Transfer of methylamphetamine and amphetamine into breast milk following recreational use of methylamphetamine

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• The extent of drug transfer into milk during recreational intravenous use of methylamphetamine has not previously been studied.
WHAT THIS STUDY ADDS
• We have shown that methylamphetamine transfers into breast milk.
• The amount a breastfed infant would receive varied over 2.5-fold range.
• A 48-h withholding period for breastfeeding is recommended following recreational use.
AIMS To investigate the transfer of amphetamines into breast milk following their recreational use and estimate drug exposure for the breastfed infant.
METHODS Two breastfeeding mothers who were occasional recreational users of intravenous amphetamines were studied. A urine sample was collected 4 h after dose, and milk samples were collected over 24 h. Drug in urine was qualitatively identified by gas chromatography-mass spectrometry and quantification in milk was by high-performance liquid chromatography. Absolute infant dose via milk was estimated.
RESULTS The urines contained predominantly methylamphetamine together with smaller amounts of amphetamine. In the 24 h after dose, average concentrations in milk were 111 µg l⁻¹ and 281 µg l⁻¹ for methylamphetamine and 4 µg l⁻¹ and 15 µg l⁻¹ for amphetamine in cases 1 and 2, respectively. Absolute infant doses for methylamphetamine plus amphetamine (as methylamphetamine equivalents) were 17.5 µg kg⁻¹ day⁻¹ and 44.7 µg kg⁻¹ day⁻¹, respectively, for cases 1 and 2.
CONCLUSION These limited data suggest that breastfeeding should be withheld for 48 h after recreational amphetamine use.     

The effects of ziprasidone on steady‐state lithium levels and renal clearance of lithium

Aims   To assess the potential of ziprasidone to alter the renal clearance and steady‐state serum levels of lithium.
Methods  Healthy subjects who had stable serum lithium levels during the first 7 days of treatment with lithium 900 mg day^{− 1}, given as two divided daily doses, were randomized to receive concomitant treatment with either ziprasidone, 40 mg day^{− 1}, given as two divided daily doses, on days 9–11 followed by 80 mg day^{− 1}, given as two divided daily doses on days 12–15 ( n  = 12), or placebo twice daily ( n  = 13). Ziprasidone or placebo was administered 2 h before each dose of lithium.
Results   Ziprasidone administration was associated with a 0.07 mmol l^{− 1} (13%) mean increase in steady‐state serum lithium levels compared with a mean increase of 0.06 mmol l^{− 1} (10%) with placebo. Mean renal clearance of lithium decreased by 0.09 l h^{− 1} (5%) in the ziprasidone group and by 0.14 l h^{− 1} (9%) in the placebo group. None of these differences between the two groups was statistically or clinically significant.
Conclusions   Ziprasidone does not alter steady‐state serum lithium concentrations or renal clearance of lithium.     

Pharmacodynamics of benserazide assessed by its effects on endogenous and exogenous levodopa pharmacokinetics*

Aims The objectives of the study were to investigate the pharmacodynamics of the peripheral decarboxylase inhibitor benserazide during multiple-dose regimens.
Methods Two groups of eight healthy male subjects were consecutively treated for periods of 14 days with benserazide 5, 25, 100  mg three times daily and 12.5, 50, 200  mg three times daily, respectively. Plasma levels of levodopa, 3- O -methyldopa (3-OMD) and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined before benserazide treatment and during all benserazide dosing regimens, as existing endogenously and after administration of 250  mg  levodopa.
Results Endogenous concentrations of levodopa and 3-OMD increased dose-dependently (from 8 up to 52  μg  l⁻¹ and from 0.02 up to 0.50  mg  l⁻¹, respectively, at doses of 200  mg) with ascending doses of benserazide whereas DOPAC levels remained unchanged. There were no indications of a plateau in the effects of benserazide on the plasma levels of the analytes. The area under the concentration-time curve (AUC) of exogenously administered levodopa increased from 1.2 in the control group to 5.9  mg  l⁻¹  h at benserazide doses of 100–200  mg three times daily. Benserazide caused a dose-dependent increase in the AUC of 3-OMD from 7.4 to 106  mg  l⁻¹   h at doses of 200  mg. Formation of DOPAC was dose-dependently suppressed, with benserazide 5  mg three times daily already halving its AUC.
Conclusions The benserazide-dose response data obtained suggest that even at very high doses extracerebral decarboxylase is not yet completely inhibited.     

