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Biomedical subjects

Kenneth F Ilett

Publications and source records attributed to Kenneth F Ilett.

52 records · Page 3Linked to original sources
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↗
PubMed2003

Toxicity related to chloroquine treatment of resistant vivax malaria.

OBJECTIVE: To report a case of severe chloroquine toxicity in the presence of high-grade chloroquine-resistant Plasmodium vivax. CASE SUMMARY: A febrile 36-year-old seaman from Mumbai (Bombay) was prescribed >5 times the usual dose of chloroquine for malaria diagnosed empirically onboard ship. His fever resolved, but he developed symptoms consistent with those of chloroquine toxicity. Fever recurred 30 days after his initial presentation, and blood smear-positive vivax malaria was diagnosed. A serum chloroquine concentration at this time (91 micro g/L) was above that considered effective for chloroquine-sensitive P. vivax (>15 micro g/L). The patient responded to atovaquone plus proguanil followed by primaquine. DISCUSSION: The patient was given chloroquine by his captain in a dosage regimen appropriate for quinine (2 tablets 3 times daily for 7 d). Pharmacokinetic modeling suggested that the patient's initial over-treatment was as reported and that the predicted maximum serum concentration of chloroquine (902 micro g/L) was within the range seen in fatal chloroquine overdose. CONCLUSIONS: Chloroquine-resistant vivax malaria is increasingly widespread, and transmission can occur within large tropical population centers. For drugs with a narrow therapeutic index such as chloroquine, recommended dosing regimens should be respected, and adequate information sources must be available where such drugs are dispensed by untrained personnel.

Adult↗
PubMed2003

Two aerosolized nitric oxide adducts as selective pulmonary vasodilators for acute pulmonary hypertension.

STUDY OBJECTIVES: To determine the selective vasodilatory effects of two inhaled "NONOate" aerosols in a closed chest pig model of acute pulmonary hypertension (APH). METHODS: APH was induced by IV infusion of the prostaglandin H(2)/thromboxane A(2) receptor agonist (U46619). Aerosolized diethylenetriamine nitric oxide (NO) adduct (DETA/NO, n = 4), dipropylenetriamine NO adduct (DPTA/NO, n = 4) [60 micro mol each], or placebo (n = 4) was delivered via the trachea. Hemodynamic parameters and blood samples were measured before and after inhalation therapy. RESULTS: Compared to control animals, pulmonary vascular resistance and pulmonary arterial pressure were significantly reduced from 10 to 105 min after DETA/NO administration and from 10 to 45 min after DPTA/NO aerosol administration (p < 0.05). Both aerosols had no significant effect on systemic vascular resistance or systemic BP. Serum nitrite significantly increased after the inhalation of both NONOates (p < 0.01). There was a tendency for reduced intrapulmonary shunting, particularly after treatment with DETA/NO. CONCLUSION: Both DETA/NO and DPTA/NO administered as aerosols selectively reduced pulmonary hypertension induced by U46619.

Aerosols↗
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

The pharmacokinetic properties of intramuscular artesunate and rectal dihydroartemisinin in uncomplicated falciparum malaria.

AIMS: To obtain pharmacokinetic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.m. ARTS and rectal DHA administration. METHODS: Twelve Vietnamese patients with uncomplicated falciparum malaria were randomized to receive either i.v. or i.m. ARTS (120 mg), with the alternative preparation given 8 h later in an open crossover design. A further 12 patients were given i.v. ARTS (120 mg) at 0 h and rectal DHA (160 mg) 8 h later. RESULTS: Following i.v. bolus, ARTS had a peak concentration of 42 microm (16 mg l(-1), elimination t1/2 = 3.2 min, CL = 2.8 l h(-1) kg(-1) and V = 0.22 l kg(-1) . The Cmax for DHA was 9.7 microm (2.7 mg l(-1) ), t1/2 = 59 min, CL = 0.64 l h(-1) kg(-1) and V = 0.8 l kg(-1) . Following i.m. ARTS, Cmax was 2.3 microm (3.7 mg l(-1)), the apparent t1/2 = 41 min, CL = 2.9 l h(-1) kg(-1) and V = 2.6 l kg(-1). The relative bioavailability of DHA was 88%, Cmax was 4.1 microm (1.16 mg l(-1)) and t1/2 = 64 min. In the rectal DHA study, relative bioavailability of DHA was 16%. CONCLUSIONS: For patients with uncomplicated falciparum malaria i.m. ARTS is a suitable alternative to i.v. ARTS, at equal doses. To achieve plasma DHA concentrations equivalent to parenteral administration of ARTS, rectal DHA should be given at approximately four-fold higher milligram doses. Further studies are needed to determine whether these recommendations can be applied to patients with severe malaria.

