Sugammadex hypersensitivity and underlying mechanisms: a randomised study of healthy non-anaesthetised volunteers.

BACKGROUND: We investigated potential for hypersensitivity reactions after repeated sugammadex administration and explored the mechanism of hypersensitivity. METHODS: In this double-blind, placebo-controlled study (NCT00988065), 448 healthy volunteers were randomised to one of three arms to receive three repeat i.v. administrations of either sugammadex 4 mg kg-1, 16 mg kg-1, or placebo. Primary endpoint was percentage of subjects with hypersensitivity (assessed by an independent adjudication committee). Secondary endpoint of anaphylaxis was classified per Sampson and Brighton criteria. Exploratory endpoints included skin testing, serum tryptase, anti-sugammadex antibodies [immunoglobulin (Ig) E/IgG], and other immunologic parameters. RESULTS: Hypersensitivity was adjudicated for 1/148 (0.7%), 7/150 (4.7%), and 0/150 (0.0%) subjects after sugammadex 4 mg kg-1, 16 mg kg-1, and placebo, respectively. After sugammadex 16 mg kg-1, one subject met Sampson criterion 1 and Brighton level 1 (highest certainty) anaphylaxis criteria; two met Brighton level 2 criteria. After database lock it was determined that certain protocol deviations could have introduced bias in the reporting of hypersensitivity signs/symptoms in a subject subset. Objective laboratory investigations indicated that potential underlying hypersensitivity mechanisms were unlikely to have been activated; the results suggest that most of the observed hypersensitivity reactions were unlikely IgE/IgG-mediated. CONCLUSION: Dose-dependent hypersensitivity or anaphylaxis reactions to sugammadex were observed when administered without prior neuromuscular blocking agent. Laboratory investigations do not suggest prevalent allergen-specific IgE/IgG-mediated immunologic hypersensitivity. Because it could not be fully excluded that estimates of hypersensitivity/anaphylaxis incidence were unbiased, an additional study was conducted to characterise the potential for hypersensitivity reactions and is described in a companion report. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT00988065; Protocol number P06042.

[The development of a guideline to improve the efficiency and effectiveness of FACT board meetings using a Delphi study]. / Delphi-studie voor de ontwikkeling van een handreiking ter bevordering van een effectief en efficiënt FACT-bordoverleg.

BACKGROUND: The FACTboard meeting structures the multidisciplinary meetings held by FACT teams, held for the 10-20% most care intensive patients. The FACT manual only provides a general outline for the FACTboard meeting, leaving out criteria specifying the methods to structure meetings. Precisely describing these criteria could improve the quality of these meetings. AIM: To develop a more detailed guideline on how to structure a FACTboard meeting by means of a Delphi study. METHOD: The panel of the Delphi study existed of 22 professions working in certified FACT teams and 8 experts in the field of FACT. Panel members individually assessed 113 items according to whether the statement should be included in the guideline. Statements rated important or essential by ≥80% of the panel members were included in the guideline. The panel members' commentary was used to shape and adjust the statements to clarify why they were regarded as important or unimportant. RESULTS: 54 statements were rated essential or important by ≥80% of the panel members. These statements pertained to the organization and structure of the FACTboard meeting and the roles and responsibilities of the team members. CONCLUSION: The developed guideline could be used by FACT and possibly ACT teams to structure the FACTboard meeting.

Metabolism and excretion of asenapine in healthy male subjects.

The metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1:1)] were studied after sublingual administration of [(14)C]-asenapine to healthy male volunteers. Mean total excretion on the basis of the percent recovery of the total radioactive dose was ∼90%, with ∼50% appearing in urine and ∼40% excreted in feces; asenapine itself was detected only in feces. Metabolic profiles were determined in plasma, urine, and feces using high-performance liquid chromatography with radioactivity detection. Approximately 50% of drug-related material in human plasma was identified or quantified. The remaining circulating radioactivity corresponded to at least 15 very polar, minor peaks (mostly phase II products). Overall, >70% of circulating radioactivity was associated with conjugated metabolites. Major metabolic routes were direct glucuronidation and N-demethylation. The principal circulating metabolite was asenapine N(+)-glucuronide; other circulating metabolites were N-desmethylasenapine-N-carbamoyl-glucuronide, N-desmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N(+)-glucuronide. Other excretory metabolites were N-desmethylasenapine-N-carbamoylglucuronide, 11-hydroxyasenapine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combinations of these routes were found) and N-formylasenapine in combination with several hydroxylations, and most probably asenapine N-oxide in combination with 10,11-hydroxylations followed by conjugations. In conclusion, asenapine was extensively and rapidly metabolized, resulting in several regio-isomeric hydroxylated and conjugated metabolites.

