Availability of antidotes at acute care hospitals in Ontario.

BACKGROUND: Acutely poisoned patients sometimes require immediate treatment with an antidote, and delays in treatment can be fatal. We sought to determine the availability of 10 antidotes at acute care hospitals in Ontario. METHODS: Mailed questionnaire with repeated reminders to pharmacy directors at all acute care hospitals in Ontario. RESULTS: Responses were obtained from 179 (97%) of 184 hospitals. Only 9% of the hospitals stocked an adequate supply of digoxin immune Fab antibody fragments, a life-saving antidote for patients with severe digoxin toxicity, whereas most of the hospitals stocked sufficient supplies of ipecac syrup (88%) and flumazenil (92%), arguably the least crucial antidotes in the survey. Only 1 hospital stocked adequate amounts of all 10 antidotes. Certain hospital characteristics were associated with adequate antidote stocking (increased annual emergency department volume, teaching hospital status and designation as a trauma centre). Conversely, antidote supplies were particularly deficient at small hospitals and, paradoxically, geographically isolated facilities (those most reliant on their own inventory). The cost of antidotes correlated only weakly with stocking rates, and many examples of excessive antidote stocking were identified. INTERPRETATION: Most acute care hospitals in Ontario do not stock even minimally adequate amounts of several emergency antidotes, possibly jeopardizing the survival of an acutely poisoned patient. Much of this problem could be rectified at no additional cost by reducing excessive stock of expensive antidotes and redistributing the resources to acquire deficient antidotes.

Efficacy and safety of desensitization to allopurinol following cutaneous reactions.

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.

The effect of food or sucralfate on the bioavailability of S(+) and R(-) enantiomers of ibuprofen.

This randomized, multiple cross-over pharmacokinetic study was undertaken to determine if food or sucralfate alter the bioavailability of the active S(+) enantiomer of ibuprofen. Eleven healthy adult male volunteers were given three single 600-mg doses of ibuprofen (separated by 1 week) administered either in a fasting state, after a standardized breakfast, or with sucralfate 1 g. The main outcome measures were area under the concentration (AUC), maximum peak plasma concentration (Cmax), and time to reach peak concentration (tmax) for total, S(+), and R(-) enantiomer serum ibuprofen levels, drawn up to 10 hours after dosing. The AUC for R(-) ibuprofen was significantly lower than S(+) ibuprofen in all three treatment groups. The treatments had no different effects on AUC for S(+), R(+), or total ibuprofen. There was no difference in the ratio of S(+):R(-) enantiomers across different treatment groups, but the intersubject variability was significant (P < .05). The S(+) ibuprofen Cmax was greater than the R(-) ibuprofen Cmax for all treatment groups (P < .05). Sucralfate reduced the peak concentration of both S(+) and R(-) enantiomers when compared with fasting (P < .05). There was a slight but nonsignificant increase in the mean time to achieve peak concentration of both S(+) and R(-) enantiomers. Neither food nor sucralfate has a significant effect on ibuprofen enantiomer pharmacokinetics, but interindividual variability contributes significantly to the variability of enantiomer bioavailability.

Desensitization to allopurinol in patients with gout and cutaneous reactions.

PURPOSE: To determine the efficacy and safety of slow oral desensitization in the management of allopurinol-related pruritic cutaneous eruptions. PATIENTS AND METHODS: Nine patients with renal insufficiency and chronic tophaceous gouty arthritis, who had to interrupt their allopurinol therapy because of an allergic-type pruritic maculopapular eruption, were enrolled in an allopurinol oral desensitization protocol using a schedule of gradually increasing doses. RESULTS: Cautious reinstitution of allopurinol was successfully accomplished in all nine patients, but four individuals required dose adjustment because of development of a mild, recurrent, macular rash early during the protocol at allopurinol doses of less than or equal to 5 mg/d. Transient, postdesensitization cutaneous reactions occurred in two patients, one of whom also had an early rash. CONCLUSION: Oral desensitization to the minor rashes induced by allopurinol is a feasible and acceptably safe approach to therapy, particularly for those with renal insufficiency in whom no substitute urate-lowering drug is available.

