)

• ~-blockers (atenolol and acebutololt ) • calcium antagonists (amlodipine, nifedipine, nitrendipine, t

verapamil)

• diuretics (hydrochlorothiazide, chlorthalidone»)4] One large trial deserving special mention is the Treat­

ment of Mild Hypertension Study (TOMHS»)9] Selected results from this study are shown in the Differential Features table, and are discussed further below.

Few differences were observed between the drug treat­ments although:

• the most favourable changes in lipid levels occurred in doxazosin recipients

• chlorthalidone had the greatest effect on left ventricular mass

• improvements in quality of life were more marked for chlorthalidone and acebutolol than the other drugs

• based on the percentage of patients continuing with their assigned therapy, amlodipine was the best-tolerated drug. In an overall analysis, data from all patients receiving

drug therapy plus lifestyle modification were combined and compared with those from patients receiving lifestyle modification alone. The addition of drug therapy was associated with a greater reduction in blood pressure, fewer clinical events (such as cerebrovascular deaths, coronary heart disease events) and fewer ECG abnormalities than lifestyle modification alone)9]

t Doxazosin is registered in France and is not available in Australia; acebutolol is not available in Australia; nitrendipine is not available in Australia.

Vol. 6, No.5; September 4, 1995

5

6 ~ - S & mPllh Jet In "i"

Differential Features

Comparison of the features of doxazosin and other drugs included in the Treatment of Mild Hypertension Study (TOMHs)a

Drug Doxazosin Acebutolol Amlodipine Chlorthalidone Enalapril

Drug closs <ll-Blocker ~-Blocker with ISA Calcium Thiozide diuretic ACE inhibitor antaganist

TOMHS results at48 months(9) % of patients taking initially 661 778 82.S 67 .S 68.1 assigned medication only Mean reduction in BP (mm Hg) 13 . .4/11.2 (;:O P) 13.9/11.5 (~P) 1.4.1/12.2 (>P) 1.4.6/11 1 (~P) 11 .3/9.7 (NS) Mean reduction in LV mass (g) 2.4 (NS) 24 (NS) 25 (NS) 3.4 (~P) 23 INS) Change in OOL indexesb NS ;:.P, ~D NS ;:.P NS Effects on blood lipidsc ;::P NS NS NS NS

Main adverse effectsl l) Orthostatic Bronchospasm, Headache, Electrolyte Cough, rash, peripheral dizziness, disturbances, hypotension,

syncope, vasoconstriction, peripheral metabolic a~ioneuratic o ema,

weakness, Fatigue, insomnia , oedema, disturbances, hyperkalaemia, taste disturbance metabolic sexual halpitatians,

eadache disturbances, reduced tachycardia

dysfunction exerCI se tolerance

Place in therapydll) No concomitant conditions + ++ + ++ + Antno pectoris + ++ ++ + + Ast ma + + + + Heart failure + ++ ++ 100M ++ + ++ ++ ++ NIDDM ++ + ++ + ++ Dyslipidaemia ++ + ++

Doily adult dose (no of doses) 1-16mg (1) 200- 1 200mg (lor 2) 2.S-1 Omg (I) 12.S-S0mg (I) 2,S-.40mg (I ar 2)

A(~uisition cosl" In t e US ($)181 26.60 28.08 3S.36 2.27 21 .53 In the UK (£)15) 15,09 9.28 12.70 0.6.4 8.42

a TOMHS was a randomised, double-blind, placebo-controlled trial comparing the effects of 5 antihypertensive agents in combination with lifestyle modiFication in 902 patients with mild hypertension (diastalic BP 90 to 99mm Hg). Initial drug dosages were: chlorthalidone I 5 mg/day, acebutolol .400 mg/ day, doxazosin 1-2 mg/ day, amlodipine Smg/ day or enalapril S mg/ day. Initial dosages were daubled iF inadequate response was obtained. b Results af overall test for the combined 7 OOL domains: general health; energy and Fatigue; mental health; general functioning; satisFaction with physical abilities; social functioning; social contacts. c Total and low-density lipoprotein cholesterol levels. d Based on recommendations For the respective drug classes as initial therapy made in the fifth report of the Joint Notional CammiHee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). e For 30 days' treatment with the lowest recommended maintenance dosage. Abbreviations and symbols: 100M = insulin-dependent diabetes mellitus; ISA = intrinsic sympothomimetic activity; LV = left ventricular; NS = not signiFicantly different From placebo; NIOOM = non-insulin-dependent diabetes mellitus; OOL = quality of life; ;:.0 = improvement significantly greater than in doxazosin recipients; ;:.P = improvement sjgnifican~y greater than in placebo recipients; ++ = recommended as preferred First-line aption; + = acceptable alternative First-line option/some limitations; - = relatively or absolutely contraindicated.

