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L P Hackett

Publications and source records attributed to L P Hackett.

At least 19 recordsLinked to original sources
PubMed2003

Application of a multi-faceted approach for the assessment of treatment response in falciparum malaria: a study from Malaysian Borneo.

Thirty-two patients reporting to the Lundu District Hospital, Sarawak, Malaysian Borneo, with uncomplicated falciparum malaria were recruited into a multifaceted study to assess treatment response. Following combined chloroquine and sulphadoxine/pyrimethamine treatment the patients were followed for 28 days according to the World Health Organisation in vivo drug response protocol. The in vivo study revealed that 13 (41%) of the patients had a sensitive response to treatment, five (16%) cleared asexual stage parasites but had persistent gametocytes, 11 (34%) had RI type resistance and three (9%) had RII type resistance requiring quinine intervention before day 7 for parasite clearance. Although clinically insignificant, patients with persistent gametocytes, surviving chloroquine and sulphadoxine/pyrimethamine treatment during maturation, were placed in the reduced response to treatment group for analysis. Allelic typing detected 100% prevalence of the pfcrt K76T marker associated with chloroquine resistance and 78% prevalence of the pfdhfr NRNL haplotype associated with sulphadoxine/pyrimethamine treatment failure. High serum chloroquine levels and pfdhfr haplotypes with <or=2 point mutations were independently associated with a sensitive response to treatment. However four patients in the sensitive response group had both low serum chloroquine levels and the pfdhfr NRNL haplotype. A degree of immunity, consistent with malaria endemicity, may account for the apparently paradoxical presence of markers of drug resistance in the sensitive group.

Animals↗
PubMed2003

Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity.

AIMS: To investigate the spectrum of toxicity of moclobemide overdose, the occurrence of serotonin toxicity, and to estimate toxicokinetic parameters. METHODS: All moclobemide overdoses presenting over a 10-year period to the Hunter Area Toxicology Service were reviewed. Clinical features, complications, length of stay (LOS) and intensive care (ICU) admission rate were extracted from a standardized, prospectively collected database. Comparisons were made between moclobemide alone and moclobemide with a serotonergic coingestant poisoning. Serotonin toxicity was defined by a combination of Sternbach's criteria and a clinical toxicologist's diagnosis. In five patients serial moclobemide concentrations were measured. Time to maximal plasma concentration (Tmax), peak plasma concentration (Cmax) and terminal elimination half-lives were estimated. RESULTS: Of 106 included patients, 33 ingested moclobemide alone, 21 ingested moclobemide with another serotonergic agent (in some cases in therapeutic doses) and 52 ingested moclobemide with a nonserotonergic agent. Eleven (55%) of 21 patients coingesting a serotonergic drug developed serotonin toxicity, which was significantly more than one (3%) of 33 moclobemide-alone overdoses (odds ratio 35, 95% confidence interval 4, 307; P < 0.0001). In six of these 21 cases severe serotonin toxicity developed with temperature >38.5 degrees C and muscle rigidity requiring intubation and paralysis. The 21 patients had a significantly increased LOS (34 h) compared with moclobemide alone overdoses (12 h) (P < 0.0001) and a significantly increased ICU admission rate of 57% vs. 3% (P < 0.0001). Time to peak plasma concentration was delayed in two patients where prepeak samples were obtained. Cmax increased slightly with dose, but all three patients ingesting > or = 6 g vomited or had charcoal. The mean elimination half-life of moclobemide in the five patients in whom serial moclobemide concentrations were measured was 6.3 h and elimination was first order in all cases. There was no evidence of a dose-dependent increase in half-life. CONCLUSIONS: The effects of moclobemide alone in overdose are minor, even with massive ingestions. However, moclobemide overdose in combination with a serotonergic agent (even in normal therapeutic doses) can cause severe serotonin toxicity. The elimination half-life is prolonged by two to four times in overdose, compared with that found in healthy volunteers given therapeutic doses. This may be a result of wide interindividual variation in overall elimination, also seen with therapeutic doses, but appears not to be due to saturation of normal elimination pathways.