Safety and tolerability of single intravenous doses of sugammadex administered simultaneously with rocuronium or vecuronium in healthy volunteers.

BACKGROUND: Sugammadex rapidly reverses rocuronium- and vecuronium-induced neuromuscular block. To investigate the effect of combination of sugammadex and rocuronium or vecuronium on QT interval, it would be preferable to avoid the interference of anaesthesia. Therefore, this pilot study was performed to investigate the safety, tolerability, and plasma pharmacokinetics of single i.v. doses of sugammadex administered simultaneously with rocuronium or vecuronium to anaesthetized and non-anaesthetized healthy volunteers. METHODS: In this phase I study, 12 subjects were anaesthetized with propofol/remifentanil and received sugammadex 16, 20, or 32 mg kg(-1) combined with rocuronium 1.2 mg kg(-1) or vecuronium 0.1 mg kg(-1); four subjects were not anaesthetized and received sugammadex 32 mg kg(-1) with rocuronium 1.2 mg kg(-1) or vecuronium 0.1 mg kg(-1) (n=2 per treatment). Neuromuscular function was assessed by TOF-Watch SX monitoring in anaesthetized subjects and by clinical tests in non-anaesthetized volunteers. Sugammadex, rocuronium, and vecuronium plasma concentrations were measured at several time points. RESULTS: No serious adverse events (AEs) were reported. Fourteen subjects reported 23 AEs after study drug administration. Episodes of mild headache, tiredness, cold feeling (application site), dry mouth, oral discomfort, nausea, increased aspartate aminotransferase and gamma-glutamyltransferase levels, and moderate injection site irritation were considered as possibly related to the study drug. The ECG and vital signs showed no clinically relevant changes. Rocuronium/vecuronium plasma concentrations declined faster than those of sugammadex. CONCLUSIONS: Single-dose administration of sugammadex 16, 20, or 32 mg kg(-1) in combination with rocuronium 1.2 mg kg(-1) or vecuronium 0.1 mg kg(-1) was well tolerated with no clinical evidence of residual neuromuscular block, confirming that these combinations can safely be administered simultaneously to non-anaesthetized subjects. Rocuronium and vecuronium plasma concentrations decreased faster than those of sugammadex, reducing the theoretical risk of neuromuscular block developing over time.

Immunospecific targeting of immunoliposomes, F(ab')2 and IgG to red blood cells in vivo.

In this report a model to study the fate of target cells in the blood circulation after injection of appropriate immunoliposomes is discussed. The effect of intravenous administration of antimouse RBC immunoliposomes, F(ab')2 or IgG on the fate of intravenously injected 51Cr-labelled mouse RBC (Cr-mRBC) in the mouse and, particularly, in the rat was studied. The immunoliposome was of the Fab'-MPBPE-REV type (Fab'-fragments covalently linked to reverse phase evaporation vesicles by maleimido-4-(p-phenylbutyrate)phosphatidylethanolamine). In the rat model a high blood level (80%) of the injected dose of target cells, Cr-mRBC, was maintained for several hours. The elimination by Fab'-liposomes, F(ab')2 or IgG of Cr-mRBC, and subsequent uptake into liver and spleen was dose dependent. Administration of Fab'-liposomes or F(ab')2 resulted in a preferential uptake into the spleen (above a certain dose also, but much lower, uptake into the liver was observed), while after IgG administration 51Cr-label was mainly recovered in the liver. At equal protein doses (+/- 130 micrograms) Fab'-liposomes induced a faster elimination of the Cr-mRBC and a higher uptake into the spleen than F(ab')2. The potential advantage of the use of drug-loaded immunoliposomes to eliminate target cells from the blood stream and to induce a certain pharmacological effect in the target cells, in comparison with the free antibody administration of F(ab')2 or IgG is discussed.

Therapeutic effect of chloroquine(CQ)-containing immunoliposomes in rats infected with Plasmodium berghei parasitized mouse red blood cells: comparison with combinations of antibodies and CQ or liposomal CQ.

