Acute Effects of Lysergic Acid Diethylamide on Circulating Steroid Levels in Healthy Subjects.

Lysergic acid diethylamide (LSD) is a serotonin 5-hydroxytryptamine-2A (5-HT2A ) receptor agonist that is used recreationally worldwide. Interest in LSD research in humans waned after the 1970s, although the use of LSD in psychiatric research and practice has recently gained increasing attention. LSD produces pronounced acute psychedelic effects, although its influence on plasma steroid levels over time has not yet been characterised in humans. The effects of LSD (200 µg) or placebo on plasma steroid levels were investigated in 16 healthy subjects using a randomised, double-blind, placebo-controlled, cross-over study design. Plasma concentration-time profiles were determined for 15 steroids using liquid-chromatography tandem mass-spectrometry. LSD increased plasma concentrations of the glucocorticoids cortisol, cortisone, corticosterone and 11-dehydrocorticosterone compared to placebo. The mean maximum concentration of LSD was reached at 1.7 h. Mean peak psychedelic effects were reached at 2.4 h, with significant alterations in mental state from 0.5 h to > 10 h. Mean maximal concentrations of cortisol and corticosterone were reached at 2.5 h and 1.9 h, and significant elevations were observed 1.5-6 h and 1-3 h after drug administration, respectively. LSD also significantly increased plasma concentrations of the androgen dehydroepiandrosterone but not other androgens, progestogens or mineralocorticoids compared to placebo. A close relationship was found between plasma LSD concentrations and changes in plasma cortisol and corticosterone and the psychotropic response to LSD, and no clockwise hysteresis was observed. In conclusion, LSD produces significant acute effects on circulating steroids, especially glucocorticoids. LSD-induced changes in circulating glucocorticoids were associated with plasma LSD concentrations over time and showed no acute pharmacological tolerance.

Urinary and plasma catecholamines and metanephrines in dogs with pheochromocytoma, hypercortisolism, nonadrenal disease and in healthy dogs.

BACKGROUND: Diagnosis of pheochromocytoma (PC) is based on a combination of clinical suspicion, finding an adrenal mass, increased plasma, and urine concentrations of catecholamine metabolites and is finally confirmed with histopathology. In human medicine, it is controversial whether biochemically testing plasma is superior to testing urine. OBJECTIVES: To measure urinary and plasma catecholamines and metanephrines in healthy dogs, dogs with PC, hypercortisolism (HC), and nonadrenal diseases (NAD) and to determine the test with the best diagnostic performance for dogs with PC. ANIMALS: Seven PC dogs, 10 dogs with HC, 14 dogs with NAD, 10 healthy dogs. METHODS: Prospective diagnostic clinical study. Urine and heparin plasma samples were collected and stored at -80°C before analysis using high-pressure liquid chromatography (HPLC) coupled to electrochemical detection or tandem mass spectrometry were performed. Urinary variables were expressed as ratios to urinary creatinine concentration. RESULTS: Dogs with PC had significantly higher urinary normetanephrine and metanephrine:creatinine ratios and significantly higher plasma-total and free normetanephrine and plasma-free metanephrine concentrations compared to the 3 other groups. There were no overlapping results of urinary normetanephrine concentrations between PC and all other groups, and only one PC dog with a plasma normetanephrine concentration in the range of the dogs with HC and NAD disease. Performances of total and free plasma variables were similar. Overlap of epinephrine and norepinephrine results between the groups was large with both urine and plasma. CONCLUSION AND CLINICAL IMPORTANCE: Measurement of normetanephrine is the preferred biochemical test for PC and urine was superior to plasma.

Effects of iatrogenic hypercortisolism on gallbladder sludge formation and biochemical bile constituents in dogs.

