Allopurinol
The optimal use of allopurinol: an audit of allopurinol use in South Auckland.

Stamp L, Gow P, Sharples K, Raill B.

Middlemore Hospital, South Auckland, New Zealand.

BACKGROUND: Gout is a common and challenging problem in South Auckland, New Zealand. Allopurinol is widely used but urate reduction remains unsatisfactory. Allopurinol dosing guidelines and a therapeutic range for plasma oxypurinol levels have been published. AIMS: We aimed to determine the appropriateness of allopurinol dosing according to current guidelines and to assess the relationship between plasma creatinine, oxypurinol and urate. In addition, we assessed the clinical usefulness of the oxypurinol level. METHODS: Thirty-one patients, on a stable dose of allopurinol for at least three weeks, had plasma creatinine, urate and oxypurinol measured as part of routine clinical assessment. Relationships between the various methods were examined using regression analysis. Fisher's exact test was used to test associations with categorical variables. RESULTS: Fifty-five per cent of patients were on higher than recommended doses of allopurinol. There was a statistically significant relationship between calculated creatinine clearance and plasma oxypurinol level. Only 50% of patients with a plasma oxypurinol within the therapeutic range (30-100 micromol/L) had a plasma urate < 0.42 mmol/L and this did not increase significantly in the patients with an oxypurinol level > 100 micromol/L. CONCLUSIONS: There is poor adherence to the current recommended dosing guidelines for allopurinol. Creatinine clearance rather than plasma creatinine needs to be used to predict the dose of allopurinol. The current role of the oxypurinol level is to identify non-compliers with allopurinol therapy. We need further research to clarify whether increasing the dose of allopurinol outside the recommended dose range to reach an oxypurinol level of close to 100 micromol/L may be of benefit in those who have not had sufficient urate reduction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11108066&dopt=Abstract allopurinol Zyloprim



Allopurinol
Sulfinpyrazone reduces cyclosporine levels: a new drug interaction in heart transplant recipients.

Caforio AL, Gambino A, Tona F, Feltrin G, Marchini F, Pompei E, Testolin L, Angelini A, Dalla Volta S, Casarotto D.

Department of Cardiology, University of Padova, Padova, Italy. acaforio ux1.unipd.it

BACKGROUND: Management of cyclosporine (CsA)-associated hyperuricemia in heart transplantation (HT) is difficult. Because of the myelotoxicity of combined allopurinol and azathioprine, we tested sulfinpyrazone. METHODS: We studied 120 HT recipients (109 men; mean age at HT, 52+/-10 years). All had received allopurinol for at least 6 months, which was stopped for 1 month before initiation of sulfinpyrazone. Mean follow-up from HT to onset of sulfinpyrazone (200 mg/day) was 59+/-41 months. We stopped the drug after 6+/-2 months. We compared CsA level and daily dose, serum creatinine, blood urea, and uric acid at onset and before interruption of sulfinpyrazone and, as control, in the last 6 months of allopurinol. RESULTS: Mean uricemia decreased with allopurinol (0.58+/-0.12 vs. 0.41+/-0.07 mmol/liter, p = 0.0001) as well as with sulfinpyrazone (0.51+/-0.13 vs. 0.40+/-0.12 mmol/liter, p = 0.0001). Mean creatinine increased (171+/-42 and 164+/-35 micromol/liter, p = 0.01) with allopurinol, whereas it tended to decrease with sulfinpyrazone (160+/-35 and 154+/-48 micromol/liter, p = NS). Mean urea did not change with allopurinol (14+/-5 vs. 15+/-7 mmol/liter, p = NS), but fell with sulfinpyrazone (14.01+/-5 vs. 12.60 +/-5 mmol/liter, p = 0.0004). Mean CsA levels were constant with allopurinol (193+/-73 vs. 188+/-65 ng/ml, p = NS), although CsA dose was slightly reduced (2.7+/-0.8 vs. 2.6+/-0.8 mg/kg/day, p = 0.007). Conversely, CsA levels dropped with sulfinpyrazone (183+/-89 vs. 121 +/-63 ng/ml, p = 0.0001) despite an increase in CsA daily dose (2.6 +/-0.9 vs. 2.8+/-0.9 mg/kg/day, p = 0.0001). Two subjects were treated for acute rejection. We observed no other side effects. In HT recipients sulfinpyrazone, as an alternative to allopurinol, is effective in achieving metabolic control of hyperuricemia. However, this drug reduced CsA levels, thus the risk of rejection is present.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11124491&dopt=Abstract allopurinol Zyloprim



Allopurinol
Allopurinol enhances the contractile response to dobutamine and exercise in dogs with pacing-induced heart failure.