Single dose pharmacokinetics of oral artemether in healthy Malaysian volunteers

Aims To determine the pharmacokinetics of artemether (ARM) and its principal active metabolite, dihydroartemisinin (DHA) in healthy volunteers.
Methods Six healthy male Malaysian subjects were given a single oral dose of 200  mg artemether. Blood samples were collected to 72  h. Plasma concentrations of the two compounds were measured simultaneously by reversed-phase h.p.l.c. with electrochemical detection in the reductive mode.
Results Mean (± s.d.) maximum concentrations of ARM, 310±153  μg  l⁻¹, were reached 1.88±0.21  h after drug intake. The mean elimination half-life was 2.00±0.59  h, and the mean AUC 671±271  μg  l⁻¹ h. The mean C _max of DHA, 273±64  μg  l⁻¹, was observed at 1.92±0.13  h. The mean AUC of DHA was 753±233  μg  h  l⁻¹. ARM and DHA were stable at ≤−20°  C for at least 4 months in plasma samples.
Conclusions The relatively short half-life of ARM may be one of the factors responsible for the poor radical cure rate of falciparum malaria with regimens employing daily dosing. In view of the rapid loss of DHA in plasma samples held at room temperature (26°  C) it is recommended to store them at a temperature of ≤−20°  C as early as possible after sample collection.     

A comparison of the effects of fluvastatin and bezafibrate on exercise metabolism: a placebo-controlled study in healthy normolipidaemic subjects

1 We have examined the interaction between aerobic exercise and lipid-lowering drugs in a crossover study of 16 healthy normolipidaemic volunteers who each received 21 days' treatment with bezafibrate (400  mg), fluvastatin (40  mg), and placebo, in random order.
2 Fluvastatin treatment reduced pre-exercise total cholesterol (TC) by 23% ( P <0.0001), low-density lipoprotein cholesterol (LDL-C) by 33% ( P <0.0001), and plasma triglycerides by 11%, compared with pre-treatment values. Bezafibrate reduced TC by 11% ( P <0.01); LDL-C by 9%; and plasma triglycerides by 40% ( P <0.01), compared with pre-treatment values.
3 During exercise, in comparison with placebo, and fluvastatin treatment, respectively, bezafibrate significantly reduced mean fat oxidation: 31% vs 39%, P =0.035, 31% vs 39%, P =0.002, plasma free fatty acid (FFA) availability, e.g. after 90  min of exercise: ( t 90) 520 vs 662  μmol  l⁻¹, P =0.054, 520 vs 725  μmol l⁻¹, P =0.016, and plasma levels of glycerol ( t 90): 59 vs 74  μmol l⁻¹, P =0.037, 59 vs 73  μmol l⁻¹, P =0.016. Fluvastatin had no impact on fat metabolism in comparison with placebo.
4 Reduced plasma FFA concentration and lower fat oxidation during prolonged exercise on bezafibrate treatment may be due to an inhibition of hepatic acetyl coenzyme A carboxylase, resulting in reduced FFA release from adipose tissue.
5 The possibility that impaired fat metabolism on fibrates could induce premature fatigue during exercise of moderate duration and intensity should be examined in hyperlipidaemic patients.     

Effect of troleandomycin on the pharmacokinetics of imipramine in Chinese: the role of CYP3A

Aims In vitro data indicate that imipramine (IMI), a widely used tricyclic antidepressant drug, is N -demethylated by several isoforms of cytochrome P450, which include CYP3A4. The aim of this study was to investigate the role of CYP3A in the in vivo N -demethylation of IMI.
Methods Healthy subjects were given troleandomycin (TAO), a selective inhibitor of CYP3A, 250  mg daily for 2 days before a single oral dose of 100  mg IMI was administered.
Results Pretreatment with TAO significantly increased the AUC of IMI by 59% (1971±938 vs 3134±2000  μg l⁻¹  h, 95% confidence interval for difference between means: 218 to 2108  μg  l⁻¹  h, P <0.05) and decreased its oral clearance by 30% (60.9±27.4 vs 42.5±22.7  l h⁻¹, 95% confidence internal for difference between means: 7.2 to 31.7  l h⁻¹, P <0.05).
Conclusions We conclude that CYP3A may play an important role in the in vivo N -demethylation of IMI.     

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)  μg  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  μg  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.     