An association between gallbladder mucoceles and hypercortisolism (HC) was recently described in dogs. Because the formation of a mucocele from clear bile without the transitional formation of microprecipitates appears unlikely, the aim of this study was to investigate the effects of iatrogenic HC on sludge formation and changes in the biochemical composition of bile. Bile samples from 6 dogs obtained by percutaneous ultrasound-guided cholecystocentesis before (day 0), during (days 28, 56, and 84), and after (days 28p, 56p, and 84p) oral administration of hydrocortisone (8 mg/kg every 12 h) were analysed for calcium, cholesterol and bilirubin concentrations and pH. In addition the gallbladder was examined ultrasonographically for sludge. Six dogs receiving a placebo served as controls. Although gallbladder sludge was observed in all treated dogs at day 56, it was also noted in 50% of control dogs, and no significant differences were seen between groups at any sampling time. Bilirubin and cholesterol concentrations decreased significantly and reversibly during treatment, and calcium concentration showed a similar trend. Bile pH was consistently slightly alkaline during iatrogenic HC, whereas it was slightly acidic in control animals. A 3-month period of iatrogenic HC does not lead to ultrasonographically detectable gallbladder sludge or to an increase in bile constituents that are commonly implicated in sludge formation in humans.

Phosphate concentration in ophthalmic corticoid preparations.

BACKGROUND: Topical preparations, high in phosphate, may cause calcification when used on a damaged corneal surface. The knowledge of the phosphate concentration in medications helps to prevent corneal calcifications. Our study gives an overview of the amount of phosphate contained in ophthalmic corticoid preparations. METHODS: Samples of 38 commercially available corticoid preparations were tested. The quantification of phosphate was performed using the molybdate method on a Modular P autoanalyzer. RESULTS: 18 of 38 preparations (47%) had a phosphate concentration above physiological levels (>1.45 mmol/l). It varied greatly, and ranged from less than 0.1 mmol/l (18 preparations) to 62.6 mmol/l. The corticoids that were tested included betamethasone sodium phosphate (18.3-35.5 mmol/l), dexamethasone (0.1-17.6 mmol/l), dexamethasone sodium phosphate (<0.1-62.6 mmol/l), fluorometholone (<0.1-22.5 mmol/l), and prednisolone acetate (<0.1-0.5 mmol/l). CONCLUSIONS: The phosphate concentration in corticoid-phosphate formulations varies greatly, and is mainly determined by the chosen buffer. The prednisolone acetate preparations showed physiological phosphate concentrations. For a treatment on a damaged corneal surface, preparations with physiological phosphate concentrations should be used.

Phosphate concentrations in antiglaucoma medication.

BACKGROUND: Eye drops may contain phosphates as part of their buffer system. In the presence of epithelial keratopathy a high concentration of phosphate favours corneal calcification. To date European legislation does not require a quantitative declaration of the phosphates since buffers are regarded as additives. The knowledge of the phosphate concentration in medications helps to prevent corneal calcifications. Our study gives an overview on the amount of phosphate contained in antiglaucoma drops. METHODS: 21 samples of commercially available antiglaucoma drops were tested. The quantification of phosphate was performed using the molybdate method on a Modular P autoanalyzer. RESULTS: 10 of 21 (47 %) glaucoma drops had a phosphate concentration above physiological levels (> 1.45 mmol/L). A concentration higher than 100 mmol/L was found in four preparations that contained timolol. CONCLUSIONS: Many antiglaucoma drops contain unphysiological levels of phosphate, very high concentrations are found in some beta-blockers. These preparations have the potential to favour the formation of insoluble crystalline calcium phosphate deposits when used on a damaged corneal surface, and should therefore be avoided.

["Ghost peak" in gas chromatography in a delirious woman with severe metabolic acidosis. Intoxication with an unknown substance?]. / "Geisterpeak" in der Gas-Chromatografie bei schwerer metabolischer Azidose. Intoxikation mit unbekannter Substanz?