Adult↗
PubMed2002

Transfer of metformin into human milk.

AIMS/HYPOTHESIS: The aim of this study was to characterize the milk-to-plasma ratio and infant dose for metformin in breastfeeding women, and to measure plasma concentrations and assess any effects in their infants. We hypothesized that metformin used by mothers is safe for their breastfed infants. METHODS: Seven women taking metformin (median dose 1500 mg orally daily) and their infants were studied. Metformin concentrations in plasma and milk were measured by high performance liquid chromatography. Infant exposure was estimated as the product of estimated milk production rate and the average concentration of the drug in milk and also expressed as a percentage of the weight-normalized maternal dose. RESULTS: The mean milk-to-plasma ratio for metformin was 0.35 (95%CI 0.2-0.5). The mean of its average concentrations in milk over the dose interval was 0.27 mg/l (0.15-0.39 mg/l). The absolute infant dose averaged 0.04 mg x kg(-1) x day(-1) (0.02-0.06 mg x kg(-1) x day(-1)) and the mean relative infant dose was 0.28% (0.16-0.4%). Metformin was present in very low or undetectable concentrations in the plasma of four of the infants who were studied. No health problems were found in the six infants who were evaluated. CONCLUSIONS/INTERPRETATION: The concentrations of metformin in breast milk were generally low and the mean infant exposure to the drug was only 0.28% of the weight-normalized maternal dose. As this is well below the 10% level of concern for breastfeeding, and because the infants were healthy, we conclude that metformin use by breastfeeding mothers is safe. Nevertheless, each decision to breastfeed should be made after conducting a risk:benefit analysis for each mother and her infant.

Adult↗
PubMed2001

Quantification of naltrexone and 6,beta-naltrexol in plasma and milk using gas chromatography-mass spectrometry. Application to studies in the lactating sheep.

A selective gas chromatography-mass spectrometry method using solid-phase extraction has been developed for the detection and quantification of naltrexone and its metabolite, 6,beta-naltrexol in plasma and milk from humans and sheep at pharmacologically relevant concentrations. Di- or tri-acetyl derivatives were formed and quantified by selected-ion monitoring. Recoveries of naltrexone (30 microg/l) and 6,beta-naltrexol (250 microg/l) from both human plasma and milk were greater than 70%. Intra-assay and inter-day precision ranged from 3 to 21% for naltrexone and 2-18% for 6,beta-naltrexol for all matrices investigated, with an overall mean accuracy of 104% for naltrexone, and 99% for 6,beta-naltrexol. Human samples containing these analytes were stable for at least 3 weeks at -20 degrees C or 6 weeks at -80 degrees C. Analysis of the plasma and milk from the lactating sheep showed mean milk-to-plasma ratios of 55 for naltrexone and 3 for 6,beta-naltrexol.

Animals↗
PubMed2001

Cyclosporin immunosuppression of sheep: pharmacokinetics and allograft survival.

A chronically immunosuppressed sheep model was established using a regimen of cyclosporin A (CsA; 2-3mg/kg twice daily) and ketoconazole (10mg/kg twice daily). Blood CsA concentrations reached a steady-state after 17 days of treatment. The clearance of CsA decreased from a mean (95% CI) of 9.47 (6.2-12.7)ml/min/kg after a single (first) dose (3mg/kg i.v.) to 1.62 (1.38-1.86)ml/min/kg after 18 days of CsA (3mg/kg i.v. twice daily) co-administration with ketoconazole. These data indicated that the combination of CsA and ketoconazole could be used to give stable high concentrations of CsA in the sheep. Using this regimen in the sheep, the long-term survival of skin allografts was monitored as an indicator of effective immunosuppression. CsA in blood was measured daily and CsA dose adjusted to various target concentration ranges. Provided that the trough concentration of blood CsA was maintained between 1500-2500 mg/l, long-term healthy skin allografts were maintained on the sheep without significant adverse effects on haematological or biochemical parameters.

