Fatty acid derivatives of clozapine: prolonged antidopaminergic activity of docosahexaenoylclozapine in the rat.

Stable amides of clozapine derived from fatty acids prominent in cerebral tissue might enhance the central activity of clozapine and reduce its exposure to peripheral tissues. Such derivatives might enhance the safety of this unique drug, which is the only agent with securely established superior antipsychotic effectiveness, but with a risk of potentially lethal systemic toxicity. Amide derivatives of clozapine were prepared from structurally varied fatty acid chlorides and evaluated for ability to inhibit behavioral arousal in rat induced by dopamine agonist apomorphine and to induce catalepsy. Their duration-of-action and potency were compared to free clozapine, and concentrations of clozapine were assayed in brain and blood. Selected agents were also evaluated for affinity at dopamine receptors and other potential drug-target sites. Clozapine-N-amides of linoleic, myristic, oleic, and palmitic acids had moderate initial central depressant activity but by 6 h, failed to inhibit arousal induced by apomorphine. However, the docosahexaenoic acid (DHA) derivative was orally bioavailable, 10-times more potent (ED(50) 5.0 micromol/kg) than clozapine itself, and very long-acting (>/= 24 h) against apomorphine, and did not induce catalepsy. DHA itself was inactive behaviorally. Clozapine showed expected dopamine receptor affinities, but DHA-clozapine was inactive at these and other potential target sites. After systemic administration of DHA-clozapine, serum levels of free clozapine were very low, and brain concentrations somewhat lower than after administering clozapine. DHA-clozapine is a long-acting central depressant with powerful and prolonged antidopaminergic activity after oral administration or injection without inducing catalepsy, and it markedly reduced peripheral exposure to free clozapine. It lacked the receptor-affinities shown by clozapine, suggesting that DHA-clozapine may be a precursor of free, pharmacologically active clozapine. Such agents may represent potential antipsychotic drugs with improved central/peripheral distribution, and possibly enhanced safety.

Dosing of intravenous ganciclovir for the prophylaxis and treatment of cytomegalovirus infection in solid organ transplant recipients.

BACKGROUND: The optimal regimen for the prevention and treatment of cytomegalovirus (CMV) disease in solid organ transplant recipients remains to be defined, particularly for patients with abnormal or changing renal function. METHODS: A prospective trial was conducted in patients receiving i.v. ganciclovir using a standardized dosing nomogram that corrects for renal function. Steady state peak (P) and trough (T) serum levels were determined by high-performance liquid chromatography and correlated with therapeutic outcomes and toxicities attributable to ganciclovir. RESULTS: Over the study period, 44 individuals received ganciclovir prophylaxis (5 mg(kg/day) and 25 patients were treated (5 mg/kd q12 hr) for symptomatic CMV disease. Ganciclovir levels (microg/ml+/-SD) achieved in prophylaxis were P: 7.98+/-3.34, T: 3.03+/-2.63; and in treatment were P: 9.00+/-3.72, T: 2.65+/-1.82. Despite corrections for renal dysfunction, undialyzed patients with serum creatinine >3.0 mg/dl had trough levels in excess of the population mean (T: range 3-8 microg/ml). Failure of prophylaxis (disease) or therapy (relapse) occurred in 14 patients; 8 of these were at risk for primary infection (donor CMV seropositive, recipient seronegative, P<0.01). Patients at greatest risk for relapse after treatment of CMV disease were liver transplant recipients, patients with ganciclovir-resistant viral isolates, and renal patients with six antigen MHC donor-recipient mismatches. CONCLUSIONS: This trial demonstrates the efficacy of a nomogram for ganciclovir dosing during renal dysfunction; reduced doses can be used for prophylaxis for undialyzed patients with renal dysfunction (1.25 mg/kg/day for Cr > or =3.0, 1.25 mg/kg QOD for Cr > or =5.0). Some groups of transplant recipients may require more intensive anti-CMV regimens.

Absence of effect of stimulants on the phamacokinetics of desipramine in children.