HISTORY AND CLINICAL FINDINGS: A 31-year-old female with known type 1 diabetes mellitus was referred because of symptomatic hyperglycemia. On admission she was delirious and impressed with marked Kussmaul breathing. All other vital signs were normal. INVESTIGATIONS: Blood serum glucose concentration was 26.4 mmol/l. Arterial blood gas analysis revealed massive metabolic acidosis (pH 6.80) with an elevated anion gap (21 mmol/l) and a marginally increased osmolar gap (21,5 mOsm/l). TREATMENT AND COURSE: Despite normalization of the serum glucose and acidemia after administration of normal saline, insulin and bicarbonate, the delirium persisted, and the possibility of an additional intoxication had to be considered. Serum headspace analysis for intoxication with solvents (gas chromatography) finally detected a "ghost peak", which could not be assigned to any established substance. The same peak was, however, found in a healthy subject's serum and was found to be a "toluene peak". Toluene is contained as "contaminator" in gels in blood collection tubes. The patient gradually regained consciousness and "merely" suffered from diabetic ketoacidosis associated with cocaine use. CONCLUSION: The differential diagnosis of high anion gap metabolic acidosis includes among other reasons intoxications with different kinds of solvents. When looking for solvents in the serum when poisoning is suspected (headspace analysis), only blood collection tubes without gel (EDTA plasma) should be used, because all gels contain solvents (in this case toluene).

Corneal calcification following intensified treatment with sodium hyaluronate artificial tears.

AIM: To report a potential adverse effect of intensified treatment with sodium hyaluronate artificial tears. METHODS: Five cases of deep calcium deposition in the cornea associated with ocular surface disease and frequent use of hyaluronic acid artificial tears are described. All patients used one formulation of phosphate buffered hyaluronate eye drops when rapid calcification developed. All eyes required corneal graft surgery for visual rehabilitation. Specimens at keratoplasty were available for light microscopy and investigation by dispersive x ray analysis. The phosphate concentration in the medication used for topical treatment was measured and compared to alternative hyaluronate preparations. RESULTS: Light microscopy showed dense mineralisation of the entire stroma. The crystalline deposits consisted of hydroxyapatite, Ca5(PO4)3OH. A 50-fold higher concentration of phosphate was measured in the sodium hyaluronate eye drops used for treatment (50.9 mmol/l) when compared with normal serum. The other hyaluronate formulations showed phosphate concentrations from <0.1 mmol/l to 10.9 mmol/l. CONCLUSIONS: The hyaluronate artificial tear formulation "Hylo-Comod" favours the formation of insoluble crystalline calcium phosphate deposits in presence of epithelial keratopathy. This is because of its high phosphate concentration and typically frequent instillation. Manufacturers and prescribers should be aware that topical preparations may contain considerable amounts of phosphate which may lead to sight threatening corneal complications.

Phosphate concentration in artificial tears.

BACKGROUND: Irrigating solutions and eye drops may contain phosphates as part of their buffer system. In the presence of epithelial keratopathy, a high concentration of phosphate favours corneal calcification. Knowledge of the phosphate concentration in artificial tear products helps to prevent this sight-threatening complication. This study gives an overview on the amount of phosphate contained in artificial tears. METHODS: Fifty-nine samples of commercially available artificial tear preparations were tested. The quantification of phosphate was performed using the molybdate method on a Modular P autoanalyzer. RESULTS: Twenty-six of 59 (44%) artificial tear products had a phosphate concentration above physiological levels (>1.45 mmol/l). A phosphate concentration above 25 mmol/l was found in nine products (15%), a concentration higher than 50 mmol/l in three (5%). CONCLUSIONS: Many artificial tear formulations contain unphysiological levels of phosphate, but very high concentrations are found only in a few products. These preparations have the potential to favour the formation of insoluble crystalline calcium phosphate deposits when used on a damaged corneal surface, and should therefore be used cautiously.

Thiopurine S-methyltransferase polymorphisms: efficient screening method for patients considering taking thiopurine drugs.

OBJECTIVE: More than 11% of the Caucasian population are heterozygous or homozygous carriers of thiopurine S-methyltransferase (TPMT) mutants and are at risk for toxic side effects when treated with thiopurine drugs. Therefore, screening for TPMT polymorphisms in a patient prior to prescribing these agents is recommended. The goal of this study was to determine a cut-off concentration of the TPMT activity assay beyond which genotyping of the TPMT gene should be performed. METHODS: The TPMT activity of 240 unrelated Caucasian subjects was measured using high-performance liquid chromatography. Genotyping for the most frequent allelic variants, TPMT*2, *3A, *3B, *3C and *7 was performed by LightCycler technology and sequencing. RESULTS: The inter-individual TPMT activity showed a range from 23 nmol MTG/g*Hb*h(-1) to 97 nmol MTG/g*Hb*h(-1) with a median of 56 nmol MTG/g*Hb*h(-1). Using a cut-off concentration of 45.5 nmol MTG/g*Hb*h(-1), a test sensitivity of 100% and a specificity of 89% were reached for heterozygous carriers of a TPMT mutation. We identified 1 carrier of TPMT*2, 14 carriers of TPMT*3A and 3 carriers of TPMT*3C, resulting in a TPMT heterozygosity prevalence of 7.5%. CONCLUSIONS: This study defines the cut-off value for the TPMT phenotyping assay at 45.5 nmol/g*Hb*h(-1), beyond which additional genotyping elucidates the individual risk for drug therapy. Using this cut-off concentration, the number of genotyping assays could be reduced by about 60%.