Animals↗
PubMed2001

Distribution of R- and S-methadone into human milk during multiple, medium to high oral dosing.

AIMS: To measure the interdose milk to plasma ratio (M/P) of R- and S-methadone during multiple dosing in lactating mothers taking medium to high doses of methadone (> 40 mg daily), and to assess likely infant exposure. METHODS: Eight mother/child pairs were studied, initially during their postpartum hospital stay (immature milk), and where possible again after 15 days (mature milk). The women were on a methadone maintenance programme with daily doses of >or=40 mg day-1. Venous blood was collected at 0, 1, 2, 4, 6, 8, 12, and 24 h and milk was collected from both breasts at 0-4, 4-8, 8-12, 12-16, 16-20, and 20-24 h after dose. R- and S-methadone were quantified by h.p.l.c. The areas under the plasma and milk concentration-time curves (AUC) were estimated and M/P(AUC) was calculated. The relative infant dose of both enantiomers was estimated as the product of drug concentration in milk and an average daily milk intake of 0.15 l kg(-1). RESULTS: For immature milk (n = 8) the M/P(AUC) for R-methadone was 0.68 (95% CI 0.48, 0.89) and for S-methadone 0.38 (0.26, 0.50). For mature milk (n = 2) the M/P(AUCs) for R-methadone were 0.39 and 0.54 and for S-methadone 0.24 and 0.30, respectively. The estimated doses of R- and S-methadone that would be received by the infant via immature milk were 3.5% (2.05, 5.03%) and 2.1% (1.3, 2.8%), respectively, of the maternal dose (assuming 50% of each enantiomer in the dose). The relative infant dose for R- plus S-methadone together was 2.8% (1.7, 3.9%). CONCLUSIONS: Breastfeeding during medium to high dose methadone appears to be 'safe' according to conventional criteria because the dosage is < 10%. However because the absolute dose received by the infant is dependent on the maternal dose rate, the risk-benefit ratio should be considered for each individual case. The doses of methadone received via milk are unlikely to be sufficient to prevent the neonatal abstinence syndrome.

Administration, Oral↗
PubMed2001

Caudal ropivacaine in infants: population pharmacokinetics and plasma concentrations.

BACKGROUND: Ropivacaine is a new long-acting amino-amide local anesthetic. However, there are no data on its use in infants. In the current study, the authors investigated the pharmacokinetics of caudal ropivacaine in 30 infants younger than 12 months. METHODS: Two groups of infants (group 1 [n = 15], aged 0-3 months; group 2 [n = 15], aged 3-12 months) were given a caudal bolus dose of 0.2% ropivacaine (2 mg/kg) and a standardized general anesthetic technique. Serial blood samples taken for up to 12 h were analyzed for total and free ropivacaine using high-performance liquid chromatography. Population pharmacokinetic modeling was performed to yield estimates of clearance, volume of distribution, and absorption rate constant. An analysis of covariates on the kinetic parameters also was made. RESULTS: Median maximum free ropivacaine concentration was significantly higher in group 1 (99 micog/l) than in group 2 (38 microg/l) (P = 0.0002), as was the median free fraction of ropivacaine (10% vs. 5%; P = 0.01). Pharmacokinetic variables of the total population were best described by a one-compartment model with first-order absorption. Mean clearance was 0.31 l.h(-1).kg(-1) (coefficient of variation [CV], 51%), volume of distribution was 2.12 l/kg (CV, 34%), and absorption rate constant was 1.61 h(-1) (CV, 46%). Mean absorption and elimination half-lives were 0.43 and 5.1 h, respectively. Age and percentage of free ropivacaine were significant covariates for clearance. Posterior Bayesian estimates of clearance were significantly higher (38%) in older children. CONCLUSION: Total and free plasma ropivacaine concentrations after caudal ropivacaine (0.2%, 2 mg/kg) in infants were within the range of concentrations previously reported in adults and older children. Age and percentage of free ropivacaine were significant covariates of clearance.