We conducted a retrospective chart review to examine the pharmacokinetic interaction between desipramine and the stimulants methylphenidate and dexedrine using routinely monitored desipramine serum concentrations in children receiving desipramine either alone or with a stimulant. Subjects were 142 children and adolescents (age 6-17 yrs; 113 taking desipramine, 29 taking desipramine-stimulants) in whom 401 dose- and weight-normalized serum concentrations were evaluated (333 desipramine, 68 desipramine-stimulants). Desipramine pharmacokinetic parameters were similar for both groups, including mean weight-corrected dose (3.66+/-1.36 mg/kg, desipramine; 3.66+/-1.09 mg/kg, desipramine-stimulants; p=0.97), weight- and dose-normalized serum concentrations (47.26+/-39.26 [microg/L]/[mg/kg], desipramine, 39.02+/-19.92 [microg/L]/[mg/kg], desipramine-stimulants; p=0.09), and clearance (0.690+/-0.913 [L/kg]/hr, desipramine; 0.613+/-0.514 [L/kg]/hr, desipramine-stimulants; p=0.499). When stratified by age, gender, and type of stimulant, no difference was detected (p>0.05) between groups. Our findings indicate the absence of a clinically significant interaction between desipramine and stimulants.

Olanzapine overdose with serum concentrations.

Olanzapine, a new atypical antipsychotic drug, has been prescribed in the treatment of schizophrenia and psychotic mood disorders for approximately 2.3 million patients worldwide. Considering the increase in olanzapine prescriptions and the increased risk of suicide in this patient population, the number of reported cases of olanzapine overdose may be expected to increase. This report describes the clinical course and serum concentrations in a patient who consumed an olanzapine overdose (800 mg). Profound central nervous system depression and tachycardia without arrhythmia occurred within 2 hours after the ingestion. Additional clinical findings (ie, fever, mutism, agitation, dystonia, akathisia, elevated creatine kinase, and increased leukocyte count) were similar to those of neuroleptic malignant syndrome. After intubation, gut decontamination, and supportive care, the patient recovered and was discharged.

Pharmacokinetics of doxepin in subjects with pruritic atopic dermatitis.

BACKGROUND: Doxepin applied topically by itself or in combination with triamcinolone acetonide is a safe and effective treatment for atopic dermatitis. OBJECTIVE: We evaluated the pharmacokinetic profile of doxepin and desmethyldoxepin after topical application of doxepin hydrochloride 5% cream alone or in combination with 0.025% triamcinolone acetonide (doxepin/TAC). METHODS: Twenty-four subjects with atopic dermatitis received either doxepin or doxepin/TAC cream 4 times daily for 7 days in a randomized, double-blind, controlled trial. Serum samples were obtained and pharmacokinetic parameters estimated from the dose-normalized serum concentrations of doxepin and desmethyldoxepin. Efficacy and adverse experiences were determined by physician and subject evaluations. RESULTS: Pharmacokinetic parameters (K(e ), t(1/2 ) and AUC) calculated in 9 subjects (doxepin/TAC = 4 subjects, doxepin = 5 subjects) with detectable serum concentrations were similar for both groups. Pruritus relief and lessening of pruritus severity were significantly greater with doxepin/TAC than doxepin alone. CONCLUSION: Topically applied doxepin is safe and effective therapy for pruritus.

Desipramine clearance in children and adolescents: absence of effect of development and gender.

OBJECTIVE: To examine the influence of development and gender on the pharmacokinetics of desipramine (DMI) in the pediatric population. METHOD: DMI pharmacokinetic parameters were calculated from 407 routinely drawn, dose- and weight-normalized serum concentrations in 173 youths receiving DMI (90 children, 83 adolescents; 29 were female, 144 were male). RESULTS: Mean pharmacokinetic parameters for the entire population included dose (3.78 +/- 1.51 mg/kg), weight- and dose-normalized serum concentration (45.41 +/- 47.39 [micrograms/L]/[mg/kg]), and DMI clearance (0.68 +/- 1.51 [L/kg]/hr). No between-group differences for children and adolescents were detected in dose (child, adolescent) (3.73 +/- 1.40 mg/kg, 3.83 +/- 1.68 mg/kg), weight- and dose-normalized serum concentrations (44.52 +/- 39.6 [micrograms/L]/[mg/kg], 46.34 +/- 34.89 [micrograms/L]/[mg/kg]; p = .62), and clearance (0.680 +/- 0.890 [L/kg]/hr, 0.695 +/- 1.05 [L/kg]/hr; p = .103). No between-group gender differences were detected in dose (male, female) (3.83 +/- 1.55 mg, 3.39 +/- 1.84 mg), weight- and dose-normalized serum concentrations (45.15 +/- 37.76 [micrograms/L]/[mg/kg], 47.14 +/- 34.96 [micrograms/L]/mg/kg]; p = .720), and clearance (0.699 +/- 0.89 [L/kg]/hr, 0.606 +/- 0.535 [L/kg]/hr; p = .390). CONCLUSIONS: These results suggest that age and gender do not significantly influence DMI clearance or dose-normalized serum concentrations in the pediatric population.