Risk of recurarization during retransfusion of autologous blood withdrawn after injection of muscle relaxants: a comparison of rocuronium and mivacurium.

STUDY OBJECTIVES: In the context of acute normovolemic hemodilution (ANH) recurarization, defined as significant decrease of train-of-four ratio (TOFR) during retransfusion of autologous blood withdrawn after induction of anesthesia, has been described for vecuronium and atracurium. The present study for the first time examined this risk for rocuronium and mivacurium. DESIGN: Prospective, randomized, unblinded clinical study. SETTING: University Hospital in Zurich/Switzerland. PATIENTS: 20 ASA physical status I and II patients undergoing general anesthesia for major maxillofacial surgery. INTERVENTIONS: Anesthesia was induced and maintained with propofol and remifentanil, and rocuronium (0.9 mg kg(-1)) or mivacurium (0.25 mg kg(-1)) was given to facilitate intubation. Thereafter, ANH was started with the removal of 500 mL autologous blood and the subsequent replacement by the same amount of 6% hydroxyethyl starch. The withdrawn blood was stored at 4 degrees C until retransfusion at the end of surgery. MEASUREMENTS: To estimate the risk of recurarization during retransfusion, the degree of recurarization during retransfusion of the autologous blood was assessed mechanomyographically. Plasma levels of rocuronium and mivacurium in the patients' plasma and the autologous blood were determined after its removal and before retransfusion. MAIN RESULTS: The TOFR before retransfusion was 0.97 (range: 0.96 to 0.98) for rocuronium (n = 10) and 0.98 (range: 0.96 to 1.0) for mivacurium (n = 8); n.s. During retransfusion, a slight, but statistically significant reduction of TOFR occurred in one patient in each group. In the mivacurium group, this recurarization occurred 10 minutes after the start of retransfusion; in the rocuronium group, it occurred 20 minutes after retransfusion. The plasma levels of rocuronium and mivacurium in the autologous blood did not change during storage. The plasma concentration of mivacurium in the autologous blood after its removal was 420 +/- 142 microg/L; before retransfusion, it was 384 +/- 147 microg/L. The respective concentrations for rocuronium were 2930 +/- 516 microg/L and 2660 +/- 464 microg/L. CONCLUSIONS: Recurarization during retransfusion may occur with both neuromuscular blocking drugs, mivacurium and rocuronium, when these drugs were injected before the removal of the autologous blood.

Clonidine decreases propofol requirements during anaesthesia: effect on bispectral index.

Assessment of the effect of clonidine on depth of anaesthesia is difficult because clonidine combines analgesic, sedative and direct haemodynamic effects. We thus evaluated the influence of clonidine on the bispectral index (BIS) and its potential dose-sparing effect on propofol. After induction of anaesthesia with target-controlled infusion of propofol and obtaining an unchanged bispectral index (pre-BIS), clonidine 4 microg kg(-1) or placebo was administered randomly to 50 patients in a double-blind manner. Subsequently, if there was a decrease in BIS we reduced the target concentration of propofol until pre-BIS was reached. The pre-BIS was maintained and a remifentanil infusion was added during surgery. The courses of the BIS, heart rate and blood pressure were recorded and the total amounts of intra-operative propofol and remifentanil were determined. Assessment of implicit memory during anaesthesia was performed with an auditory implicit memory test consisting of item sequences. Administration of clonidine resulted in a decrease in the BIS from 45 (SD 4) to 40 (6) (P<0.001), which allowed a reduction of propofol target concentration from 3.3 (0.6) to 2.7 (0.7) microg ml(-1) (P<0.001) and measured propofol concentration from 2.9 (0.6) to 2.5 (0.7) kg ml(-1) (P=0.009) in order to maintain the pre-BIS value. During subsequent surgery, propofol requirements were reduced by 20% (P=0.002) in the clonidine group and a similar amount of remifentanil was used in each group. The increase in anaesthetic depth given by clonidine can therefore be measured with bispectral EEG analysis and allows reduction of the propofol dose to achieve a specific depth of anaesthesia.

