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Originals

Fomepizole may change indication for hemodialysis in methanol poisoning: prospective study in seven cases

K.E. Hovda, S. Froyshov, H. Gudmundsdottir, N. Rudberg and D. Jacobsen

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Volume 64 (2005) p. 190 - 197

Abstract

K.E. Hovda, S. Froyshov, H. Gudmundsdottir, N. Rudberg and D. Jacobsen

¹Department of Acute Medicine, ²Department of Nephrology, and ³Department of Clinical Chemistry, Ullevaal University Hospital, Oslo, Norway
Background: Treatment of methanol poisoning includes administration of buffer, antidote and hemodialysis. The role of hemodialysis using the new antidote fomepizole has not been studied. We studied the kinetics of methanol and formate during hemodialysis, and the possibility for delayed hemodialysis in the methanol poisoned patients without severe metabolic acidosis or visual disturbances. Patients and methods: Prospective case series study on methanol, formate and dialysis kinetics in 7 cases of severe methanol poisoning treated with buffer, fomepizole and hemodialysis (average 7 hours, range 5 – 8). Four patients were dialyzed early after diagnosis was obtained, while three were dialyzed “electively” the next day. Results: The median pH upon admission was 6.9 (range 6.6 – 7.5) and median base deficit 20.4 mmol/l (range 5.1 – 30.0). Their median S-methanol was 76.3 mmol/l (range 15.6 – 140.6) and S-formate 13.6 mmol/l (range 3.3 – 21). The median half-life of methanol during fomepizole treatment before dialysis was 71.2 hours (range 69.3 – 77); compared to 2.5 hours (range 1.7 – 3.3) during procedure. The median half-life of formate during dialysis was 1.7 hours (range 1.5 – 1.9). The median dialysis clearance of methanol was 222 ml/min (range 204 – 232) and for formate 225 ml/min (range 220 – 229) at a blood flow of 250 ml/min. One patient died and 2 were discharged with permanent visual and cerebral sequelae, whereas one died one year later. All three patients, in whom “elective” hemodialysis was performed, were discharged without sequelae. Conclusion: The efficacy and side effect profile of fomepizole may change the role of hemodialysis in methanol poisoning. More patients may be stabilized in local hospitals and transferred for “elective” dialysis, if methanol removal is still indicated after correction of metabolic acidosis.Correspondence to:
K.E. Hovda, MD
Department of Acute Medicine
Ullevaal University Hospital
0407 Oslo, Norway
Email: [email protected],[email protected]

Pharmacodynamic Modeling

Improved glycemic control with decreased hypoglycemia prevents long-term complications in type 2 diabetes patients: long-term simulation analysis using the ?Diabetes Mellitus Model?

S. Maxion-Bergemann, E. Huppertz, L.-D. Jacobs, E. M

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Volume 43 p. 271 - 281

Abstract

S. Maxion-Bergemann, E. Huppertz, L.-D. Jacobs, E. M

¹Analytica International GmbH, L
Objective: The purpose of this study was to compare the effect of insulin glargine (glargine) and NPH insulin (NPH) on long-term outcomes in type 2 diabetes patients using the Diabetes Mellitus Model (DMM). Methods: The DMM predicts short- and long-term complications over ten years using data in studies published previously. The main effect on outcome is the influence of the treatment on the HbA1c level which is simulated over time. The simulation was based on a cohort size of 10,000 type 2 diabetes patients taking either glargine or NPH. The best scenario, baseline scenario and worst case scenario were simulated based on differences of 0.13%, 0.44% and 0.85%, respectively, in HbA1c values and corresponding to potentially attainable improvements with comparable or lower hypoglycemia rates in glargine-treated patients and NPH-treated patients. Assumptions for scenarios 1, 2 and 3 were based on a regression analysis of clinical trial data (pooled data clinical trials comparing glargine and NPH) in which the effect of glargine on the HbA_1c/hypoglycemia incidence ratio was superior to that of NPH. Results: The relative risks (RR, glargine/NPH) obtained for scenarios 1, 2 and 3 were 0.97, 0.89 and 0.81, respectively, for long-term microvascular complications and 0.99, 0.95 and 0.91, respectively, for long-term macrovascular complications. RR reductions ranged from 1% in the less optimistic scenario to > 20% in the ?best case? scenario. Sensitivity analyses showed that variations in the mean baseline HbA_1c values and duration of the diabetes were without effect on these outcomes. Conclusions: Although there is a need to corroborate the results of these simulations with real, long-term clinical data, they have demonstrated that, assuming comparable or lower rates of hypoglycemia, a better glycemic control (HbA_1c reduction) can be expected with glargine when compared to NPH together with a reduction in long-term complications, mortality and associated costs.Correspondence to:
S. Maxion-Bergemann Analytica International GmbH Untere Herrenstra
Email: [email protected]

Original Research

Randomized, open-label, 5-way crossover study to evaluate the pharmacokinetic/pharmacodynamic interaction between furosemide and the non-steroidal anti-inflammatory drugs diclofenac and ibuprofen in healthy volunteers

C.A. Paterson, D. Jacobs, S. Rasmussen, S.P. Youngberg and N. McGuinness

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Volume 49 p. 477 - 484

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 8/2011 (477-490)

C.A. Paterson¹, D. Jacobs², S. Rasmussen³, S.P. Youngberg³ and N. McGuinness²

¹Pfizer, Inc., Cary, NC, ²Pfizer, Inc., Bridgewater, NJ, and ³Celerion, Inc., Lincoln, NE, USA
Objective: Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce renal complications in patients taking loop diuretics. This study investigated the pharmacokinetic/pharmacodynamic effects and safety profile of orally administered diclofenac sodium, ibuprofen and diclofenac epolamine topical patch (DETP) on furosemide in healthy adult subjects. Methods: This open-label, randomized, 5-way crossover study was conducted in 40 subjects (aged 19 – 45 y). Diclofenac (75 mg taken orally twice daily), DETP (1.3% applied topically twice daily), or ibuprofen (800 mg taken orally thrice daily) was administered for 3 consecutive days, followed by co-administration with furosemide (given intravenously as 20 mg/2 min). Plasma furosemide and NSAID concentrations, urine furosemide, sodium and potassium concentrations and urine output were determined throughout the 24 h period following furosemide administration. Results: Orally administered ibuprofen significantly increased furosemide AUC_0–t (37%) and AUC_0–inf (36%) and decreased total body CL (27%), R_max (19%) and CL_R (23%) geometric mean ratios compared with furosemide control. Oral and topical diclofenac had no pharmacokinetic effects on furosemide. Ibuprofen increased sodium excretion (Ae_0–24, 16%) and decreased sodium R_max (15%), and oral diclofenac decreased urine output (Vu_0–24, 15%). DETP had no effect on furosemide pharmacodynamics; total systemic exposure to diclofenac during DETP treatment was < 1% that of oral diclofenac. Treatments were generally safe, with 25 subjects reporting a total of 112 adverse events. Conclusions: Pharmacodynamic effects were seen with oral diclofenac (urine output) and ibuprofen (urine sodium excretion). Furosemide also affected plasma and urine pharmacokinetic profiles. Pharmacologic effects of DETP on furosemide were not observed under these conditions. Additional research is warranted to delineate the potential interactions of other NSAIDs with furosemide and other loop diuretics.Correspondence to:
Dr. D. Jacobs
Senior Director of Pfizer, Inc.
400 Crossing Boulevard
Bridgewater, NJ 08807, USA
Email: [email protected]

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