The potential therapeutic application of chloroquine-containing immunoliposomes (Fab'-lipCQ) in a Plasmodium berghei malaria model was studied. Extending a previously described in vivo model (Peeters et al. (1988) Biochim. Biophys. Acta 943, 137-147) it was demonstrated that injection of antimouse red blood cell (anti-mRBC) Fab'-lipCQ was significantly more effective than liposome-encapsulated chloroquine (lipCQ) or free chloroquine in delaying or preventing a patent infection after intravenous injection of parasitized mouse red blood cells (p-mRBC) in rats. The results could be improved by injecting synchronized infected cells instead of non-synchronous p-mRBC in order to minimize the presence of free parasites which could easily infect rat RBC. It was further demonstrated that sequential injection of anti-mRBC IgG and lipCQ or chloroquine resulted in complete inactivation of the injected parasitized cells while Fab'-lipCQ administration resulted in a maximum score of 50% at an equal chloroquine, protein and phospholipid dose. In this report the potential of the concept of drug targeting for the effective treatment of a disease, which manifests in blood cells, was demonstrated.

Microdosing of a Carbon-14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages.

Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of NBEs in humans can be successfully obtained early in the drug development process by the use of microdosing in a small group of healthy subjects combined with ultrasensitive accelerator mass spectrometry (AMS). After only minimal preclinical testing, we performed a first-in-human phase 0/phase 1 trial with a human recombinant therapeutic protein (RESCuing Alkaline Phosphatase, human recombinant placental alkaline phosphatase [hRESCAP]) to assess its safety and kinetics. Pharmacokinetic analysis showed dose linearity from microdose (53 µg) [(14) C]-hRESCAP to therapeutic doses (up to 5.3 mg) of the protein in healthy volunteers. This study demonstrates the value of a microdosing approach in a very small cohort for accelerating the clinical development of NBEs.

Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects.

INTRODUCTION: Bosentan (Ro 47-0203) is a potent and mixed ETA-and ETB-receptor antagonist. Its activity has been studied in a variety of preclinical disease models. METHODS: Two double-blind placebo-controlled studies were performed to investigate the pharmacokinetics and pharmacodynamics of bosentan after single oral and intravenous doses in healthy volunteers; doses of 3, 10, 30, 100, 300, 600, 1200, and 2400 mg were given in a single ascending oral dose study, and doses of 10, 50, 250, 500, and 750 mg were given in a single ascending intravenous dose study (six subjects received active drug and two received placebo at each dose level). In an open-label crossover added to the second study, six subjects received a single oral dose of 600 mg and a single intravenous dose of 250 mg in randomized order. At regular intervals, blood pressure, pulse rate, and skin responses to intradermally injected endothelin-1 (ET-1) were recorded, and plasma levels of ET-1, proendothelin-1 (big ET-1), and ET-3, and drug and urinary levels of ET-1 and drug were determined. RESULTS: Systemic plasma clearance and volume of distribution decreased with increasing dose to limiting values of around 6 L/hr and 0.2 L/kg, respectively. The absolute bioavailability was 50% and appeared to decrease with doses above 600 mg. Plasma ET-1 increased maximally twofold (oral) and threefold (intravenous), and this increase was directly related to bosentan plasma concentrations according to an Emax model. Bosentan reversed the vasoconstrictor effect of ET-1 measured in the skin microcirculation. There was a tendency toward decreased blood pressure (approximately 5 mm Hg) and increased pulse rate (approximately 5 beats/min), neither was clearly dose dependent. Oral bosentan was well tolerated. Vomiting and local intolerability was observed at the higher intravenous doses. CONCLUSION: Bosentan is an orally bioavailable, well-tolerated, and active ET-1 antagonist with a low clearance and a moderate volume of distribution. Its intravenous use is limited because of local intolerability.

Immunospecific targeting of liposomes to erythrocytes.

Immunoliposomes were made by covalently linking Fab' fragments (from rabbit antimouse erythrocyte IgG) to reverse-phase evaporation vesicles (REV) via maleimido-4-(p-phenylbutyrate) phosphatidylethanolamine (MPB-PE) as anchor molecule. These immunoliposomes were characterized in terms of size, charge, stability and antigen binding capacity. The effect of the liposomal Fab' density on the interaction with the target cell was studied. Two isolation methods were tested to separate free Fab' from liposomally bound Fab'. The necessity of deactivation of remaining reactive sites with dithiothreitol preincubation to increase the specificity of immunoliposome target cell interactions was demonstrated.

Effect of an evening dose of regular and effervescent formulations of ranitidine or cimetidine on intragastric pH in healthy volunteers.

