James G. Flood

Effect of Marathon Running on Hematologic and Biochemical Laboratory Parameters, Including Cardiac Markers

Participants in marathon races may require medical attention and the performance of laboratory assays. We report the changes in basic biochemical parameters, cardiac markers, CBC counts, and WBC differentials observed in participants in a marathon before, within 4 hours, and 24 hours after a race. The concentrations of glucose, total protein, albumin, uric acid, calcium, phosphorus, serum urea nitrogen, creatinine, bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, total creatine kinase, creatine kinase-MB, myoglobin, and the anion gap were increased after the race, consistent with the effects of exertional rhabdomyolysis and hemolysis. The increase in WBC counts was due mainly to neutrophilia and monocytosis, with a relative decrease in circulating lymphocytes, consistent with an inflammatory reaction to tissue injury. A significant percentage of laboratory results were outside the standard reference ranges, indicating that modified reference ranges derivedfrom marathon runners might be more appropriatefor this population. We provide a table of modified reference ranges (or expected ranges) for basic biochemical, cardiac, and hematologic laboratory parameters for marathon runners.

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.

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.

Measurement of Mercury Levels in Concentrated Over-the-Counter Fish Oil Preparations Is Fish Oil Healthier Than Fish?

CONTEXT Fish consumption has been associated with a decreased risk of coronary artery disease. Recent studies have illustrated that the high mercury content in cold-water fish may negate the cardiovascular benefits of fish meals. Fish oils have similar antiatherogenic properties to fish, and similar studies should be performed to determine the level of mercury in fish oils. OBJECTIVE To determine the concentration of mercury in 5 over-the-counter brands of fish oil. RESULTS The levels of mercury in the 5 different brands of fish oil ranged from nondetectable (<6 microg/L) to negligible (10-12 microg/L). The mercury content of fish oil was similar to the basal concentration normally found in human blood. CONCLUSIONS Fish are rich in omega-3 fatty acids, and their consumption is recommended to decrease the risk of coronary artery disease. However, fish such as swordfish and shark are also a source of exposure to the heavy metal toxin, mercury. The fish oil brands examined in this manuscript have negligible amounts of mercury and may provide a safer alternative to fish consumption.

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.

Measurement of Organochlorines in Commercial Over-the-Counter Fish Oil Preparations: Implications for Dietary and Therapeutic Recommendations for Omega-3 Fatty Acids and a Review of the Literature

CONTEXT The consumption of fish high in omega-3 fatty acids is advocated by the American Heart Association to decrease the risk of coronary artery disease. However, fish contain environmental toxins such as mercury, polychlorinated biphenyls, and organochlorine pesticides, which may negate the beneficial cardiovascular effects of fish meals. Toxin levels vary depending on both the fish source and the specific toxin, and neither farm-raised nor wild fish are toxin free. Fish oil supplements also prevent the progression of coronary artery disease and reduce cardiovascular mortality. However, only sparse data exist on the level of toxins in fish oil. In a previous study we showed that the amount of mercury in 5 over-the-counter brands of fish oil was negligible. OBJECTIVE To determine the concentrations of polychlorinated biphenyls and other organochlorines in 5 over-the-counter preparations of fish oil. DESIGN The contents of 5 commercial fish oil brands were sent for organochlorine analysis. RESULTS The levels of polychlorinated biphenyls and organochlorines were all below the detectable limit. CONCLUSIONS Fish oil supplements are more healthful than the consumption of fish high in organochlorines. Fish oils provide the benefits of omega-3 fatty acids without the risk of toxicity. In addition, fish oil supplements have been helpful in a variety of diseases, including bipolar disorder and depression.

Clozapine pharmacokinetics in children and adolescents with childhood-onset schizophrenia

Clozapine (CLZ) dose-related adverse effects may be more common in children than adults, perhaps reflecting developmental pharmacokinetic (PK) differences. However, no pediatric CLZ PK data are available. Accordingly, we studied CLZ and its metabolites, norclozapine (NOR), and clozapine-N-oxide (NOX) in six youth, ages 9–16 years, with childhood onset schizophrenia (COS). At the time of the PK study, mean CLZ dose was 200 mg (3.4 mg/kg). Serum was collected during week 6 on CLZ before and 0.5–8 h after a morning dose. Serum concentrations were assayed by liquid chromatography/UV-detection. Mean concentration, area-under-the-curve (AUC), and clearance were calculated. CLZ clearance averaged 1.7 L/kg-h. NOR concentrations (410) exceeded CLZ (289) and NOX (63 ng/ml) and AUC0–8h of NOR (3,356) > CLZ (2,359) > NOX (559 ng/ml-h) [53, 38, and 9% of total analytes, respectively]. In adults, NOR serum concentrations on average are 10–25% < CLZ, differing significantly from our sample. Dose normalized concentrations of CLZ (mg/kg-d) did not vary with age and were similar to reported adult values. Clinical improvement seen in 5/6 patients correlated with serum CLZ concentrations. In addition, clinical response and total number of side effects correlated with NOR concentrations. NOR (a neuropharmacologically active metabolite) and free CLZ may contribute to the effectiveness and adverse effects in youth.

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].

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.

Developmental Changes in Serum Concentrations of Desipramine and 2-Hydroxydesipramine during Treatment with Desipramine

Abstract 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.