Single-dose pefloxacin pharmacokinetics and metabolism in patients undergoing continuous ambulatory peritoneal dialysis (CAPD).

Seven adult patients on continuous ambulatory peritoneal dialysis (CAPD) received one dose of pefloxacin, a novel quinolone antibiotic, orally and intravenously on two separate occasions to characterize the pharmacokinetics and metabolism of the drug. Concentrations of both pefloxacin and its active metabolite N-desmethyl-pefloxacin (norfloxacin) were measured in serum and dialysate by HPLC. Half-life, total body clearance and peritoneal clearance were determined. The overall elimination half-life was 19.9h. Relative to the IV dose the bioavailability following oral administration of pefloxacin was 76%. The mean serum and dialysate concentrations were similar up to 24 h after the oral or IV dose. After a 6-h dwell time the dialysate concentration of pefloxacin was 2.24 mg/L which is above the MIC90 for most bacteria responsible for peritonitis in CAPD patients. The peritoneal clearance of pefloxacin averaged 2.5 mL/min. Serum concentrations of the metabolite norfloxacin were less than 0.5 mg/L during the 24 h study period. We conclude that pefloxacin might be equally effective in the treatment of peritonitis of CAPD after oral or IV administration. Since the peritoneal clearance contributes insignificantly to the elimination of pefloxacin during CAPD, the proposed maintenance regimen of an oral or IV 400 mg dose/day seems to be a reasonable therapy for infections in CAPD patients.

Bioavailability of iron in oral ferrous sulfate preparations in healthy volunteers.

The bioavailability of iron in five ferrous sulfate preparations was studied in 10 healthy male volunteers. The preparations were an oral solution, two types of film-coated tablets and two types of enteric-coated tablets. Blood samples were drawn hourly from 8 am to 6 pm on the day before each study day to assess baseline serum iron concentrations and on the study day. Spectrophotometry was used to measure the serum iron concentrations. The area under the curve (AUC), the maximum concentration and the time to achieve the maximum concentration were compared by analysis of variance. The enteric-coated preparations resulted in AUCs less than 30% of the AUC for the oral solution. The two film-coated products produced AUCs essentially equivalent to that of the oral solution. We conclude that the bioavailability of iron in the enteric-coated preparations was low, relative to that of the film-coated products and the oral solution, and that these products should not be considered interchangeable.

Trimethoprim-sulfamethoxazole pharmacokinetics during continuous ambulatory peritoneal dialysis (CAPD).

Ten adult patients on continuous ambulatory peritoneal dialysis (CAPD) received one dose of trimethoprim-320 mg (TMP) and sulfamethoxazole 1600 mg (SMX) orally (p.o.), intravenously (i.v.), and intraperitoneally (i.p.) on three separate occasions to characterize the pharmacokinetics of both drugs. Concentrations of both TMP and SMX were measured in serum and dialysate by HPLC to 48 h. Half-life, total body clearance (TBC), and peritoneal clearance (PCl) were determined. The mean half-life of TMP was 28 h, while for SMX it was 12.5 h. Relative to the i.v. dose, the bioavailability following oral administration for TMP was 98% and 87% for SMX. Intraperitoneal bioavailability was 73% for TMP and 65% for SMX after a 4-h dwell. After 24 h, regardless of the route of administration, less than 3% of TMP and less than 6% of SMX appeared in dialysate. We conclude that peritoneal losses contribute insignificantly to TMP/SMX elimination during CAPD.

Drug therapy in patients undergoing peritoneal dialysis. Clinical pharmacokinetic considerations.