Effects on other CHD risk factors

Hypertension is a major risk factor for coronary heart disease (CHD), but other modifiable risk factors that contribute to an increased risk include elevated total and low-density lipoprotein (LDL)-cholesterol levels, reduced high-density lipoprotein (HDL)-cholesterol levels, smoking, left ven­tricular hypertrophy, diabetes mellitus, obesity, sedentary lifestyle, renal disease and microalbuminuria.l3] Thus, in the context of overall cardiovascular risk, it appears to be important that antihypertensive drugs do not adversely affect any of these other risk factors.

Doxazosin appears to have favourable or neutral effects on a number of these risk factors, as follows.

Metabolic effects The beneficial effects of doxazosin on the blood lipid

profile are well established. Changes include decreased levels of total cholesterol, LDL-cholesterol and triglycer­ides, and increased levels of HDL-cholesterol.l4] These changes have been demonstrated in randomised double-

Vol. 6, No.5; September 4, 1995

blind trials and a large general practice trial, as well as in patients with non-insulin-dependent diabetes mellitus (NIDDM) or hypercholesterolaemia, and in smokers.l4] Moreover, the effects of doxazosin on lipid levels appear to be more favourable than those of ~-blockers, thiazide diuretics and calcium antagonists, and similar to those of ACE inhibitors.l9]

Several small noncomparative trials have indicated that doxazosin has either neutral or favourable effects on glycae­mic control among patients with and without NIDDMJ4] In TOMHS, no significant between-group differences in blood glucose levels were observed.l9] The drug appears to have minimal effects on vasoactive hormone levels, although plasma noradrenaline levels may be slightly elevated. l4]

Cardiovascular and renal effects Doxazosin has been shown to reduce left ventricular

mass, although the TOMHS results indicated that, with the exception of chlorthalidone, the addition of any drug to lifestyle modification was no more effective than lifesty Ie modification alone.l9]

1172-0360/95/00017-006/$01.00 ©Adis International Limited. All rights reserved

The effects of doxazosin on fibrinolysis and platelet function have not been fully defined, but available data suggest that the drug does not have adverse effects.[4]

In patients with normal renal function, doxazosin does not alter glomerular filtration rate, renal plasma flow or renal vascular resistance.l4] In nondiabetic patients with hyper­tension and microalbuminuria, it has shown comparable beneficial effects to felodipine, ramipril and metoprolol.[lO] In other studies in patients with moderate renal impairment and hypertension, doxazosin has reduced blood pressure without affecting renal function.l4]

Useful in prostatic hypertrophy {X-Blockers have a role in benign prostatic hypertrophy

(BPH) because they are able to reduce (XI-mediated con­striction of prostatic smooth muscle, and thus relieve bladder outflow obstruction)ll] Doxazosin has recently been approved for this indication in the US.

The symptoms of BPH fluctuate with time and there is a high placebo response; thus, only data from placebo­controlled trials may be used to establish the efficacy of drugs in this condition) II] In randomised, double­blind trials in patients with BPH, administration of doxazosin I to 12 mg/day for 5 to 29 weeks was associated with mean changes in peak urinary flow of -0.4 to 3.9 mllsec, compared with changes of -l.6 to l.1 ml/sec in placebo recipients.l4]

Clinically significant improvements in urinary flow (defined variously as an increase in maximum urinary flow of >3 ml/sec, :2:20% or :2:50%) were also significantly more common among doxazosin than placebo recipients. Such responses were observed in between 36 and 52% of doxazosin and 17 and 30% of placebo recipients.l12-141

Doxazosin has not been directly compared with other drugs used in men with BPH. Table 1 compares the features of doxazosin with those of finasteride, the only agent from a drug class other than {X-blockers currently approved by the US FDA for this condition. Both drugs act primarily on the obstructive symptoms of BPH, but also provide some relief from irritative symptoms, such as urinary frequency, urgency and nocturia)4,15]

Prescribing and formulary considerations

In hypertension

Doxazosin is an effective drug that may be considered among the first-line options for treating hypertension. At present, there are no outcomes data to distinguish doxazosin from other agents; diuretics and ~-blockers remain the only agents proven to reduce mortality)l]

Consideration of overall CHD risk, concomitant con­ditions, the need for once-daily administration, acquisition costs and tolerability may direct prescribing decisions.