Transplacental distribution of salbutamol enantiomers at Caesarian section

Aims To investigate the transplacental distribution of salbutamol enantiomers after administration of racemate to women prior to Caesarian section.
Methods Five women about to undergo elective Caesarian section were administered a single 0.25  mg bolus intravenous dose of (R,S)-salbutamol. The time from drug administration to delivery was different for each woman (27–105  min). Maternal and foetal umbilical cord venous blood samples were collected immediately after delivery and the plasma fraction analysed for salbutamol enantiomer concentrations by enantioselective high pressure liquid chromatography.
Results The concentrations (mean±  s.d.) of the active (R) enantiomer of salbutamol in cord and maternal plasma were 0.46±0.35 and 0.89±0.50  ng  ml⁻¹, respectively, and the difference was statistically significant (95% confidence interval (CI) of the difference: 0.12–0.74  ng  ml⁻¹ ). The corresponding concentrations of the (S) enantiomer of 0.92±0.45 and 1.11±0.67  ng  ml⁻¹, respectively, were not significantly different (95% CI of the difference −0.08–0.48  ng  ml⁻¹ ). The ratio of (R):(S) in cord plasma was significantly less than that in maternal plasma ( P =0.016).
Conclusions Transplacental distribution of salbutamol enantiomers at Caesarian section after prior administration of racemate to mothers leads to concentrations in cord plasma that are significantly less for the active (R) enantiomer and not significantly different for the (S) enantiomer than in maternal plasma presumably due to enantioselective placental-foetal metabolism.     

Excretion of citalopram in breast milk

Aims The objective of this study was to measure the secretion of the selective serotonin uptake inhibitor citalopram in breast milk.
Methods The excretion of citalopram in breast milk was studied at steady-state conditions in two patients with depression and in one healthy volunteer after ingestion of a single dose citalopram.
Results Milk/serum concentration ratios based on single pairs of samples from the two patients ranged from 1.16 to 1.88. Based on milk concentration data from the patients, the absolute dose ingested by a suckling infant would be 4.3–17.6  μg  kg⁻¹ day⁻¹, and the relative dose 0.7–5.9% of the weight-adjusted maternal dose. Based on area-under-the-time-concentration curves from the healthy volunteer, the milk/serum ratio was 1.00, the absolute dose to the infant during steady-state conditions would be 11.2  μg  kg⁻¹ day⁻¹ and the relative dose 1.8% of the weight-adjusted maternal dose.
Conclusion The study shows that the relative dose to a suckling infant is close to that reported for fluoxetine, and higher than reported for fluvoxamine, paroxetine and sertraline.     

Neurological, cardiovascular and metabolic effects of mefloquine in healthy volunteers: a double-blind, placebo-controlled trial

1 To assess neurological, cardiovascular, metabolic and other side-effects of mefloquine given in conventional prophylactic dose to healthy volunteers, a double-blind, randomized, placebo-controlled trial was conducted. In addition, the identity of the active drug was concealed until the end of the trial.
2 A total of 106 healthy adults were recruited, of whom 95 (mean age 24 years; 45% males) completed the full study protocol.
3 Subjects had a baseline assessment, received placebo as first dose, were randomized to mefloquine 250  mg or placebo weekly for 4 weeks starting a week later, and were reassessed after the 2nd and 4th active/placebo doses. Subjects kept a daily symptom diary from 2 weeks before until 2 weeks after the dosing period.
4 Plasma mefloquine assay suggested compliance in all 46 subjects allocated active treatment (week 5 mean±s.d.; 2.35±0.94  μmol l⁻¹). Mefloquine did not alter calcium homoeostasis but produced a mean 0.5  mmol l⁻¹ fall in serum glucose over the study period ( P <0.001) and relative hyperinsulinaemia. Symbol digit modalities, and digit forwards and backwards test scores, were similar in active and placebo groups across the three assessments, as were lying/standing blood pressure and high-tone hearing loss. Electrocardiographic QT_c interval prolongation and diarrhoea were mild but transient side-effects of mefloquine ( P <0.01). Neurological symptoms were comparable in the two groups throughout the study. There was no evidence of drug toxicity in 11 subjects who withdrew.
5 Mefloquine prophylaxis does not appear to produce low-grade but debilitating neurological symptoms or to alter the results of sensitive tests of cerebral function. However, there may be situations in which mefloquine might contribute to hypoglycaemia and cardiac dysrhythmias.     

Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio

1 Statins inhibit synthesis of mevalonate, a precursor of ubiquinone that is a central compound of the mitochondrial respiratory chain. The main adverse effect of statins is a toxic myopathy possibly related to mitochondrial dysfunction.
2 This study was designed to evaluate the effect of lipid-lowering drugs on ubiquinone (coenzyme Q10) serum level and on mitochondrial function assessed by blood lactate/pyruvate ratio.
3 Eighty hypercholesterolaemic patients (40 treated by statins, 20 treated by fibrates, and 20 untreated patients, all 80 having total cholesterol levels >6.0  mmol l⁻¹) and 20 healthy controls were included. Ubiquinone serum level and blood lactate/pyruvate ratio used as a test for mitochondrial dysfunction were evaluated in all subjects.
4 Lactate/pyruvate ratios were significantly higher in patients treated by statins than in untreated hypercholesterolaemic patients or in healthy controls ( P <0.05 and P <0.001). The difference was not significant between fibrate-treated patients and untreated patients.
5 Ubiquinone serum levels were lower in statin-treated patients (0.75  mg l⁻¹±0.04) than in untreated hypercholesterolaemic patients (0.95  mg l⁻¹±0.09; P <0.05).
6 We conclude that statin therapy can be associated with high blood lactate/pyruvate ratio suggestive of mitochondrial dysfunction. It is uncertain to what extent low serum levels of ubiquinone could explain the mitochondrial dysfunction.     

Stimulatory as well as inhibitory effects of ethinyloestradiol on the metabolic clearances of propranolol in young women

1   The metabolism of a single 80  mg oral dose of propranolol was determined in nine young women before and after administration of ethinyloestradiol alone (EE₂) or in combination with norethindrone (OC).
2   Whereas the total clearance of propranolol (2713±404  ml min⁻¹ (mean±s.e.mean)) was not significantly altered by either EE₂ (3365±347  ml min⁻¹) or the combined OC (2905±345  ml min⁻¹), significant changes in all three primary metabolic pathways were observed.
3   The clearance through side-chain oxidation decreased from 345±55  ml min⁻¹ to 262±33  ml min⁻¹ after EE₂ ( P <0.05). A similar reduction of cytochrome P450 metabolism by EE₂ has been observed for other drugs.
4   The clearance through glucuronidation increased from 364±61  ml min⁻¹ to 625±117  ml min⁻¹ after EE₂ ( P <0.01). Similar stimulation of glucuronic acid conjugation by EE₂ has also been observed for other drugs.
5   The clearance through ring oxidation increased from 697±109  ml min⁻¹ to 1280±162  ml min⁻¹ after EE₂ ( P <0.01). This observation appears to be a novel finding with EE₂ and cytochrome P450 metabolism.
6   The treatment with OC produced changes in propranolol's metabolic clearances which were qualitatively similar to those generated by EE₂.     

Pharmacokinetics of recombinant human interleukin-11 (rhIL-11) in healthy male subjects

Aims To study the pharmacokinetics of recombinant human interleukin-11 (rhIL-11) in healthy male volunteers following subcutaneous (s.c.) and intravenous (i.v.) administration.
Methods RhIL-11 was infused intravenously at 10–50  μg  kg⁻¹ for 1 or 3  h, or administered subcutaneously at 3–50  μg  kg⁻¹ to volunteers. RhIL-11 was also administered at 3  μg  kg⁻¹ s.c. once daily for 7 days. Plasma and urinary concentrations were measured by enzyme-linked immunosorbent assay (ELISA).
Results RhIL-11 showed linear pharmacokinetics after both intravenous infusion and s.c. administration. Comparison of t _1/2 and MRT values after i.v. administration with those after s.c. administration indicated that rhIL-11 pharmacokinetics after s.c. administration were absorption rate-limited. Bioavailability after s.c. administration was about 65%. Since RhIL-11 was not detected in urine after a single 50  μg  kg⁻¹ s.c. dose, rhIL-11 was considered to be eliminated by metabolism. There was no significant change in the pharmacokinetic profile of rhIL-11 following repeated s.c. administration.
Conclusions RhIL-11 demonstrated linear pharmacokinetics at these dose ranges after single and repeated s.c. administration or constant-rate i.v. infusion in healthy volunteers.     