Administration, Rectal↗
PubMed2002

The ratio of polymorphonuclear leucocytes (PMN) to non-PMN cells--a novel method of assessing acute lung inflammation.

Polymorphonuclear leucocyte (PMN) numbers are an indicator of the degree of acute lung inflammation. However, there is no standardized system for accurately quantifying their numbers in tissue sections. Also, the effect of lung inflation on the quantification of PMN's is usually overlooked. Lung specimens obtained from clinical biopsies are usually deflated, while inflated lung tissue is commonly used in experimental studies. We report a method, which is independent of the degree of inflation, for measuring the degree of PMN infiltration in the both inflated and non-inflated lungs. Using light microscopy, we counted the numbers of PMN and non-PMN cells in 240 fields from each of five inflated and five non-inflated lung sections and calculated a ratio of PMN: non-PMN cells (the PMN ratio). The effect on accuracy and precision of number of fields counted was investigated by randomly selecting 200, 160, 80 or 40 readings from the original 240 fields. The mean PMN ratio, its 95% confidence interval (CI) and the coefficient of variation (CV) were calculated for each of the four levels of sampling. Both CI and CV increased as the number of readings decreased. Inflated lung tissue had consistently higher values for CV compared to non-inflated lung. In practice, we recommend that for both inflated and non-inflated lungs, 80-160 fields (approximate 0.23-0.45 mm2 of absolute area evaluated) need to be counted to yield a PMN ratio with acceptable accuracy and precision. The PMN ratio provides a simple and objective way of quantifying the degree of acute inflammation in clinical histopathology and experimental toxicology studies involving lungs. It is suitable for use in research of lung inflammation, and as an accessory diagnostic tool and an objective descriptor for clinical histopathology.

Animals↗
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

Cyclosporin monitoring in Australasia: 2002 update of consensus guidelines.

Therapeutic drug monitoring of cyclosporin (CsA) has been established as part of the routine clinical treatment of patients following organ transplantation for more than 20 years, and based on contemporary knowledge, many consensus guidelines have been published to assist clinics and laboratories attain optimal strategies for patient care. This article addresses the newer directions in CsA monitoring, with particular reference to the Australasian situation that has evolved since the 1993 Australasian guideline. These changes have included the introduction of alternative assay methodologies, changed CsA formulation from Sandimmun to Neoral throughout Australasia, and alternatives to trough concentration (C0) monitoring, especially 2-hour concentration (C2) monitoring and associated validated dilution protocols to accurately quantitate the higher whole blood CsA concentrations. The revision was prepared following a recent survey of all Australasian CsA-monitoring laboratories where discordant practices were evident.

Area Under Curve↗
PubMed2002

Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases.