Arterial and venous pharmacokinetics of intravenous heroin in subjects who are addicted to narcotics.

BACKGROUND: In Switzerland, medical prescription of heroin (diacetylmorphine) is currently being evaluated as a treatment option for heavily dependent addicts. Therefore the diacetylmorphine pharmacokinetics in opioid-addicted patients was studied. METHODS: Three different diacetylmorphine doses (up to 210 mg) and 20 mg deuterium-labeled morphine (morphine-d3) were administered intravenously to 8 heroin-addicted patients. Arterial and venous plasma samples were collected, and diacetylmorphine, monoacetylmorphine, morphine, morphine-3-glucuronide, morphine-6-glucuronide, and morphine-d3 plasma concentrations were measured by liquid chromatography-mass spectrometry. RESULTS: Maximal arterial concentrations of diacetylmorphine, monoacetylmorphine, and morphine were 2.4, 5.4, and 1.4 times higher and occurred 2 to 3 minutes earlier than maximal venous concentrations. Venous areas under the concentration-time curves (AUC) of diacetylmorphine and monoacetylmorphine were 35% and 26% lower than arterial AUC values, whereas for morphine the venous AUC was 15% higher. Morphine-3-glucuronide and morphine-6-glucuronide exhibited no arteriovenous differences. AUCs for diacetylmorphine, monoacetylmorphine, and morphine increased linearly with dose. Diacetylmorphine was completely metabolized to morphine. Substantial morphine input into the arterial circulation persisted for up to 90 minutes. The arterial clearances of diacetylmorphine, monoacetylmorphine, and morphine-d3 were 8.7 +/- 2.6, 6.7 +/- 1.6, and 2.3 +/- 0.3 L/min, respectively. The arterial half-lives of diacetylmorphine and morphine-d3 were 2. 4 +/- 0.8 and 88 +/- 21 minutes, respectively. CONCLUSIONS: These data indicate that substantial arteriovenous differences exist for diacetylmorphine and metabolite kinetics, that the pharmacokinetics of diacetylmorphine and metabolites is linear even in the high dose range used by opioid addicts, and that not only diacetylmorphine but also monoacetylmorphine is substantially metabolized peripherally to morphine.

Sensitive stereospecific determination of acenocoumarol and phenprocoumon in plasma by high-performance liquid chromatography.

We describe a normal-phase HPLC method for the stereospecific determination of R- and S-acenocoumarol and R- and S-phenprocoumon with S-warfarin as internal standard. The compounds were separated using a Whelk-O1 chiral stationary phase, detected by UV at 310 nm and quantified in the internal standard mode. Linearity was verified for acenocoumarol in the range of 15-2000 microg/l and for phenprocoumon from 15 to 2200 microg/l, respectively. The detection limits were 5 microg/l for all compounds. The recovery was >84% for R- and S-acenocoumarol and >74% for R- and S-phenprocoumon. The imprecision (C.V.) (50-1800 microg/l) for R- and S-acenocoumarol was <4.7% within-day and <7.8% between-day. For R- and S-phenprocoumon the respective values were <5.6% and <5.9%. The accuracy for all compounds was 96.5-110%.

St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4.