Serum levels of clozapine and norclozapine in patients treated with selective serotonin reuptake inhibitors.

OBJECTIVE: The selective serotonin reuptake inhibitor (SSRI) fluoxetine can increase serum levels of clozapine and norclozapine, but effects of other SSRIs are unknown. Thus, the authors evaluated interactions of clozapine with fluoxetine, paroxetine, and sertraline. METHOD: Serum clozapine and norclozapine concentrations were assayed in 80 psychiatric patients, matched for age and clozapine dose, given clozapine (mean dose = 279 mg/day) alone or with fluoxetine (mean dose = 39.3 mg/day), paroxetine (mean = 31.2 mg/day), or sertraline (mean = 92.5 mg/ day). Each patient's dose of clozapine was stable for at least a month before serum sampling. RESULTS: Concentrations of clozapine plus norclozapine averaged 43% higher, and the risk of levels higher than 1000 ng/ml was 10-fold greater (25%), in the patients taking SSRIs, with minor differences between patients taking the individual SSRIs. CONCLUSIONS: SSRIs can increase circulating concentrations of clozapine and norclozapine, sometimes to potentially toxic levels.

Erythromycin-induced clozapine toxic reaction.

Clozapine, used in the treatment of patients with schizophrenia resistant to other neuroleptic medication, is metabolized by the hepatic microsomal system to demethyl-clozapine and clozapine-N-oxide. Changes in clozapine serum concentrations have been documented after initiation of therapy with medications known to induce or inhibit liver microsomal enzymes. These interactions are of clinical importance when diminished efficacy or increased toxic effects of clozapine therapy occur. A 34-year-old schizophrenic man had increased clozapine serum concentrations, leukocytosis, and adverse effects as a result of concomitant erythromycin therapy given for suspected lower respiratory tract infection. Symptoms included somnolence, difficulty in coordination and ambulation, slurred speech, disorientation, and incontinence. The symptoms resolved after treatment with clozapine and erythromycin were discontinued, and treatment with clozapine was gradually resumed.

Relation of leukocyte counts during clozapine treatment to serum concentrations of clozapine and metabolites.

OBJECTIVE: This study was done to test the hypothesis that serum concentration of norclozapine is a risk factor for leukopenia during treatment with clozapine. METHOD: Maximum decreases in leukocyte counts in 44 unselected patients treated with clozapine were determined and then correlated with drug doses and serum concentrations of clozapine, norclozapine, and clozapine-N-oxide. RESULTS: White cell and granulocyte counts decreased by up to 60%-73%, but there were no positive correlations between these decrements and drug dose, drug level, ratio of drug level to drug dose, or ratio of norclozapine level to clozapine level, nor were the decreases related to age or gender. CONCLUSIONS: While these results do not suggest in vivo hemotoxicity of norclozapine, further study of patients with clinically significant leukopenia is required.

Fatty acid ethyl ester synthase catalyzes the esterification of ethanol to cocaine.

Fatty acid ethyl esters (FAEE), esterification products of ethanol and fatty acids, have been implicated as mediators of ethanol induced organ damage. It has been shown that FAEE synthase, the enzyme responsible for the formation of FAEE, is present selectively in the organs damaged by ethanol abuse. Cocaethylene is a cocaine metabolite generated in the presence of ethanol which has been established as enhancing cocaine toxicity. In the present study we show that purified FAEE synthase also catalyzes the formation of cocaethylene. A linear relationship (r = 0.998) was demonstrated between the amount of purified FAEE synthase (microgram) and cocaethylene synthesis (nmol/hr). We further showed a correlation (r = 0.804) between the two enzyme activities in selected tissues. These findings provide evidence that purified FAEE synthase has cocaethylene synthetic ability and FAEE synthase may be responsible for a portion of cocaethylene synthesis in vivo.