The aim of this study was to elucidate the metabolic pathways for dihydroartemisinin (DHA), the active metabolite of the artemisinin derivative artesunate (ARTS). Urine was collected from 17 Vietnamese adults with falciparum malaria who had received 120 mg of ARTS i.v., and metabolites were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Human liver microsomes were incubated with [12-(3)H]DHA and cofactors for either glucuronidation or cytochrome P450-catalyzed oxidation. Human liver cytosol was incubated with cofactor for sulfation. Metabolites were detected by HPLC-MS and/or HPLC with radiochemical detection. Metabolism of DHA by recombinant human UDP-glucuronosyltransferases (UGTs) was studied. HPLC-MS analysis of urine identified alpha-DHA-beta-glucuronide (alpha-DHA-G) and a product characterized as the tetrahydrofuran isomer of alpha-DHA-G. DHA was present only in very small amounts. The ratio of the tetrahydrofuran isomer, alpha-DHA-G, was highly variable (median 0.75; range 0.09-64). Nevertheless, alpha-DHA-G was generally the major urinary product of DHA glucuronidation in patients. The tetrahydrofuran isomer appeared to be at least partly a product of nonenzymic reactions occurring in urine and was readily formed from alpha-DHA-G by iron-mediated isomerization. In human liver microsomal incubations, DHA-G (diastereomer unspecified) was the only metabolite found (V(max) 177 +/- 47 pmol min(-1) mg(-1), K(m) 90 +/- 16 microM). Alpha-DHA-G was formed in incubations of DHA with expressed UGT1A9 (K(m) 32 microM, V(max) 8.9 pmol min(-1) mg(-1)) or UGT2B7 (K(m) 438 microM, V(max) 10.9 pmol mg(-1) min(-1)) but not with UGT1A1 or UGT1A6. There was no significant metabolism of DHA by cytochrome-P450 oxidation or by cytosolic sulfotransferases. We conclude that alpha-DHA-G is an important metabolite of DHA in humans and that its formation is catalyzed by UGT1A9 and UGT2B7.

Adult↗
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

Inhaled diazeniumdiolates (NONOates) as selective pulmonary vasodilators.

Selective pulmonary vasodilators cause vasodilatation limited to the pulmonary vasculature, within well-ventilated lung regions. Selective pulmonary vasodilators ideally cause only a minimal effect on the systemic circulation and improve ventilation/perfusion matching. NONOates are a novel group of chemical compounds that spontaneously and continuously release nitric oxide under physiological conditions, over periods of up to 24 h. Inhaled NONOates retain the benefits of gaseous nitric oxide without many of its therapeutic disadvantages. This review focuses on the therapeutic potential of inhaled NONOates in pulmonary hypertension, other lung conditions associated with right ventricular dysfunction and in asthma. The potential toxicity of NONOates is also discussed.

Acute Disease↗
PubMed1994

Concentrations of morphine, morphine-6-glucuronide and morphine-3-glucuronide in serum and cerebrospinal fluid following morphine administration to patients with morphine-resistant pain.

Recent studies have suggested that morphine-3-glucuronide (M3G) may antagonize the analgesic effects of morphine and morphine-6-glucuronide (M6G). To investigate this hypothesis, steady-state concentrations of morphine, M6G and M3G in serum and cerebrospinal fluid (CSF) were measured in 11 patients receiving chronic morphine therapy (9 orally and 2 subcutaneously) for treatment of cancer-related pain. All patients appeared to have morphine-resistant pain and had elected to proceed to intrathecal bupivacaine or percutaneous cordotomy. Morphine, M6G and M3G concentrations were measured by high-performance liquid chromatography. The concentrations (median and range) for morphine, M6G and M3G in serum were 193 (14-1086) nmol/l, 847 (210-4113) nmol/l and 4553 (1324-24035) nmol/l, respectively, while in CSF concentrations of morphine, M6G and M3G were 200 (21-1461) nmol/l, 115 (30-427) nmol/l and 719 (249-3252) nmol/l, respectively. Median molar ratios of M6G/morphine and M3G/morphine in serum were 3.79 and 22.1, respectively, while in CSF the same ratios were 0.42 and 2.39, respectively. Median molar ratios of M3G/M6G in serum and CSF were 5.84 and 6.61, respectively. The median molar ratios for CSF/serum distribution of morphine, M6G and M3G were 1.23, 0.12 and 0.14, respectively. Thus, despite their relatively poor ability to penetrate into the CSF, the high serum concentrations of M6G and M3G resulted in substantial concentrations of these metabolites in the CSF. Nevertheless, M3G/M6G ratios in our morphine-resistant patients were similar to published values in patients with well-controlled pain, suggesting that the hypothesis that M3G plays a major role in morphine-resistance is not correct.

Adult↗