Ukai T, Cheng CP, Tachibana H, Igawa A, Zhang ZS, Cheng HJ, Little WC.

Cardiology Section, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA.

BACKGROUND: Superoxide (O(2)(-)) generated by enhanced xanthine oxidase (XO) activity may contribute to the increased myocardial oxidative stress in heart failure (CHF). Because blocking XO with allopurinol augments myofilament Ca(2+) sensitivity in reperfusion injury and CHF, we hypothesized that it may improve adrenergic inotropic responsiveness in CHF. METHODS AND RESULTS: We studied the effect of allopurinol on the contractile response to dobutamine and exercise in 7 chronically instrumented conscious dogs before and after producing CHF by rapid pacing. Left ventricular (LV) contractile performance was measured by the slopes of the LV end-systolic pressure-volume relation (E(ES)) and stroke work-end-diastolic volume relation (M(SW)). Before CHF, allopurinol produced no change in LV contractile performance and did not alter the response to dobutamine or exercise. After CHF, allopurinol produced significant (P:<0.05) increases in E(ES) (5.0+/-0.6 versus 3.3+/-0.6 mm Hg/mL) and M(SW). Dobutamine and allopurinol produced greater increases in E(ES) (5.4+/-0.6 versus 7.4+/-0.6 mm Hg/mL) and M(SW) (60.1+/-7.4 versus 73.7+/-4.4 mm Hg) than did dobutamine alone. After allopurinol, dP/dt(max), stroke volume, and M(SW) were higher during CHF exercise. LV diastolic pressures were lower during CHF exercise after allopurinol. CONCLUSIONS: Allopurinol has no discernable effects on LV contractile function or adrenergic responsiveness in normal, conscious animals. In pacing-induced CHF, however, allopurinol improves LV systolic function at rest and during adrenergic stimulation and exercise.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11156889&dopt=Abstract allopurinol Zyloprim



Allopurinol
An alternative parameter for monitoring the therapeutic benefits of allopurinol simultaneously in renal ischaemia-reperfusion injury: MDA/ATP Ratio.

Bor MV, Durmus O, Cayci B, Turkozkan N.

Department of Biochemistry, Gazi University School of Medicine, Ankara, Turkey. vakbor hotmail.com

The therapeutic benefits of allopurinol pretreatment in renal ischaemia-reperfusion injury were investigated by monitoring renal malondialdehyde (MDA) and ATP levels together with calculated MDA/ATP ratio in ischaemic (45 min) and reperfused (15 min) rat kidneys. MDA levels remained unchanged during ischaemia, but increased after the subsequent reperfusion. ATP content of the ischaemic kidney was decreased significantly and the recovery of ATP was incomplete after the reperfusion, whereas the MDA/ATP ratio increased at both periods. Allopurinol pretreatment (40 mg kg(-1) iv) maintained higher ATP levels during the ischaemia and inhibited the MDA formation during the reperfusion and decreased the MDA/ATP ratio at both periods. Our findings demonstrate that allopurinol exerts a biphasic protective action by preserving tissue ATP and by inhibiting lipid peroxidation during ischaemia and the reperfusion period, respectively. These findings suggest the selective involvement of two protective mechanisms in the different periods of renal ischaemia-reperfusion injury. The MDA/ATP ratio could be a useful parameter for monitoring these protective actions of allopurinol simultaneously. Copyright 2000 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11180284&dopt=Abstract allopurinol Zyloprim



Allopurinol
Oxygen free radical generation in healthy blood donors and cardiac patients: the protective effect of allopurinol.