Clozapine and metabolites: concentrations in serum and clinical findings during treatment of chronically psychotic patients.

Clozapine (CLZ) and metabolites norclozapine and clozapine-N-oxide were assayed with a new, sensitive (2 pmol), and selective method in 68 serum samples from 44 psychotic subjects, 20 to 54 years old, ill 16 years, and treated with CLZ for 2.2 years (currently at 294 mg, 3.4 mg/kg daily). CLZ levels averaged 239 ng/ml (0.73 microM; 92 ng/ml per mg/kg dose) or 48% of total analytes (norclozapine = 41% [91% of CLZ] and clozapine-N-oxide = 11%); metabolite and CLZ levels were highly correlated (rs = 0.9), and CLZ levels varied with daily dose (rs = 0.7). Sampling twice yielded similar within-subject analyte levels (r = 0.8 to 0.9; difference = 24% to 33%). Range and variance narrowed when levels were expressed per weight-corrected dose (ng/ml per mg/kg). Levels per dose were 40% higher in nonsmoking women than men, despite a 60% lower milligram per kilogram dose in women, and did not vary by diagnosis or age in this limited sample. Fluoxetine increased serum CLZ analytes by 60%; valproate had less effect. Patients rated treatment very positively; observer-assessed benefits typically were more moderate. Common late side effects were sialorrhea (80%), excess sedation (58%), obesity (55% > 200 lb), mild tachycardia (51%), constipation (32%), and enuresis (27%); there were no seizures or leukopenia. There was little evident relationship of drug dose or serum level to current clinical measures or side effect risks.

Serum concentrations of clozapine and its major metabolites: effects of cotreatment with fluoxetine or valproate.

Serum concentrations of clozapine, norclozapine, and clozapine-N-oxide were assayed in psychotic patients treated with clozapine alone (N = 17), clozapine with fluoxetine added (N = 6), or clozapine with valproic acid added (N = 11). Subjects were matched for age and other treatments, and concentrations were corrected for daily dose of clozapine (milligrams per kilogram of body weight). With valproic acid, there was a minor increase in total clozapine metabolites, which was even less with dose correction. Fluoxetine increased all clozapine analytes, in some cases to twice the levels in the subjects given only clozapine.

Tissue concentrations of clozapine and its metabolites in the rat.

Clozapine (CLZ) and its metabolites norclozapine (NOR) and clozapine-N-oxide (NOX) were assayed in rat serum and brain tissue after intraperitoneal injection of CLZ. Clozapine levels rose with dose, averaging 28 ng/ml (87 nmol/L) serum per milligram/kilogram dose. Brain- and serum-CLZ levels correlated closely, averaging 24-fold higher in brain. Norclozapine and NOX averaged approximately 58% and 13% of CLZ in serum, respectively, whereas in brain, NOR was detected only at doses greater than or equal to 10 mg/kg (approximately 5.6% of CLZ) and NOX was undetectable. Levels peaked within 30 minutes, and elimination of CLZ from brain and CLZ or NOR from blood was very rapid (half-life = 1.5 to 1.6 hours). A week of daily dosing with CLZ led to no accumulation of drug in brain; a week of fluoxetine pretreatment increased analyte concentrations (serum, 86%; brain, 61%), but valproate had little effect.

Determination of clozapine, norclozapine, and clozapine-N-oxide in serum by liquid chromatography.

We report a new assay to measure the serum concentrations of the atypical antipsychotic drug clozapine and two major metabolites, norclozapine and clozapine-N-oxide. The analytes and an internal standard (triprolidine) were extracted from alkalinized samples into ethyl acetate and back-extracted into 0.1 mol/L HCl. The acid extracts were chromatographed on a reversed-phase liquid chromatographic column with photodiode array detection (210-340 nm). With the 254-nm signal, between-run imprecision (CV) was < 2% for clozapine and norclozapine at 400 micrograms/L, and 4.1% for clozapine-N-oxide at 100 micrograms/L. Absolute recovery exceeded 65%, and the detection limit was approximately 3-4 micrograms/L. In 25 patients at steady state at a mean daily clozapine dosage of 269 mg (3.09 mg/kg), clozapine averaged 231 +/- 144 micrograms/L (mean +/- SD); norclozapine and clozapine-N-oxide concentrations averaged 84% and 23% that of clozapine. Analyte concentrations were significantly correlated with daily dose. The method's ability to quantify clozapine and two major metabolites simultaneously with precision and sensitivity makes it useful in pharmacokinetic studies and therapeutic monitoring.

