PubMed Health⌕ Search

Biomedical subjects

L Peter Hackett

Publications and source records attributed to L Peter Hackett.

28 records · Page 2Linked to original sources
PubMed2003

Intentional warfarin overdose.

Warfarin toxicity is common and usually results from dose changes or drug interactions. There are few reported cases of intentional overdose. The management of warfarin overdose is usually complicated by the patient using warfarin therapeutically, often for a mechanical heart valve or pulmonary embolus prophylaxis. Untreated patients have a significant bleeding risk, but treatment carries a significant risk of complete reversal of anticoagulation and consequent risk of thrombosis. The objective of this study was to describe warfarin overdoses and complications of treatment and develop a safe approach to management. Three patients are described. Two patients received a single 10-mg dose of vitamin K. Both required anticoagulation, and in one, warfarin resistance persisted for 2 weeks. In a third patient serial INR, factor levels and warfarin concentrations were measured, and incremental doses of vitamin K (up to 7.5 mg) were given based on INR. This patient did not require anticoagulation, and regular warfarin therapy was recommenced after 4 days. Patients intentionally overdosing on warfarin can be classified into three groups based on preexisting indications for warfarin: nontherapeutic, moderate risk, and major risk for thromboembolic complications. All patients should have regular INR measurements (6-hourly) to catch rapid rises. Patients not on warfarin therapeutically can be given 10 mg of vitamin K1 and repeat INRs as an outpatient. Titrating intravenous vitamin K with doses of 0.5 to 2.0 mg when INR > 5 is appropriate to reduce INR without causing warfarin resistance. The high-risk group must be kept anticoagulated, and warfarin resistance avoided.

Adult↗
PubMed2003

Transfer of olanzapine into breast milk, calculation of infant drug dose, and effect on breast-fed infants.

OBJECTIVE: This study characterized infant drug doses and breast-milk-to-plasma area-under-the-curve ratios for olanzapine and determined plasma concentrations and effects of this drug on breast-feeding infants. METHOD: Seven mother-infant nursing pairs were studied. Olanzapine was measured in plasma and milk with high-performance liquid chromatography over a dose interval (for six patients) or at a single time after dose ingestion (for one patient) at steady state. Infant drug exposure was estimated as the product of an assumed milk production rate and average drug concentration in milk, normalized to body weight, and expressed as a percentage of maternal drug dose, normalized to body weight. RESULTS: The median infant dose of olanzapine ingested through milk was 1.02% of the maternal dose; the median milk-to-plasma area-under-the-curve ratio was 0.38 for the six patients with data collected over the dose interval. Corresponding values in the patient with single-point data were 1.13% and 0.75. Olanzapine was not detected in the plasma of the six infants with an evaluable plasma sample. All of the infants were healthy and experienced no side effects. CONCLUSIONS: Breast-fed infants were exposed to a calculated olanzapine dose of approximately 1%-well below the 10% notional level of concern. In infant plasma, olanzapine was below the detection limit; there were no adverse effects on the infants. These data support the use of olanzapine during breast-feeding. However, the authors recommend that breast-fed infants be monitored closely and the decision to breast-feed be made after individual risk-benefit analysis.

Adult↗
PubMed2002

Determination of olanzapine in plasma by high-performance liquid chromatography using ultraviolet absorbance detection.

A rapid method for the determination of olanzapine in plasma using high-performance liquid chromatography with ultra violet detection is described. Olanzapine was extracted from plasma with a mixture of hexane/dichloromethane (85:15), and then back extracted into phosphate buffer pH 2.8. Separation was achieved on a RP Select B C(18) column and commonly administered drugs did not interfere with the assay. The limit of quantitation was 1.5 microg/l and the inter-day and intra-day relative standard deviations were less than 10%. Olanzapine was shown to be stable in plasma for up to 7 days when stored at 4 degrees C. Moreover, the addition of ascorbic acid was not necessary for the achievement of chemical stability during storage, or during the assay procedure. The method has been used to measure olanzapine concentrations in patients treated with various doses of the drug varying from 5 to 40 mg/day.