In prostatic hypertrophy

Treatment for men with BPH must be individualised, with particular attention paid to the distress caused by the various symptoms. Men with identical values for peak urinary flow may have very different views on the effect of these symptoms on their quality of life.l 16]

There are several options available for men with BPH, ranging from watchful waiting, through drug therapy and minimally invasive surgery, to prostatic resection.[16]

1172-0360/95/00017-007/$01.00 © Adis International Limited. All rights rese",ed

Table 1. Comparison of the features of doxazosin and finasteride[4, 11 ,15,16]

Feature

Mode of action

Daily dose

Mean change in peak urinary Row"

Response rate'>

Time to maximal response

Effect on PSA level

Adverse effects<

Ploce in therapyd Mild disease Moderate disease Severe disease Urinary retention

Doxazosin

a -Blocker; reloxotion of prostotic smooth muscle

1-12mg

-0.4 to 3.9 ml/sec

36-52%

;,:2 weeks

None

DIzziness, hypotension, fatigue, oedema, dyspnoea

x ,/

./ x

Finasteride

Sa-reductose inhibitor; shrinkage of the prostate gland

5mg

1 to 4.3 ml/sec

33%

6 months

~50% reduction

Decreased libido, ejaculation disorders, impotence

x ./ ./ x

a From baseline in placebo-controlled trials. b Response defined variously as on increase of peak urinary now rate of >3 ml/sec or ;e:20% or ;e:50%. c DeFined as those that occurred in significantly more drug recipients than placebo recipients in patients with benign prostatic hypertrophy. d Severity of disease os determined by American Urological Associotion questionnaire. Abbreviation and symbols: PSA = prostate-specific antigen, ./ = suitable for use in this indication; x = not suitable for use in this indication.

Drug therapy appears to be most appropriate for men who are bothered by the symptoms of BPH, do not have urinary obstruction and do not want, or are unsuitable for, invasive procedures.

The decision regarding whether to use finasteride or an {XI-blocker as initial therapy may be based on the need for rapid response, concomitant conditions such as hyperten­sion, local policies on using prostate-specific antigen to screen for prostate cancer, and the patient's ability to tolerate the likely adverse effects of the drugs. In men with both BPH and hypertension, an {XI-blocker appears to be a logical choice.

~

Adis Evaluation

Key points in the overall evaluation of doxazosin CLINICAL BENEFITS _. __________ _

• Generally as effective as other antihypertensives

• Favourable effects on blood lipid profile in potients with hypertension

• Provides relief from obstructive and irritative symptoms of benign prostatic hypertrophy

POTENTIAL LIMITATIONS __________ _

• Higher acquisition costs than some alternative antihypertensives

• Improvements in prostatic hypertrophy are relatively modest

Vol. 6, No.5; September 4, 1995

7 -

8

When an <XI-blocker is required, doxazosin appears to be suitable choice. Local availability, need for a long duration of action, and acquisition costs may determine whether it is preferred over other <XI-blockers.

References I. Joint National Committee on Detection, Evaluation, and Treatment

of High Blood Pressure. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment fo High Blood Pressure (JNC V). Arch Intern Med 1993 Jan 25; 153: 154-83

2. Sever P, Beevers G, Bulpitt C, et al. Management guidelines in essential hypertension: report of the second working party of the British Hypertension Society. BMJ 1993 Apr 10; 306: 983-7

3. Guidelines Sub-Committee. 1993 guidelines for the management of mild hypertension: memorandum from a World Health Organization/ International Society of Hypertension meeting. J Hypertension 1993; 1l(9): 905-18

4. Fulton B, Wagstaff AJ, Sorkin EM. Doxazosin: an update of its clinical pharmacology and therapeutic applications in hypertension and benign prostatic hyperplasia. Drugs 1995 Feb; 49(2): 295-320

5. British National Formulary No. 29. London: The Pharmaceutical Press, 1995

Superoxide dismutase has wide clinical potential

Knowledge that reactive oxygen metabolites play an important role in the pathophysiology of several disease states has led to the investigation of antioxidants in diverse conditions such as transplant rejection, brain trauma, cancer and osteoarthritis.

Superoxide dismutase t is an enzymatic antioxidant produced by the body, which forms a defence against reactive oxygen metabolites generated as a result of normal metabolic processes)l] It has shown preliminary efficacy in improving the function and survival of renal grafts, and in improving the outcome of patients with severe head injuries.