AIMS: To compare the effects on intragastric acidity of a single evening dose of either standard or effervescent formulations of ranitidine (300 mg) or cimetidine (800 mg). METHODS: Twelve healthy subjects were studied, using a four-period randomized cross-over design and an ambulatory intragastric pH monitoring technique. The subjects received a standard evening meal at 17.00 hours and one of the H2-receptor antagonist formulations was given at 23.00 hours. RESULTS: Both effervescent formulations caused a transient rapid increase in intragastric pH, reaching a maximum at about 3 min after ingestion. After both effervescent formulations a significantly higher pH was measured during the first 45 min after ingestion (P < 0.05), compared to the regular formulations. The onset of action of the H2-receptor antagonists was similar for both formulations of ranitidine and the effervescent cimetidine, but tended to be slower for the regular cimetidine (P = 0.06). Nocturnal intragastric pH was significantly increased by all four formulations, but more effectively so by the two ranitidine formulations. The duration of action (taken as time with pH > 4) of both ranitidine formulations was longer than that of both cimetidine formulations (P < 0.002). CONCLUSIONS: A single evening dose of 300 mg ranitidine produces a stronger decrease of nocturnal gastric acid secretion than 800 mg cimetidine. The effervescent formulations of both drugs offer the advantage of a rapid decrease (within minutes) of intragastric acidity, with preservation of the sustained systemic effect.

Excretion and metabolism of desogestrel in healthy postmenopausal women.

The metabolism of desogestrel (13-ethyl-11-methylene-18,19-dinor-17alpha-pregn-4-en-20-yn-17-ol), a progestagen used in oral contraceptives and hormone replacement therapy, was studied in vivo after a single oral administration of 150 microg [14C]-labeled desogestrel and 30 microg ethinylestradiol under steady state conditions to healthy postmenopausal women. After this oral administration, desogestrel was extensively metabolized. The dosed radioactivity was predominantly ( approximately 60%) excreted via urine, while about 35% was excreted via the feces. Desogestrel was metabolized mainly at the C3-, C5-, C6- and C13-CH(2)CH(3) positions. At the C3-position, the 3-keto moiety was found and in addition, 3beta-hydroxy and 3alpha-hydroxy groups were observed in combination with a reduced Delta(4)-double bond (5alpha-H). Hydroxy groups were introduced at the C6- (6beta-OH), the C13-ethyl (C13-CH(2)CH(2)OH) and possibly the C15- (15alpha-OH) position of desogestrel. Conjugation of the 3alpha-hydroxy moiety with sulfonic acid and conjugation with glucuronic acid were also major metabolic routes found for desogestrel in postmenopausal women. The 3-keto metabolite of desogestrel (the biologically active metabolite) was the major compound present in plasma at least up to 24 h after administration of the radioactive dose. Species comparison of the metabolic routes of desogestrel after oral administration indicates that in rats and dogs desogestrel is also mainly metabolized at the C3-position, similar to what is now found for postmenopausal women. Most other metabolic routes of desogestrel were found to differ between species. Finally, major metabolic routes found in the present study in postmenopausal women are in line with outcome of previous in vitro metabolism studies with human liver tissue (microsomes and postmitochondrial liver fractions) and intestinal mucosa.

A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

The efficacy and safety of intramuscular artemotil (ARTECEF) was compared to intravenous quinine in African children with cerebral malaria. This prospective block randomized open-label study was conducted at two centers in Zambia. Subjects were children aged 0 to 10 years of age with cerebral malaria and a Blantyre Coma Score of 2 or less. Ninety two children were studied; 48 received artemotil and 44 quinine. No significant differences in survival, coma resolution time, neurologic sequelae, parasite clearance time, and fever resolution time were seen between the two regimens. Rates for negative malaria smears one month after therapy were similar in both groups. Artemotil was a well-tolerated drug in the 48 patients in this study. It appears to be at least therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria. It has the advantage of being able to be given intramuscularly once daily for only five days.

A comparison of the pharmacokinetics and tolerability of riluzole after repeat dose administration in healthy elderly and young volunteers.

The pharmacokinetics and tolerability of the novel antiexcitatory agent, riluzole, were compared in 18 healthy elderly and 18 healthy gender- and weight-matched young volunteers. All participants received riluzole 50 mg twice daily (the recommended dosage for patients with amyotrophic lateral sclerosis), administered orally for 5 days. The pharmacokinetics of riluzole, determined on the morning of the 5th day of dosing, were not significantly affected by age or gender. The mean terminal elimination half-life (t1/2), however, was statistically significant between elderly and young subjects. Riluzole was well tolerated upon repeat dose administration. Headache was the most frequent adverse event reported, and there was no overt difference in the type, frequency, or severity of adverse events between elderly and young volunteers or between genders. In conclusion, these results indicate that no dosage adjustments of riluzole are required in the elderly.