Age Factors↗
PubMed2000

Citalopram and demethylcitalopram in human milk; distribution, excretion and effects in breast fed infants.

AIMS: To characterize milk/plasma (M/P) ratio and infant dose, for citalopram and demethylcitalopram, in breast-feeding women taking citalopram for the treatment of depression, and to determine the plasma concentration and effects of these drugs in their infants. METHODS: Seven women (mean age 30.6 years) taking citalopram (median dose 0.36 mg kg(-1) day(-1)) and their infants (mean age 4.1 months) were studied. Citalopram and demethylcitalopram in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval. Infant exposure was estimated (two separate methods) as the product of milk production rate and 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 1.8 (range 1.2-3) and 1.8 (range 1.0-2.5) were calculated for citalopram and demethylcitalopram, respectively. The mean maximum concentrations of citalopram and demethylcitalopram in milk were 154 (95% CI, 102-207) microg l(-1) and 50 (23-77) microg l(-1). Depending on the method of calculation, mean infant exposure was 3.2 or 3.7% for citalopram and 1.2 or 1.4% for demethylcitalopram. Citalopram (2.0, 2.3 and 2.3 microg l(-1)) was detected in three of the seven infants. Demethylcitalopram (2.2 and 2.2 microg l(-1) was detected in plasma from two of the same infants. No adverse effects were seen in the infants, all were within appropriate percentile limits for weight and all had normal Denver developmental quotients. CONCLUSIONS: The mean combined dose of citalopram and demethylcitalopram (4.4-5.1% as citalopram equivalents) transmitted to infants via breast milk is below the 10% notional level of concern. Plasma concentrations of these drugs in the infants were very low or absent and there were no adverse effects. These data support the safety of the use of citalopram in breast feeding women. Nevertheless, each decision to breast feed should always be made as an individual risk:benefit analysis.

Adult↗
PubMed2000

Pharmacokinetics and clinical efficacy of long-term epidural ropivacaine infusion in children.

The clinical efficacy and pharmacokinetics of long-term epidural ropivacaine infusion were investigated in 18 postoperative children aged between 0.3 and 7.3 yr. A lumbar or thoracic epidural catheter was inserted after the anaesthetic induction. Sixty minutes following a bolus dose of ropivacaine 1 mg kg-1, 0.2% ropivacaine was infused at a fixed rate of 0.4 mg kg-1 h-1 for a mean of 61.3 h (range 36-96 h). Clinical evaluation comprised hourly recording of pain, sedation, motor block, nausea/vomiting, pruritus-scores, SpO2, pulse and respiratory rates, and recording of non-invasive arterial pressure every 4 h. Total and free plasma concentrations were measured by high-performance liquid chromatography at 0, 1, 6, 12, 24, 36, 48, 72 and 96 h. Analgesia was of high quality and side effects were minor. No clinical signs of local anaesthetic toxicity were seen. Total (100-3189 micrograms litre-1) and free (10-56 micrograms litre-1) ropivacaine concentrations were within the range reported to be 'safe' in previous studies in adults. Mean (95% CI) volume of distribution was 3.1 litre kg-1 (2.1-4.2 litre kg-1), total clearance was 8.5 ml kg-1 min-1 (5.8-11.1 ml kg-1 min-1), free clearance was 220 ml kg-1 min-1 (170-270 ml kg-1 min-1) and elimination half-life was 4.9 h (3.0-6.7 h).

Amides↗
PubMed2000

Drowsiness and poor feeding in a breast-fed infant: association with nefazodone and its metabolites.