Involvement of CYP2D6 but not CYP2C19 in nicergoline metabolism in humans

1 Nicergoline, an ergot derivative previously used as a vasodilator, has gained a new indication in treating the symptoms of senile dementia.
2 Nicergoline is rapidly hydrolysed to an alcohol derivative, 1-methyl-10-α-methoxy-9,10-dihydrolysergol (MMDL), which is further N -demethylated to form 10-α-methoxy-9,10-dihydrolysergol (MDL). A few individuals display aberrant metabolism of this drug, as shown by their diminished capacity to form the MDL metabolite. The aim of this study was to determine whether defective nicergoline metabolism is associated with the debrisoquine and/or the S-mephenytoin hydroxylation polymorphisms.
3 After a single, oral 30  mg dose of nicergoline, the plasma concentrations of its two metabolites were studied in 15 subjects, divided into three groups with respect to their debrisoquine and S-mephenytoin hydroxylation phenotypes.
4 The pharmacokinetic parameters of MMDL and MDL were similar in the ten subjects who were extensive metabolisers of debrisoquine (five of whom were poor metabolisers of S-mephenytoin) (mean MMDL C _max 59  nmol l⁻¹ and AUC (0, t h) 144  nmol l⁻¹h, mean MDL C _max 183  nmol l⁻¹ and AUC 2627  nmol l⁻¹h) but were markedly different from the five subjects who were poor metabolisers of debrisoquine (mean MMDL C _max 356  nmol l⁻¹ and AUC 10512  nmol l⁻¹h, MDL concentrations below limit of quantitation).
5 We conclude that the formation of MDL from MMDL in the metabolism of nicergoline is catalysed to a major extent by CYP2D6 and that the observed interindividual variation in the metabolic pattern of the drug is related to the debrisoquine hydroxylation polymorphism.     

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×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  μg  l⁻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.     

Constant rate infusion of vancomycin in premature neonates: a new dosage schedule

Aims Since vancomycin's bactericidal action has been shown to be time-dependent, a constant rate infusion over 24  h might result in a better bactericidal efficacy. The purpose of this study was to define a new dosage schedule in prematures.
Methods Two vancomycin 24  h constant rate infusion schedules were tested in two groups of neonates. Postconceptional age (PCA) was 27 to 41 weeks in group 1 ( n =24) and 28 to 51.5 weeks in group 2 ( n =29). Group 1 neonates received continuous infusion of 10 to 30  mg  kg⁻¹ day⁻¹, adjusted for PCA and weight. Group 2 was designed to take into account the significant relationship observed in group 1 between vancomycin clearance standardized on weight and PCA and consisted of a constant loading dose of 7  mg  kg⁻¹ followed by continuous infusion of 10 to 40  mg  kg⁻¹ day⁻¹ adjusted for PCA and weight.
Results Mean vancomycin serum concentration at steady state was 11±3.1  mg  l⁻¹ in group 1 and 15.4±6.2  mg  l⁻¹ in group 2. Fifty-six percent of group 1 values vs 88% of group 2 values were between 10 and 30  mg  l⁻¹ at steady state ( P <0.01). Both regimens were well tolerated.
Conclusion A loading dose of vancomycin followed by constant rate infusion of the appropriate dose adjusted for PCA and weight might improve vancomycin concentrations in neonates.     

1-Methylxanthine derived from caffeine as a pharmacodynamic probe of oxypurinol effect

Aims In the present study we have investigated the use of caffeine, administered in the form of instant coffee, as a prodrug for 1MX to validate the use of the 1MU:1MX ratio following caffeine administration as a pharmacodynamic measure of oxypurinol effect on xanthine oxidase.
Methods Five healthy volunteers took caffeine 75  mg 8 hourly administered as instant coffee over a 7 day period. They were given allopurinol 600  mg on day 4. Urine was collected in 8  h aliquots from day 1–day 7. The ratio of 1-methyluric acid (1MU) to 1-methylxanthuric (1MX) was determined.
Results The relationship between the plasma oxypurinol (the active metabolite of allopurinol) concentration at the midpoint of each caffeine dosage interval and the decrement in the urinary 1MX to 1MU ratio fitted well by a sigmoid E_max model. Mean (±s.d.) values of the oxypurinol E C ₅₀(3.9±1.4  mg  l^{− 1} ), E C ₉₀(8.7±1.8  mg  l^{− 1} ) and the exponent, n (3.0±1.2) were similar to those obtained previously following either the direct administration of 1MX or the use of theophylline as a prodrug for 1MX.
Conclusions These data indicate that the use of caffeine as a source of 1MX could provide a simple and ethically acceptable method for monitoring oxypurinol effect in patients taking allopurinol for the treatment of gout.     