Peritoneal dialysis has become an accepted treatment modality for end-stage renal disease. The introduction of continuous ambulatory peritoneal dialysis (CAPD) has further popularised this technique. The need for adjustment of drug dosage in patients with endstage renal disease and the need for supplemental dosages following haemodialysis are well recognised. Little documentation exists concerning the need for supplemental drug dosage in patients on peritoneal dialysis. Knowledge of the influence of peritoneal dialysis on the elimination of specific drugs is essential to the rational design of dosage regimens in patients undergoing this dialysis technique. This review addresses the clinical pharmacokinetic aspects of drug therapy in patients undergoing peritoneal dialysis and considers: the efficiency of the peritoneal membrane as a dialysing membrane; the effects of peritoneal dialysis on the pharmacokinetics of drugs; the pharmacokinetic models and estimation methods for peritoneal dialysis clearance and the effects of peritoneal dialysis on drug elimination; the influence of the pharmacokinetic parameters of drugs on drug dialysability; and the application of pharmacokinetic principles to the adjustment of drug dosage regimens in peritoneal dialysis patients. Data on drugs which have been studied in peritoneal dialysis are tabulated with inclusion of pharmacokinetic and dialysability information.

Steady-state plasma levels of salicylate in patients with rheumatoid arthritis: effects of dosing interval and tablet strength.

Forty patients who were admitted to hospital with rheumatoid arthritis received a total of 3.9 g/d of enteric-coated acetylsalicylic acid (ASA) (Entrophen) according to one of four dosing schedules: group 1 (n = 13), three 325-mg tablets four times daily; group 2 (n = 11), two 650-mg tablets three times daily; group 3 (n = 10), three 650-mg tablets twice daily; and group 4 (n = 6), two 975-mg tablets twice daily. Five to seven days after the start of therapy, when steady-state plasma salicylate levels had been achieved, 10 blood samples, 1 per hour, were collected. Three healthy volunteers who received plain ASA formed a control group. There was little fluctuation in the salicylate levels over the sampling period, regardless of the dosing interval, and no significant difference in the fluctuations between the five groups. Likewise, there was no significant difference in the mean salicylate levels at each sampling time, regardless of the dosing interval or tablet strength. These results suggest that different tablet strengths of enteric-coated ASA and different dosing intervals produce comparable plasma salicylate levels. Less frequent dosing may improve patient acceptance of salicylate therapy in the treatment of arthritis.

Stability and sterility of cimetidine admixtures frozen in minibags.

The stability and sterility of cimetidine hydrochloride admixtures after freezing for extended periods were investigated. Cimetidine hydrochloride, 300 mg, was added to each of six 50-ml minibags containing 5% dextrose injection. The cimetidine concentration was determined and the bags were frozen for up to 30 days. After freezing for the appropriate length of time, the bags were thawed. Cimetidine concentrations were determined by high-pressure liquid chromatography immediately and then daily for eight days while the admixtures were refrigerated. Sterility tests were carried out throughout the study. Data were analyzed by least-squares linear regression to test for trends. The cimetidine hydrochloride admixtures were stable while frozen for up to 30 days and for at least eight days following thawing when kept under refrigeration. Sterility of the admixture was maintained throughout the study period.

Fulminant colitis complicating gold therapy.

Enterocolitis is lesser known complication of gold therapy. Two cases of fulminant colitis, complicating chrysotherapy for rheumatoid arthritis are described. One patient required colectomy, whereas the other responded to intensive medical treatment. Colonic biopsies demonstrated extensive ulcerations, diffuse edema, multiple hemorrhages and a dense mononuclear cell infiltrate. Our experience emphasizes the paramount importance of early recognition and treatment of this serious complication.

Twice-daily dosing of enteric-coated aspirin in patients with rheumatic diseases.

To determine the feasibility of twice daily dosing of enteric-coated aspirin (EntrophenR), a preliminary trial on 10 patients with rheumatic diseases was conducted. Three plasma salicylate levels on 2 separate occasions, 1 day apart, were determined. In 9 of the 10 patients studied at steady-state, therapeutic levels were attained (15-30 mg/dl). There were no gastrointestinal side-effects. One case developed tinnitus which resolved with a small reduction in dosage. On the basis of this short-term study, twice-daily EC-ASA appears to be effective in maintaining adequate plasma salicylate levels, and it seems to compare favourably to ASA given in multiple daily doses. On a long-term basis, it may improve patient compliance.