Antipsychotic Agents↗
PubMed2002

Olanzapine excretion in human breast milk: estimation of infant exposure.

Newer antipsychotic drugs offer significant clinical advantages for the treatment of psychosis. In particular for the treatment of postpartum disorders newer agents may be suited due to their favourable side-effect profiles. Of concern is the passage of the drugs into breast milk and what potential risks this poses for an infant who is breastfed. The excretion of olanzapine into the breast milk of five lactating women with postpartum psychosis was examined in this study. Nine pairs of plasma and breast-milk samples were collected and the concentration of olanzapine determined by high-performance liquid chromatography. Single-point milk-to-plasma ratios were calculated and ranged from 0.2 to 0.84 with a mean of 0.46. The median relative infant dose was 1.6% (range 0-2.5%) of the weight-adjusted maternal dose. During the study period, there were no apparent ill effects on the infant as a consequence of exposure to these doses of olanzapine. As with other antipsychotic drugs this study demonstrates that olanzapine passes into breast milk. The long-term effects of exposure in infants exposed to olanzapine requires further investigation.

Adult↗
PubMed2002

Distribution of venlafaxine and its O-desmethyl metabolite in human milk and their effects in breastfed infants.

AIMS: To characterize milk/plasma (M/P) ratio and infant dose, for venlafaxine (V) and its O-desmethyl metabolite (ODV), in breastfeeding women taking venlafaxine for the treatment of depression, and to determine the plasma concentration and effects of these drugs in their infants. METHODS: Six women (mean age 34.5 years, mean weight 84.3 kg) taking venlafaxine (median dose 244 mg day(-1), range 225-300 mg day(-1)) and their seven infants (mean age 7.0 months, mean weight 7.3 kg) were studied. V and ODV in plasma and milk were measured by high-performance liquid chromatography over a 12 h dose interval at steady-state. Infant exposure was estimated as the product of estimated milk production rate (0.15 l kg(-1)day(-1)) and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean M/PAUC values of 2.5 (range 2.0-3.2) and 2.7 (range 2.3-3.2) were calculated for V and ODV, respectively. The mean maximum concentrations (95% CI) of V and ODV in milk were 1161 (95% CI, 588, 1734) microg l(-1) and 796 (362, 1230) microg l(-1). Mean infant exposure was 3.2% (1.7, 4.7%) for V and 3.2% (1.9, 4.9%) for ODV (as V equivalents). V was detected in the plasma of one out of seven infants studied (5 microg l(-1)), while ODV was detected in four of the infants, at concentrations ranging from 3 to 38 microg l(-1). All of the infants in the study were healthy, as reported by their mothers and/or by clinical examination on the study day. CONCLUSIONS: The concentrations of V and ODV in breast milk were 2.5 and 2.7 times those in maternal plasma. The mean total drug exposure (as venlafaxine equivalents) of the breastfed infants was 6.4% (5.5-7.3%), which is below the 10% notional level of concern. There were no adverse effects in any of the infants. The data support the use of V in breastfeeding. Nevertheless, since low concentrations of ODV were detected in the plasma of four out of the seven infants studied, we recommend breastfed infants should be monitored closely. Each decision to breast feed should be made as an individual risk:benefit analysis.

Adult↗
PubMed2002

Optimizing the hydrolysis of codeine and morphine glucuronides in urine.

Quality assurance data show that there is very significant inter-laboratory variation of the quantitation of codeine, especially in patient samples. The authors have examined hydrolysis procedures for codeine glucuronide (C6G) and morphine-3- and -6-glucuronides (M3G, M6G) because these are often present together in urine samples. Comparisons of hydrolysis using two different sources of beta-glucuronidases and various concentrations of hydrochloric acid were made. Samples were concentrated using solid phase extraction, derivatized and quantified by selective ion monitoring using gas chromatography-mass spectrometry (GC-MS). and beta-glucuronidase efficiently hydrolyzed M3G (90-95%), while hydrolysis of M6G was lower (60-85%) and that of C6G was very poor (45-58%). These findings were confirmed on examination of urine samples containing codeine and morphine from subjects who had taken codeine, morphine, or heroin. Erratic inter-laboratory quality assurance results for codeine are most probably a result of incomplete C6G hydrolysis. The authors' optimized hydrolysis method using 50% HCl for 1.5 hours at 120 degrees C gave reproducible results that approached the spiked concentration.