Belboul A, Roberts D, Borjesson R, Johnsson J.

Department of Thoracic and Cardiovascular Surgery, Sahlgrenska University Hospital, Goteborg, Sweden.

Cardiopulmonary bypass (CPB) activates the complement system, which leads to granulocyte activation and free radical production. Free radical activity during CPB has been associated with myocardial dysfunction. However, the relationship between cardiac enzymes and granulocytes to lipid peroxidation in cardiac surgery patients is unknown. Moreover, the effect of allopurinol on lipid peroxidation during mechanical trauma has to be explored. Thirty-four patients undergoing coronary bypass surgery and 26 healthy blood donors participated in this prospective study where granulocyte counts, cardiac enzymes and malondialdehyde (MDA) were measured and related. Allopurinol was used ex vivo, as scavenger, to explore its effect on lipid peroxidation. In the patient group, the mean preoperative MDA level (2.2 +/- 0.7, nmol/ml) significantly increased after 30 min of bypass (3.3 +/- 0.9 nmol/ml; p < 0.0001), and showed a second peak at aortic declamping (4.1 +/- 0.9 nmol/ml). There were significant correlations between MDA and granulocyte counts (r = 0.59, p < 0.0001) and cardiac enzymes (r = 0.55, p < 0.0001). In an ex vivo setting, further mechanical trauma to blood significantly increased the MDA levels, both in the control (p < 0.0001) and in the patient group (p < 0.0001) and this effect could be reduced by allopurinol (p < 0.0001). CPB and mechanical trauma generate oxygen free radicals. Allopurinol was found to reduce lipid peroxidation of red cells following mechanical trauma and this has to be further investigated regarding its ability to reduce morbidity in patients undergoing open heart surgery.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11192309&dopt=Abstract allopurinol Zyloprim



Allopurinol
Efficacy and safety of desensitization to allopurinol following cutaneous reactions.

Fam AG, Dunne SM, Iazzetta J, Paton TW.

Sunnybrook Health Science Centre, University of Toronto, Ontario, Canada.

OBJECTIVE: To evaluate the long-term efficacy and safety of slow oral desensitization in the management of patients with hyperuricemia and allopurinol-induced maculopapular eruptions. METHODS: A retrospective evaluation of an oral desensitization regimen using gradual dosage-escalation of allopurinol in 32 patients (30 with gout and 2 with chronic lymphocytic leukemia) whose therapy was interrupted because of a pruritic cutaneous reaction to the drug. RESULTS: Twenty-one men and 11 women with a mean age of 63 years (range 17-83 years), a mean serum urate level of 618 micromoles/liter (range 495-750) (or, mean 10.4 mg/dl [range 8.3-12.6]), and a mean serum creatinine level of 249 micromoles/liter (range 75-753) (or, mean 2.8 mg/dl [range 0.8-8.5]) were studied. Desensitization failed in 4 patients because of unmanageable recurrent rash. Twenty-eight patients completed the desensitization procedure to a target allopurinol dosage of 50-100 mg/day, 21 without deviation from the protocol for a mean of 30.5 days (range 21-56 days) and 7 requiring dosage adjustments because of a recurrent rash over 53.8 days (range 40-189 days). Seven of these 28 patients developed late cutaneous reactions 1-20 months postdesensitization, 4 responding to dosage modification and 3 discontinuing the drug. Twenty-five of the 32 patients (78%) continued to take allopurinol; their mean duration of followup was 32.6 months (range 3-92 months) and the mean postdesensitization serum urate level was 318 micromoles/liter (range 187-452) (or, mean 5.3 mg/dl [range 3.0-7.5]). CONCLUSION: The study confirms the long-term efficacy and safety of slow oral desensitization to allopurinol in patients with maculopapular eruptions, particularly in those with gout, who cannot be treated with uricosurics or other urate-lowering drugs. Although pruritic skin eruptions may recur both during and after desensitization, most of these cutaneous reactions can be managed by temporary withdrawal of allopurinol and dosage adjustment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11212165&dopt=Abstract allopurinol Zyloprim