OBJECTIVE: To investigate whether adverse effects in a premature neonate could be attributed to nefazodone exposure via breast milk. CASE SUMMARY: The breast-fed white infant (female, 2.1 kg, 36 weeks corrected gestational age) of a 35-year-old woman (60 kg) taking nefazodone 300 mg/d was admitted to the hospital because she was drowsy, lethargic, unable to maintain normal body temperature, and was feeding poorly. A diagnosis of exposure to nefazodone via breast milk was considered only after other more likely diagnoses had been excluded. After breast feeding was discontinued, the infant's symptoms resolved slowly over a period of 72 hours. The maternal plasma and milk concentration-time profiles for nefazodone and its metabolites, triazoledione, HO-nefazodone, and m-chlorphenylpiperazine, were quantified by HPLC. The calculated infant dose for nefazodone and its active metabolites (as nefazodone equivalents) via the milk was only 0.45% of the weight-adjusted maternal nefazodone daily dose. DISCUSSION: Our data suggest a putative association between maternal nefazodone ingestion and adverse effects in a premature breast-fed neonate. The measured amount of drug exposure would normally be considered safe in a full-term infant. However, there was a temporal relationship between resolution of adverse effects in the infant and cessation of breastfeeding. CONCLUSIONS: This case highlights the importance of individualizing the risk-benefit analysis for exposure to antidepressants in breast milk, especially when dealing with premature neonates.

Adult↗
PubMed1999

Distribution and excretion of fluoxetine and norfluoxetine in human milk.

AIMS: To characterize milk/plasma (M/P) ratio and infant dose, for fluoxetine and norfluoxetine, in breast-feeding women taking fluoxetine for the treatment of depression, and to determine the plasma concentration of these drugs in their infants. METHODS: Fourteen women (mean age 32.2 years) taking fluoxetine (mean dose 0.51 mg kg-1 day-1 ) and their infants (mean age 3.4 months) were studied. Fluoxetine and norfluoxetine in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval in four patients, and by single point data collection in 10 patients. Infant exposure was estimated as the product of estimated milk production, and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean M/P values of 0.68 (95% CI 0.52-0.84) and 0.56 (95% CI 0.35-0.77) were calculated for fluoxetine and norfluoxetine, respectively. Mean total infant exposure (fluoxetine equivalents) was estimated to be 6.81% (range 2.15-12%) of the weight-adjusted maternal dose of fluoxetine. Contributions from fluoxetine and norfluoxetine were approximately equal. Fluoxetine (range 20-252 microgram l-1 ) was detected in five of the nine infants from whom samples were collected, and norfluoxetine (range 17-187 microgram l-1 ) was detected in seven of the nine infants. The highest of these concentrations was about 70% of the maternal plasma concentrations. CONCLUSIONS: The mean combined dose of fluoxetine and norfluoxetine transmitted to infants via breast milk is below the 10% notional level of concern. However, there was considerable interpatient variability in estimated infant dose and in some of the patients, the dose was >10%. Further, since adverse effects have been observed in breast-fed infants, careful monitoring of the infants is mandatory. Neonates exposed to these drugs in utero had higher concentrations of fluoxetine and norfluoxetine and are at greater risk of adverse effects.

Adult↗
PubMed1999

Paroxetine in human milk.

AIMS: The primary aims of the study were to estimate the exposure of infants to paroxetine via breast milk and to determine the maternal milk:plasma ratio (M/P) of paroxetine. Secondary aims were to compare single point and area under the curve (AUC) estimates of M/P, to assess variability of M/P in fore and hind milk, and to compare the observed M/P with that predicted by a model. METHODS: Two studies were performed. In one study, six nursing mothers who were being treated with paroxetine were studied over a 24 h dose interval at steady-state. The total amount of paroxetine in the milk was measured, which represented the 'dose' to the infant. The M/PAUC was calculated and compared with a predicted value. In the second study, four nursing mothers who were being treated with paroxetine, were studied at steady-state, around a normal infant feeding time. A single plasma sample and a prefeed milk sample were taken approximately 3 h after the morning dose of paroxetine, and a postfeed milk sample taken around 1 h later. The dose received by the infant was estimated from the average milk concentrations of the pre and postfeed samples using standard assumptions, and M/P calculated directly. Plasma concentrations of paroxetine were measured in 8 of the 10 infants in the two studies. RESULTS: The mean dose of paroxetine received by the infants in the first study was 1.13% (range 0.5-1.7) of the weight adjusted maternal dose. The mean M/PAUC was 0.39 (range 0.32-0.51). The predicted M/P was 0.22. The mean dose of paroxetine received by the infants in the second study was 1.25% (range 0.38-2.24) of the weight adjusted maternal dose. The mean M/P was 0.96 (range 0.31-3.33) and did not differ between fore and hind milk. The drug was not detected in the plasma of seven of the infants studied and was detected but not quantifiable (<4 microg l-1 ) in one infant. No adverse effects were observed in any of the infants. CONCLUSIONS: Measured M/P and estimated infant dose were similar in the two studies, although the range was wider for the single point study. Paroxetine can be considered 'safe' during breast feeding because the dose transferred to the infant is well below the recommended safety limit of 10% of the weight adjusted maternal dose, concentrations in the infants were generally undetectable, and no adverse effects were reported.