Absorption, metabolism, and excretion of intravenously and orally administered [14C]telmisartan in healthy volunteers.

The study was conducted in healthy male volunteers to evaluate the absorption, metabolic pattern, and mode of elimination of telmisartan, a nonpeptide angiotensin II receptor antagonist. [14C]telmisartan was administered orally in solution as a single 40 mg dose to 5 subjects. A further 5 subjects received short-term intravenous infusion of [14C]telmisartan 40 mg. Measurement of total 14C radioactivity in plasma showed that about 50% was absorbed following oral administration, with maximum plasma concentration observed after 0.5 to 1 hour. Absolute bioavailability was 43%. On average, 84% of total radioactivity in plasma reflected the parent compound. The remainder of total radioactivity could be ascribed to the glucuronide conjugate of telmisartan, which represented the only metabolite in man. About 99.5% of telmisartan was bound to plasma protein, mainly to albumin and alpha-1-acid glycoprotein. Telmisartan was reversibly distributed into erythrocytes. More than 90% of administered dose was excreted within 120 hours, and the excretion balance was complete 144 hours after dosing. Radioactivity was almost exclusively (> 98%) excreted via the feces; urinary excretion accounted for < 1% of the dose, irrespective of the route of administration. In the small fraction excreted into urine, the glucuronide conjugate of telmisartan was predominant. Although some telmisartan glucuronide was detected in plasma, only unchanged drug was identified in the feces. No changes in vital signs, electrocardiogram, or clinical laboratory tests were detected following telmisartan administration, and adverse events, predominantly unrelated to treatment and of mild intensity, were infrequent. One subject fainted and, on another occasion, reported faintness; these events were probably due to the antihypertensive action of the intravenous study medication.

The parenteral controlled release of liposome encapsulated chloroquine in mice.

Free (0.6 mg), and liposome encapsulated chloroquine (0.6, 3 mg), were injected intraperitoneally, intramuscularly and subcutaneously in mice. Intraperitoneal administration of liposome-encapsulated chloroquine resulted in high and long lasting concentrations of chloroquine in the blood compared with intraperitoneal administration of free chloroquine. After administration of the liposome-encapsulated chloroquine the concentrations in the spleen were also higher, indicating that chloroquine liposomes reached the blood compartment intact after intraperitoneal administration. After intramuscular and subcutaneous administration the chloroquine liposomes acted as a local depot, giving a slower release from the subcutaneous fat layer than from the muscle depot. After the 0.6 mg dose a burst effect was found at about 7 h in most of the animals; this was not found after the 3 mg dose. This finding and the slower release after the 3 mg dose than after the 0.6 mg dose could be explained by the formation of aggregates after the injection.

Pharmacokinetics of [14C]-labelled Losigamone and enantiomers after oral administration to healthy subjects.

Losigamone ((+/-)-(R*,S*)-5-(2-chlorophenylhydroxymethyl)-4-methoxy-2 (5H)-furanone; AO-33) is a new potential antiepileptic drug undergoing clinical development. In a crossover study, 200 mg [14C]-labelled Losigamone, as well as 100 mg of each of the unlabelled enantiomers, was administered to 5 healthy volunteers as an oral suspension. The objectives of the study were to determine the mode of elimination, the excretion balance, metabolic profile, the in vitro and in vivo binding to plasma proteins and the pharmacokinetics of both enantiomers in plasma. From the plasma concentration-time profiles of [14C]-radioactivity and unchanged Losigamone it can be concluded that the absorption of Losigamone occurs very rapidly and the plasma concentration of the parent compound versus total radioactivity was consistently about 40%. An overall recovery of total radioactivity of about 97% with 85% in urine and 12% in faeces was found. Protein binding was 50%. Losigamone was extensively metabolized, with only traces of unchanged drug found in urine. The predominant metabolic pathways are hydroxylation and conjugation. After administration of the pure enantiomers, significant differences in pharmacokinetics were observed. The mean oral clearance of the (-)-enantiomer was 1863 ml/min and of the (+)-enantiomer was 171 ml/min. There was no chiral inversion after administration of the enantiomers.

Desmopressin as a pharmacological tool in vasopressinergic hypothalamus-pituitary-adrenal axis modulation: neuroendocrine, cardiovascular and coagulatory effects.