BACKGROUND: St John's Wort (hypericum perforatum) is an herbal medicine that is frequently used for therapy of mild depression. Recently, St John's Wort was reported to substantially decrease blood/plasma concentrations and efficacy of cyclosporine (INN, ciclosporin), indinavir, and digoxin. In this study we investigated the mechanisms of these St John's Wort-induced drug interactions. METHODS AND RESULTS: In a preclinical study, the administration of St John's Wort extract to rats during 14 days resulted in a 3.8-fold increase of intestinal P-glycoprotein/Mdrl expression and in a 2.5-fold increase in hepatic CYP3A2 expression (Western blot analyses). In a clinical study, the administration of St John's Wort extract to 8 healthy male volunteers during 14 days resulted in an 18% decrease of digoxin exposure after a single digoxin dose (0.5 mg), in 1.4- and 1.5-fold increased expressions of duodenal P-glycoprotein/MDR1 and CYP3A4, respectively, and in a 1.4-fold increase in the functional activity of hepatic CYP3A4 (14C-erythromycin breath test). CONCLUSIONS: These results indicate direct inducing effects of St John's Wort on intestinal P-glycoprotein/MDR1 (in rats and humans), hepatic CYP3A2 (in rats), and intestinal and hepatic CYP3A4 (in humans). Therefore the results provide a mechanistic explanation for the previously observed drug interactions in patients and support the importance of intestinal P-glycoprotein/MDR1 in addition to intestinal and hepatic CYP3A4 for overall drug absorption and disposition in humans.

Metabolism of the new liposomal anticancer drug N4-octadecyl-1-beta-D-arabinofuranosylcytosine in mice.

Metabolism and excretion of the new antitumor drug N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC) was investigated in mice. Mice were injected i.v. with tritium-labeled liposomal NOAC (4 micromol/mouse). Analysis of HPLC-purified extracts of liver homogenates by liquid chromatography coupled with mass spectrometry revealed only the presence of unmetabolized drug. To study the excretion of the administered drug, mice were injected with tritium-labeled liposomal NOAC or as comparison with 1-beta-D-arabinofuranosylcytosine (ara-C; 4 micromol/mouse) and housed up to 48 h in metabolic cages. Urine and feces were collected at different time points and the kinetics of excreted radioactivity were determined. After 48 h, 39% of the injected [5-3H]NOAC radioactivity was excreted in urine and 16% in feces, whereas ara-C radioactivity was only found in urine with 48% of the injected dose. Feces extracts and urine were purified by HPLC and radioactive fractions were further analyzed by liquid chromatography coupled with mass spectrometry. The radioactivity of feces extracts of NOAC-treated mice was composed of unmetabolized NOAC, hydroxylated NOAC (NOAC + OH), its sulfated derivative (NOAC + OSO3H), and unidentified metabolites, whereas in urine, the hydrophilic molecules ara-C and ara-U were found. During the period of 48 h only 2% of the injected NOAC was eliminated in its unmetabolized form, whereas 25% was identified as main metabolite ara-C. Urine collected during 48 h in ara-C-treated mice contained 33% of the injected dose as unmetabolized drug and 13% as the main metabolite ara-U. Thus, NOAC is metabolized by two major pathways, one leading to the hydrophilic metabolites ara-C and ara-U and the other to hydroxylated and sulfated NOAC.

No clinically relevant effect of lornoxicam intake on acenocoumarol pharmacokinetics and pharmacodynamics.

OBJECTIVE: To investigate the effect of lornoxicam co-administration on acenocoumarol pharmacokinetics and pharmacodynamics. METHODS: In an open crossover study, six healthy male volunteers received racemic acenocoumarol (10 mg) orally without/with lornoxicam co-administration (8 mg twice daily). RESULTS: The median (range) areas under the concentration-time curve (AUC) for (R)-acenocoumarol were 3458 (3035-7312) microg x h 1(-1) in the absence of and 3667 (2907-7741) microg x h 1(-1) in the presence of lornoxicam. The corresponding values for (S)-acenocoumarol were 479 (381-853) microg x h 1(-1) and 612 (425-1241) microg x h 1(-1). The differences were not statistically significant. Lornoxicam co-administration did not influence the free fractions or acenocoumarol's effect on factor II and VII activities. Simulations based on the results of a model-based analysis predicted that in the case of lornoxicam co-administration, the factor VII activity of a person in steady-state at 26% will remain between 14% and 32%. CONCLUSION: Co-administration of lornoxicam at the upper limit of recommended doses does not alter the pharmocokinetics of the clinically relevant (R)-acenocoumarol or the anticoagulant activity of acenocoumarol. These data clearly differ from the results of previous studies, which showed clinically relevant influences of lornoxicam on warfarin kinetics and of piroxicam on acenocoumarol kinetics.