Adult↗
PubMed1999

Cardiovascular and neurological toxicity of venlafaxine.

1. We report a case of venlafaxine overdose and describe pharmacokinetic data on drug disposition. 2. Case report. Serial venlafaxine levels were measured and drug half-life calculated and compared to data at therapeutic concentrations. Metabolite concentrations were also measured and the potential for toxicity described with reference to individual variation in such metabolism 3. Venlafaxine can cause significant cardiac and neurotoxicity. Its potential for causing such toxicity may be dependent on whether an individual has the extensive metaboliser cytochrome CYP2D6 phenotype or the poor metaboliser phenotype

Adult↗
PubMed1998

Distribution and excretion of sertraline and N-desmethylsertraline in human milk.

AIMS: To characterise milk/plasma (M/P) ratio and infant exposure, for sertraline and N-desmethylsertraline, in breast-feeding women taking sertraline for the treatment of depression. METHODS: Eight women (mean age 28 years) taking sertraline (1.05 mg kg(-1) day(-1)) and their infants (mean age 5.7 months) were studied. Sertraline and N-desmethylsertraline in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval at steady-state. M/P values were estimated from area under the plasma and milk concentration-time curves. All milk produced was collected over the dose interval. Infant exposure was estimated as the product of actual or estimated milk production, and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean milk production was 321 ml day(-1) (range 34-974 ml). Mean M/P values of 1.93 and 1.64 were calculated for sertraline and N-desmethylsertraline respectively. Infant exposure estimated from actual milk produced was 0.2% and 0.3% of the weight-adjusted maternal dose for sertraline and N-desmethylsertraline (as sertraline equivalents) respectively. When calculated from estimated milk production (0.15 l kg(-1) day(-1)), infant exposure was significantly greater (P<0.0001) at 0.90% and 1.32% for sertraline and N-desmethylsertraline respectively. Neither sertraline nor its N-desmethyl metabolite could be detected in plasma samples from the four infants tested. No adverse effects were observed in any of the eight infants and all had achieved normal developmental milestones. CONCLUSIONS: Irrespective of the method of calculation of infant exposure, the mean total dose of sertraline and its N-desmethyl metabolite transmitted to infants via breast-feeding is low and unlikely to cause any significant adverse effects.

1-Naphthylamine↗
PubMed1998

Distribution and excretion of venlafaxine and O-desmethylvenlafaxine in human milk.