The airway effects of stopping regular oral theophylline in patients with asthma

Aims We investigated whether the deterioration in asthma control reported following cessation of theophylline was due to tolerance to theophylline.
Methods Eighteen subjects with mild stable asthma were given oral theophylline 10  mg  kg⁻¹ day⁻¹ or placebo for 2 weeks in a double-blind crossover study. FEV₁ and PD₂₀ histamine were measured before and 8  h after the first dose of treatment and 8, 32 and 56  h after the final dose. PD₂₀ AMP was measured before treatment and 9  h after the final dose.
Results Six patients did not tolerate theophylline. In the other 12 subjects there were no differences between treatments in daily PEF, symptom scores, rescue bronchodilator use, PD₂₀ histamine or FEV₁ up to 8  h post treatment. Following withdrawal of theophylline there were significantly lower values for mean FEV₁ (mean difference 0.15  l, 95% CI 0.03, 026) and PD₂₀ AMP compared to placebo but no difference in other end points.
Conclusions The small rebound deterioration in lung function following regular treatment with therapeutic doses of oral theophylline is consistent with the development of tolerance.     

Concentrations and effects of buspirone are considerably reduced by rifampicin

Aims The effects of rifampicin on the pharmacokinetics and pharmacodynamics of buspirone, a non-benzodiazepine anxiolytic agent, were investigated.
Methods In a randomized, placebo-controlled cross-over study with two phases, 10 young healthy volunteers took either 600  mg rifampicin or matched placebo once daily for 5 days. On day 6, 30  mg buspirone was administered orally. Plasma buspirone concentrations and effects of buspirone were measured up to 10  h.
Results The total area under the plasma buspirone concentration-time curve after rifampicin was 10.4% (95% CI, 6.3–14.5%) of that after placebo (1.64±0.35  ng  ml⁻¹ h vs 22.0±15.1  ng  ml⁻¹ h (mean±s.d.); P <0.01). Rifampicin decreased the peak plasma concentration of buspirone from 6.6±3.7  ng  ml⁻¹ to 0.84±0.23  ng  ml⁻¹ ( P <0.01) and the half-life from 2.8±0.7  h to 1.3±0.5  h ( P <0.01). A significant ( P <0.05) reduction in the effects of buspirone was observed in three of the six psychomotor tests employed (postural sway test with eyes closed, subjective drowsiness and overall drug effect) after rifampicin pretreatment.
Conclusions The strong interaction between rifampicin and buspirone is probably mostly due to enhanced CYP3A4-mediated first-pass metabolism of buspirone. Buspirone will most likely show a greatly reduced anxiolytic effect when used together with rifampicin or other potent inducers of CYP3A4 such as phenytoin and carbamazepine.     

Absorption kinetics of oral sotalol combined with cisapride and sublingual sotalol in healthy subjects

Aims To study the absorption kinetics of sotalol following administration of different formulations. A formulation which results in fast absorption might be useful in the episodic treatment of paroxysmal supraventricular tachycardia (SVT), atrial fibrillation (Afib) or atrial flutter (Afl).
Methods In an open randomized crossover study seven healthy male volunteers were given an intravenous infusion of 20  mg sotalol, for assessing the absolute bioavailability, an oral solution containing 80  mg sotalol, an oral solution containing both 80  mg sotalol and 20  mg cisapride and an 80  mg sotalol tablet, which was taken sublingually.
Results The addition of cisapride decreased the time at which maximum serum concentrations were reached ( t _max ) from 2.79 (1.85–4.34) h to 1.16 (0.68–2.30) h ( P =0.009) [95% CI: -2.59, −0.55] and increased the absorption rate constant ( k _a ) from 0.49 (0.31–0.69) h⁻¹ to 1.26 (0.52–5.61) h⁻¹ ( P =0.017). The absolute bioavailability of sotalol was reduced by cisapride from 1.00±0.15 to 0.70±0.26 ( P =0.006), while maximum serum concentrations of both oral solutions were not significantly different. Compared with the sublingually administered tablet with a median t _max of 2.12 (0.89–3.28) h, the sotalol/cisapride oral solution gave a smaller t _max (p=0.009) [95% CI: −1.64, −0.36]. The k _a of the sotalol/cisapride solution was significanty ( P =0.010) larger than the k _a of 0.56 (0.33–0.75) h⁻¹ found after sublingual administration of the tablet.
Conclusions The sotalol/cisapride oral solution might be suitable for the episodic treatment of SVT, Afib or Afl.