Arginine-vasopressin (AVP) is a physiological co-activator of the hypothalamus-pituitary-adrenal (HPA) axis, together with corticotrophin releasing hormone (CRH). A synthetic analogue of AVP, desmopressin (dDAVP), is often used as a pharmacological tool to assess co-activation in health and disease. The relation between dDAVP's neuroendocrine, cardiovascular, pro-coagulatory, anti-diuretic and non-specific stress effects has not been studied. A randomized, double-blind, placebo-controlled, three-way crossover study was performed in 12 healthy male and female volunteers (6 : 6). dDAVP was administered intravenously as a 10 µg bolus (over 1 min) or a 30 µg incremental infusion (over 60 min). Neuroendocrine, cardiovascular, pro-coagulatory, anti-diuretic effects and adverse events (AEs) were recorded, and autonomic nervous system (ANS) activation evaluated. The incremental infusion reached 1.8-fold higher dDAVP concentrations than the bolus. Neuroendocrine effects were similar for the 10 µg dDAVP bolus and the 30 µg incremental infusion, while cardiovascular and coagulatory effects were greater with the 30 µg dose. Osmolality and ANS activity remained uninfluenced. AEs corresponded to dDAVP's side-effect profile. In conclusion, the neuroendocrine effects of a 10 µg dDAVP bolus administered over 1 min are similar to those of a 30 µg incremental infusion administered over one hour, despite higher dDAVP concentrations after the infusion. Cardiovascular and coagulatory effects showed clear dose-related responses. A 10 µg dDAVP bolus is considered a safe vasopressinergic function test at which no confounding effects of systemic or autonomic stress were seen.

A pharmacological tool to assess vasopressinergic co-activation of the hypothalamus-pituitary-adrenal axis more integrally in healthy volunteers.

Pharmacological function tests consisting of 100 µg hCRH (corticorelin) and 10 µg dDAVP (desmopressin) mimic endogenous hypothalamus-pituitary-adrenal (HPA) axis activation. However, physiological CRH concentrations preclude informative vasopressinergic co-activation (using dDAVP) and independent quantification of both corticotrophinergic (using hCRH) and vasopressinergic (using dDAVP) activation is limited due to administration on separate occasions. This randomized, double-blind, placebo-controlled, partial five-way crossover study in healthy males and females (six : six) examined whether (1) concomitant administration of dDAVP and hCRH provides more informative vasopressinergic co-activation than dDAVP alone; and (2) whether the administration of dDAVP followed two hours later by hCRH can quantify both vasopressinergic and corticotrophinergic activation on a single test day. Combining 10 µg dDAVP with 10 µg and 30 µg hCRH caused dose-related ACTH and cortisol release which was larger than with 10 µg dDAVP alone and respectively comparable to and greater than that induced by 100 µg hCRH. Using 10 µg dDAVP alone demonstrated limited ACTH release while the effects of 100 µg hCRH two hours later were three times as large. ACTH and cortisol released by 10 µg dDAVP returned to baseline prior to 100 µg hCRH administration and dDAVP did not influence the response to subsequent hCRH administration. Dose-related vasopressinergic co-activation of the HPA axis was induced by combining 10 µg dDAVP with 10 µg and 30 µg hCRH. Combining 10 µg dDAVP with 10 µg hCRH induced the potentially most informative vasopressinergic co-activation since it is not restricted by ceiling or flooring effects. The hCRH response was not affected by prior dDAVP, allowing for a practical function test examining both HPA activation routes on the same day.

Switch in treatment from tricyclic antidepressants to moclobemide: a new generation monoamine oxidase inhibitor.

The combination of classic monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressant drugs (TCAs) has been associated with a variety of adverse events. A switch in treatment from TCAs to moclobemide, a reversible and selective inhibitor of MAO-A, was investigated in a double-blind, placebo-controlled study in healthy volunteers. Two groups of 12 subjects were treated with either amitriptyline (75 mg/day) or clomipramine (100 mg/day) until steady-state conditions had been attained (14 days). Treatment with the TCAs was discontinued abruptly and switched to either a therapeutic dose regimen of moclobemide (300 mg/day) or placebo. The tolerability and safety pattern did not reveal any clinically relevant differences between moclobemide and placebo recipients, nor was there any sign of a pharmacokinetic interaction between the TCAs and moclobemide. In conclusion, the findings of this study suggest that therapeutic doses of moclobemide up to 300 mg daily can be given 24 hours after the last dose of treatment with either amitriptyline or clomipramine without major risks.