Codeine↗
PubMed2002

Studying drugs in human milk: time to unify the approach.

The trend globally for mothers to breastfeed has highlighted the need for information on drug transfer into breast milk and the extent to which the suckling neonate may be exposed and affected. This review discusses robust study methodologies that will yield high-quality information on all aspects of this process. Methods for assessing drug transfer into breast milk are examined. The place of the milk/plasma ratio, the amount of drug in breast milk, and the volume of milk produced are discussed in the context of their utility in estimating both absolute and relative infant dose. The measurement of plasma drug concentrations and pharmacodynamic effects in the breastfed infant exposed to drugs are identified as important factors that can assist in deciding whether drug present in breast milk is a significant risk for the nursing infant.

Breast Feeding↗
PubMed2002

The amount of fluvoxamine in milk is unlikely to be a cause of adverse effects in breastfed infants.

The aim of this study was to characterize milk/plasma (M/P) ratio, as well as relative infant dose and well-being, in 2 breastfeeding women taking fluvoxamine. The women (37 and 34 years old) and their infants (26 and 0.75 months old) were studied over a 24-hour dose interval at steady state. Fluvoxamine concentrations were measured by high-performance liquid chromatography. Infant exposure was measured as concentration in milk multiplied by an estimated milk production of 0.15 L/kg/d and normalized to the weight-adjusted maternal dose. M/P values of 1.34 and 1.21 were calculated for subjects 1 and 2, respectively, and relative infant doses were estimated to be 1.38% and 0.8%, respectively. No adverse effects in the infants were detected by the mother or on clinical examination, and fluvoxamine was not detected in the infants' plasma (limit of detection 2 micrograms/L). These limited data support the prescription of fluvoxamine to breastfeeding mothers after a careful, individual risk/benefit analysis is undertaken.

Adult↗
PubMed2002

Effect of hemodialysis on leflunomide plasma concentrations.

OBJECTIVE: To report on the influence of hemodialysis on the disposition of leflunomide in a woman with end-stage renal disease. CASE SUMMARY: A 65-year-old white woman with a history of diabetes, end-stage renal disease, rheumatoid arthritis, vasculitis, and leg ulcers was admitted to the hospital with a flare in the symptoms of joint pain and vasculitis. Prior to admission, she had been treated for rheumatoid arthritis with methotrexate 7.5 mg once a week. Due to adverse effects from methotrexate and continuing painful joints, leflunomide was considered as a therapeutic alternative. A loading dose of 100 mg was followed two days later by a daily dose of 10 mg. The active metabolite of leflunomide (A771726) was measured before and after hemodialysis and between hemodialysis sessions over a period of 80 days. Pre- and post-hemodialysis concentrations were compared for 17 sessions during this time. Based on the initial measured concentrations, the leflunomide dose was increased to 20 mg/d for several weeks before being reduced to 15 mg due to elevated liver enzymes. DISCUSSION: Although renal pathways are responsible in part for excretion of A771726, the concentrations achieved in this patient at doses of 10-20 mg/d were at the low end of the range reported in the literature. It was shown that pre- and post-hemodialysis concentrations of A771726 did not differ significantly. Thus, the low concentrations of A771726 were not a result of the hemodialysis. CONCLUSIONS: Steady-state concentrations of A771726 in plasma were not affected by hemodialysis or renal impairment. Reduction of the dose of leflunomide in patients with chronic renal failure undergoing hemodialysis does not appear to be required.

Aged↗