Opposite effects of lornoxicam co-administration on phenprocoumon pharmacokinetics and pharmacodynamics.

OBJECTIVE: To investigate the effect of co-administration of the non-steroidal anti-inflammatory drug (NSAID) lornoxicam on the pharmacokinetics of (R)- and (S)-phenprocoumon and their effect on factor II and VII activities. METHODS: Six healthy male volunteers completed an open crossover study. Plasma concentrations of (R)- and (S)-phenprocoumon and activities of coagulation factors II and VII were measured after a single oral dose of 9 mg phenprocoumon racemate. In the second session, lornoxicam administration was started 3 days before phenprocoumon administration and continued twice daily until the last blood sample was drawn. RESULTS: Lornoxicam co-administration resulted in a statistically significant increase of the area under the concentration-time curve (AUC) of the more potent (S)-isomer of phenprocoumon from a median value of 100 (range 68-146) mg x h x 1(-1) to 124 (92-239) mg x h x 1(-1). For the (R)-isomer, the AUC increase from 96 (70-142) mg x h x 1(-1) in the absence to 108 (75-155) mg x h x 1(-1) in the presence of lornoxicam was not statistically significant. In a model-based analysis, an increase of (S)-phenprocoumon and (R)-phenprocoumon bioavailability of 14% [95% CI (9%, 19%)] and 6% (2%, 10%) and a decrease of their clearances by 15% (8%, 21%) and 6% (0%, 13%) was obtained. Lornoxicam co-administration did not influence the free fractions of (R)- or (S)-phenprocoumon. Contrary to what was expected from the changes in pharmacokinetics, a statistically significant decrease in the effect of phenprocoumon on factor II and VII activity was observed for the sessions with lornoxicam co-administration. For factor VII, lornoxicam was found to increase the concentration causing half-maximal effect (C50) of phenprocoumon by 70% [95% CI (38%, 111%)]. CONCLUSION: Co-administration of lornoxicam at the upper limit of recommended doses mainly altered the pharmacokinetics of the more potent (S)-isomer and to a lesser degree those of (R)-phenprocoumon. Despite these changes in pharmacokinetics, a decrease of the effect on factor II and VII activity was observed. These results suggest that in the case of lornoxicam co-administration in a patient treated with phenprocoumon the prothrombin time should be monitored closely.

Pharmacokinetic studies of mitoxantrone and one of its metabolites in serum and urine in patients with advanced breast cancer.

OBJECTIVE: Mitoxantrone (MTO) was administered to patients with advanced breast cancer either as free MTO (f-MTO) or liposomal MTO (1-MTO). The intra- and interindividual variations in serum pharmacokinetics of MTO were analysed. In addition, the excretion of MTO and its metabolite mitoxantrone dicarboxylic acid (MTOD) in urine was determined. METHODS: The concentration of MTO was measured by high-performance liquid chromatography in serum over a period of 24 h and the amount of MTO and the metabolite MTOD excreted in urine over 18 h was determined. Pharmacokinetic parameters of f-MTO and 1-MTO were calculated. RESULTS: 1-MTO had a significantly longer half-life of distribution in the deep (third) compartment and thus a larger area under the curve (AUC) than f-MTO. No difference was found with respect to distribution in the peripheral (second) compartment. The kinetics of MTO in serum did not significantly differ between patients. In four patients repeated pharmacokinetic analyses gave superimposable results. Thus, there was no enzyme induction during therapy. By contrast, two patients with oedema had a much longer mean residence time (MRT) and AUC for MTO in serum. Despite the altered pharmacokinetics of f-MTD and 1-MTO, no toxic adverse effects occurred in these two patients. CONCLUSIONS: f-MTO and 1-MTO exhibited different distribution patterns in the deep compartment with a significantly increased half-life for 1-MTO. There is no need to monitor MTO for treatment of breast cancer patients with f-MTO. In patients with oedema, the MRT of MTO is prolonged. The clinical relevance of this observation is as yet unclear.