AIMS: To characterise the transfer of venlafaxine (V) and its O-desmethyl metabolite (ODV) into human milk by measuring milk/plasma (M/P) ratio, and to estimate the likely dose received by a breast-fed infant. METHODS: Milk and plasma samples were collected from three lactating women who were taking venlafaxine for depression, and were at steady-state. In two of the patients, venous blood and milk samples were collected 0, 1, 2, 3, 4, 6, 8 and 12 h post dose, while in the third patient a single pair of blood and milk samples was obtained 0.83 h post dose. A plasma sample was obtained from each of their infants. V and ODV were measured in plasma and milk by high performance liquid chromatography. M/P was calculated and infant dose estimated as drug concentration in milk x a milk intake of 0.15 l kg(-1) day(-1), relative to the weight-adjusted maternal dose. RESULTS: Mean M/P for V was 4.1 (range 2.8-4.8) and 3.1 for ODV (range 2.8-3.8). The mean total infant dose (as V equivalents) was 7.6% (range 4.7-9.2%) of the maternal weight-adjusted dose, with approximately equal amounts of V (3.5%) and ODV (4.1%) in the dose. ODV (median 100 microg I(-1)) was detected in the plasma of all three infants. The infants were healthy and showed no acute adverse effects. CONCLUSIONS: These preliminary data show that the total dose of V and ODV ingested by breast-fed infants can be as high as 9.2% of maternal intake. Moreover there were measurable concentrations of ODV in the infants' plasma. We recommend that exposed infants should be observed closely.

Adult↗
PubMed1998

A comparison of high-performance liquid chromatography and fluorescence polarization immunoassay for therapeutic drug monitoring of tricyclic antidepressants.

Although the manufacturer of the polyclonal fluorescence polarization immunoassay (FPIA) for tricyclic antidepressants (TCA) only recommends its use in the diagnosis of overdose, the assay is nevertheless widely used in therapeutic drug monitoring. Using plasma samples from 337 patients taking one of eight different tricyclic antidepressants, the authors investigated the performance of the TDx assay procedure for eight different TCAs by comparison to specific high-performance liquid chromatography (HPLC) assay methods. The regression correlation between the TDx assay value and that for active tricyclic measured by HPLC was poor (r2 < 0.9) for amitriptyline, clomipramine, dothiepin, and doxepin. The regression line for amitriptyline also had a significant positive y-axis intercept. Moreover, the TDx method overestimated the concentration of active drug to an extent that varied considerably between different TCAs and within the usual therapeutic range for a single TCA. The authors conclude that the TDx assay is probably satisfactory for routine TDM of desipramine, imipramine, nortriptyline, and trimipramine. However, it significantly overestimates therapeutic concentrations of amitriptyline, clomipramine, dothiepin, and doxepin. The use of TDx and HPLC assay methods by different laboratories for sequential therapeutic drug monitoring of TCAs in the same patient may confuse physicians and confound dose adjustment and patient management. Although their study shows that the TDx assay can give satisfactory therapeutic drug monitoring results for some drugs, the authors conclude that its use should be restricted to the evaluation of overdose as recommended by the manufacturer.

Antidepressive Agents, Tricyclic↗
PubMed1997

Methadone distribution and excretion into breast milk of clients in a methadone maintenance programme.

AIMS: Methadone is widely used in maintenance programs for opioid-dependent subjects. The aims of the study were to quantify the distribution and excretion of methadone in human milk during the early postnatal period and to investigate exposure of breast fed infants to the drug. METHODS: Blood and milk samples were obtained from 12 breast feeding women who were taking methadone in daily doses ranging from 20-80 mg (0.3-1.14 mg kg-1). Blood was also obtained from eight of their infants. Methadone concentration in these samples was quantified by h.p.l.c. The infants were observed for withdrawal symptoms. RESULTS: The mean (95% CI) milk/plasma ratio was 0.44 (0.24-0.64). Exposure of the infants, calculated assuming an average milk intake of 0.15 l kg-1 day-1 and a bioavailability of 100% was 17.4 (10.8-24) microg kg-1 day-1. The mean infant dose expressed as a percentage of the maternal dose was 2.79 (2.07-3.51)%. Methadone concentrations in seven infants were below the limit of detection for the h.p.l.c. assay procedure, while one infant had a plasma methadone concentration of 6.5 microg l-1. Infant exposure to methadone via human milk was insufficient to prevent the development of a neonatal abstinence syndrome which was seen in seven (64%) infants. No adverse effects attributable to methadone in milk were seen. CONCLUSIONS: We conclude that exposure of breast fed infants to methadone taken by their mothers is minimal and that women in methadone maintenance programs should not be discouraged from breast feeding because of this exposure.

Adult↗