Electrocardiographic effects of desipramine and 2-hydroxydesipramine in children, adolescents, and adults treated with desipramine.

OBJECTIVE: To assess the developmental effects of desipramine (DMI) treatment on the electrocardiogram (ECG), we investigated serum concentrations of DMI ([DMI]), and its major active metabolite 2-hydroxydesipramine ([OHDMI]) and ECG parameters. METHODS: ECGs and [DMI] and [OHDMI] were analyzed from 50 children, 39 adolescents, and 30 adult psychiatric patients receiving DMI. RESULTS: There were modest overall correlations between [DMI], [OHDMI], or [OHDMI+DMI], and the PR and QRS intervals when data from all 119 subjects were pooled. Within the pediatric age groups there were no significant associations between serum drug levels and heart rate or conduction intervals; and in all subjects with ECG abnormalities, there were some findings of higher [DMI], [OHDMI], and [OHDMI+DMI]. CONCLUSIONS: These findings indicate that only modest associations of [DMI] and [OHDMI] with ECG conduction intervals were found, and are not likely to be clinically significant in any of the age groups studied. Compared with adults, children and adolescents do not appear to be at increased risks for ECG changes related to DMI treatment or to circulating concentrations of [DMI] or [OHDMI].

Accumulation of fluoxetine and norfluoxetine in human brain during therapeutic administration.

In vivo 19fluorine nuclear magnetic resonance spectroscopy was used to measure the brain concentration of fluoxetine and norfluoxetine in five patients with obsessive-compulsive disorder and three with major depression. The mean brain:plasma ratio of the parent drug plus the metabolite was significantly elevated to 2.6 (SD = 1.0) (95% confidence interval = 1.9-3.3). This accumulation may have implications for understanding both the therapeutic and the toxic effects of fluoxetine.

Detection and confirmation of cocaine and cocaethylene in serum emergency toxicology specimens.

We report the performance of a liquid chromatography (LC) assay for detection and confirmation of cocaine and cocaethylene in serum. A photodiode array (PDA) detector monitors the cyano column effluent at 230 nm for analyte detection. Confirmation of a peak's identity is performed by use of only the 226-254-nm segment of the spectra rather than a broader range such as 210-340 nm. Use of the narrower range improves the assay's sensitivity by almost 10-fold. Analyte values of 10 micrograms/L are confirmed routinely. Intra-assay imprecision at 100, 20, and 10 micrograms/L for cocaine is 5.1%, 5.7%, and 6.6% (CV), respectively. Absolute recovery of the analytes exceeds 80%. In a split-sample study (33 positives and 74 negatives), each of this method's cocaine findings were confirmed. Cocaethylene was found in 15 of these samples. A complete chromatogram can be available 15 min after the start of the procedure. The method's focus on the active drug (rather than urinary metabolites) and its ability to detect and confirm many other drugs make it well suited for emergency toxicology testing.

Developmental changes in serum concentrations of desipramine and 2-hydroxydesipramine during treatment with desipramine.

Steady-state serum concentrations of desipramine (DMI) and its metabolite, 2-hydroxydesipramine (OHDMI), were measured in 40 children, 36 adolescents, and 27 adult psychiatric patients. The authors predicted that younger patients would show more efficient elimination of DMI, with greater amounts of OHDMI. OHDMI averaged 52% lower than DMI. DMI per weight-corrected dose (ng/mL: mg/kg) rose significantly with maturation, from 50 in children and 56 in adolescents to 91 in adults. Contrary to expectation, OHDMI per DMI dose also rose with age, from 17 in children and 20 in adolescents to 26 in adults. It was concluded that: (1) similar mg/kg doses of DMI result in lower DMI and OHDMI in children; (2) children metabolize both DMI and OHDMI more rapidly than adults; and (3) children do not have high circulating concentrations of OHDMI.