Defence against superoxide anions Superoxide dismutase catalyses the conversion of 2

superoxide anion radicals (02-) to hydrogen peroxide (H202) and oxygen (02).[1] Hydrogen peroxide is a com­paratively less reactive oxidising agent than superoxide anion, because all electrons are paired. Nevertheless, it can react with transition metal ions to form the very reaqive hydroxyl radical.[1] However, another endogenous enzyme antioxidant, catalase, rapidly converts hydrogen peroxide to water and oxygen. [1]

Extending the duration of action Superoxide dismutase has a plasma half-life of only 8

minutes.[l] This suggests that it might need to be given by continuous infusion, when administered by the intrave­nous route)l] The time course of superoxide dismutase in

t Superoxide dismutase has orphan drug status in the US and Europe for certain organ transplant applications; in France, bovine superoxide dismutase has been withdrawn and recombinant human superoxide dismutase is not available; in Spain, bovine superoxide dis mutase is available, but recombinant human superoxide dismutase is not; in Germany, superoxide dismutase has been withdrawn as an antirheumatic.

VoL 6, No.5; September 4, 1995

6. Pfizer Inc. Doxazosin mesylate prescribing information. New York, NY, 1994

7. Management of drug-induced orthostatic hypotension. Drug Ther Perspect 1995 Ju124; 6(2): 12-14

8. Drugs for hypertension. Med Lett Drug Ther 1995 May 26; 37(949): 45-50 9. Neaton JD, Grimm RH, Prineas RJ, et al. Treatment of Mild

Hypertension Study: final results. JAMA 1993 Aug ll; 270(6): 713-24 10. Erley CM, Haefele U, Heyne N, et al. Microalbuminuria in essential

hypertension. Reduction by different antihypertensive drugs. Hypertension 1993 Jun; 21 (6 Pt I): 810-5

II. Andersen JT. aI-Blockers vs 5a-reductase inhibitors in benign prostatic hyperplasia. Drug Aging 1995 May; 6(5): 388-96

12. Chapple CR, Carter P, Christmas TJ, et al. A three month double-blind study of doxazosin as treatment for benign prostatic bladder outlet obstruction. Br J Urol 1994; 74; 50-6

13. Fawzy A, Braun K, Lewis GP, et al. Doxazosin in the treatment of benign prostatic hyperplasia in normotensive patients: a multicenter study. J Urol 1995 Jul; 154: 105-9

14. Christensen MM, Holme JB, Rasmussen PC, et al. Doxazosin treatment in patients with prostatic obstruction. Scand J Urol Nephrol 1993; 27(1): 39-44

15. Peters DH, Sorkin EM. Finasteride: a review of its potential in the treatment of benign prostatic hypertrophy. 1993 Jul; 46(1): 177-208

16. Oesterling JE. Benign prostatic hypertrophy: medical and minimally invasive treatment options. N Engl J Med 1995 Jan 12; 332(2): 99-109

the plasma may be extended by intramuscular or subcuta­neous injection, as this prolongs the absorption phase.l2J Alternatively, conjugation of superoxide dismutase with polyethylene glycol can increase the circulatory half-life from 8 minutes to between 24 and 35 hours)l]

Liposomal encapSUlation of superoxide dismutase has also been investigated as a means of increasing its elimi­nation half-life and cellular penetration.l2) In addition, use of cationic or anionic liposomes may improve targeting to specific organs)2]

Therapeutic applications Most clinical data relating to superoxide dismutase are

available for its use in renal transplantation and brain trauma.

Renal transplantation The pathogenesis of transplant rejection is multifac­

eted. Early damage to the organ during reperfusion is one factor that may decrease graft survival.)3) Animal studies have shown that antioxidants can decrease endothelial damage during reperfusion;[3] however, studies in patients have not been conclusive.

In I study, there was no difference in early renal graft function between those patients who received recombi­nant superoxide dismutase 200mg or placebo 2 to 10 minutes prior to reperfusion of grafts subjected to a short period of cold ischaemia.[4] Nevertheless, there was a trend towards improvement in graft function in superoxide dismutase recipients who received grafts subjected to a long period of cold ischaemia.

Another trial failed to demonstrate any improvement in early renal graft function in patients administered re­combinant superoxide dismutase 20 mg/kg compared with those administered placebo)51 In this study, storage time had no effect on graft function.

However, a retrospective analysis of the first trial 14 ) indicated that significantly fewer patients treated wi lh recombinant superoxide dismutase experienced I or more acute rejection episodes during the first year after trans-

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