Unanticipated plasma concentrations in two clozapine-treated patients

OBJECTIVE: To report two cases of lower than anticipated clozapine plasma concentrations despite near maximum recommended doses of clozapine 800-900 mg/d in two medication-compliant schizophrenic inpatients. CASE SUMMARIES: Clozapine therapy was initiated in two male schizophrenic inpatients for treatment of psychotic symptoms refractory to other typical and atypical antipsychotics. Despite receiving adequate doses of clozapine for at least two months, these patients remained symptomatic. Therapeutic drug monitoring was used to target a clozapine plasma concentration of > or =250 ng/mL, the minimum value reported in the literature to be associated with increased clinical response. Clozapine plasma concentrations remained at 200 ng/mL in one patient despite dosage increases from 600 to 800 mg/d. In the second patient, administration of the maximum recommended dose resulted in concentrations between 200 and 250 ng/mL. Increasing the clozapine dosage to 1000 mg/d did not increase the clozapine plasma concentration. Evaluation of the ratio of clozapine plasma concentration clozapine to dose yielded lower than expected values compared with those reported in the literature. DISCUSSION: These two patients exhibited lower than anticipated clozapine plasma concentrations despite receiving high doses of clozapine. Several studies evaluating clozapine serum concentrations and clinical response have suggested threshold concentrations of > or =350 ng/mL, > or =370 ng/mL, or > or =420 ng/mL. The only study that randomized patients to three concentration ranges found that patients who achieved a clozapine serum concentration in a medium range (mean 251 ng/mL) responded better than patients in a low range (mean 91 ng/mL) and similar to patients in a high range (mean 396 ng/mL). However, attaining plasma concentrations in this range for these patients proved difficult. Reasons for the low concentrations are unclear and may be related to increased metabolic activity at several cytochrome P450 isoenzymes involved in the metabolism of clozapine. CONCLUSIONS: These cases illustrate lower than anticipated clozapine plasma concentrations despite high-dose clozapine therapy. Strategies to increase clozapine plasma concentrations in such patients might include adding a drug to partially inhibit the metabolism of clozapine. If those strategies are unacceptable based on risk assessment, patient compliance, or other reasons, clinicians may consider addition of a low-dose typical or other atypical antipsychotic drug to augment clozapine response.     

Multiple inert gas elimination technique for determining ventilation/perfusion distributions in rat during normoxia, hypoxia and hyperoxia

1. The use of the multiple inert gas elimination technique (MIGET) in quantifying ventilation/perfusion distributions (V*A/Q*) in small animals, such as the rat, may cause results to be biased due to haemodilution produced by the large volume of liquid infused intravenously. 2. We tested two methods of administering inert gases in rats using the MIGET: (i) standard continuous intravenous administration of inert gases (method A); and (ii) a new method based on the physicochemical properties of each inert gas (method B). This method included acute simultaneous inert gas administration using three pathways: inhalation, intravenous infusion and rectal infusion. Both MIGET methods were applied to obtain data while breathing three different inspiratory fractions of oxygen (FIO2): normoxia, hypoxia and hyperoxia. 3. Inert gas levels obtained from blood or expired air samples were sufficient for chromatographic measurement, at least during a 2 h period. The V*A/Q* distributions reported using both methods were acceptable for all the physiological conditions studied; therefore, the alternative method used here may be useful in further MIGET studies in rats because haemodilution resulting from continuous intravenous infusion of less-soluble gases can be avoided. 4. Normoxic rats showed lower mean values of the V*A/Q* ratio of ventilation distribution and higher mean values of the V*A/Q* ratio of perfusion distribution with the usual method of inert gas administration (method A). These non-significant differences were observed under almost all physiological conditions studied and they could be caused by haemodilution. Nevertheless, the effect of interindividual differences cannot be discarded. An additional effect of the low haematocrit on cardiovascular changes due to low FIO2, such as pulmonary vasoconstriction or increased cardiac output, may explain the lower dispersion of perfusion distributions found in group A during hypoxia.     

CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations

The authors report the CYP2D6 inhibitory effects of fluoxetine, paroxetine, sertraline, and venlafaxine in an open-label, multiple-dose, crossover design. Twelve CYP2D6 extensive metabolizers were phenotyped, using the dextromethorphan/dextrorphan (DM/DX) urinary ratio, before and after administration of fluoxetine 60 mg (loading dose strategy), paroxetine 20 mg, sertraline 100 mg, and venlafaxine 150 mg. Paroxetine, sertraline, and venlafaxine sequences were randomized with 2-week washouts between treatments; fluoxetine was the last antidepressant (AD) administered. Comparing within groups, baseline DM/DX ratios (0.017) were significantly lower than DM/DX ratios after treatment (DM/DXAD) with fluoxetine (0.313, p < 0.0001) and paroxetine (0.601, p < 0.0001) but not for sertraline (0.026, p = 0.066) or venlafaxine (0.023, p = 0.485). Between groups, DM/DXAD ratios were significantly higher for fluoxetine and paroxetine compared to sertraline and venlafaxine. No differences between DM/DXAD ratios were found for fluoxetine and paroxetine although more subjects phenocopied to PM status after receiving the latter (42% vs. 83%; chi 2 = 4.44, p = 0.049, df = 1). Similarly, no differences between DM/DXAD ratios were found for sertraline and venlafaxine. Of note, the DM/DXAD for 1 subject was much lower after treatment with paroxetine (0.058) compared to fluoxetine (0.490), while another subject exhibited a much lower ratio after treatment with fluoxetine (0.095) compared to paroxetine (0.397). Significant correlations between AD plasma concentration and DM/DXAD were found for paroxetine (r2 = 0.404, p = 0.026) and sertraline (r2 = 0.64, p = 0.002) but not fluoxetine or venlafaxine. In addition, DM/DXAD correlated with baseline isoenzyme activity for paroxetine, sertraline, and venlafaxine groups. These results demonstrate the potent, but variable, CYP2D6 inhibition of fluoxetine and paroxetine compared to sertraline and venlafaxine. CYP2D6 inhibition may be related, in part, to dose, plasma concentration, and baseline isoenzyme activity, and these correlations merit further investigation.     

Chronic Arsenic Poisoning From Burning High-Arsenic-Containing Coal In Guizhou, China

Optimization of a previously disclosed sorbitol dehydrogenase inhibitor (SDI, II) for potency and duration of action was achieved by replacing the metabolically labile N,N-dimethylsulfamoyl group with a variety of heterocycles. Specifically, this effort led to a series of novel, in vitro potent SDIs with longer serum half-lives and acceptable in vivo activity in acutely diabetic rats (e.g., 62, 67, and 69). However, the desired in vivo potency in chronically diabetic rats, ED90 less than or equal to 5 mg/kg/day, was achieved only through further modification of the piperazine linker. Several members of this family, including 86, showed better than the targeted potency with ED90 values of 1-2 mg/kg/day. Compound 86 was further profiled and found to be a selective inhibitor of sorbitol dehydrogenase, with excellent pharmacodynamic/pharmacokinetic properties, demonstrating normalization of sciatic nerve fructose in a chronically diabetic rat model for approximately 17 h, when administered orally at a single dose of 2 mg/kg/day.     

Precise intraoperative location of gastrointestinal bleeding with a hand-held counter. Work in progress

The nuclear medicine bleeding scan is frequently insufficient to locate sites of bleeding precisely, in spite of its great sensitivity. A small, hand-held Geiger-Müller counter, placed directly on exposed intestine in the operating room, enables precise location of the probable bleeding site. In three patients, the technique allowed a minimal amount of intestine to be resected, distinguished between large- and small-intestinal hemorrhage, and eliminated other foci as sites of bleeding.     

Space conditions,palatal vault height,and tooth size in patients with and without palatally displaced canines: A prospective cohort study

Objectives:To assess palatal vault height, tooth size, and dental arch dimensions in patients with unilateral and bilateral palatally displaced canines compared with a control group.Materials and Methods:A sample of 66 patients (mean age: 11.5 ± 1.0 years) with 22 unilateral palatally displaced canines (UPDCs), 22 bilateral palatally displaced canines (BPDCs), and 22 controls (C) were consecutively recruited. All three groups had dental casts that were scanned digitally using the OrthoX three-dimensional model scanner. Tooth size, palatal vault height, dental arch width, dental arch depth, dental arch length, and dental arch space were measured by the same examiner using the GOM software. Remeasurements were made in 10 randomly identified patients.Results:The palatal vault height was significantly lower in the BPDC group compared with controls. A significantly smaller mesial-distal crown width and, in general, more spacing in the maxilla were found in the UPDC and BPDC groups. No differences in arch length or arch width at the molar region were seen between the groups, while the arch length at the canine region was smaller in the UPDC and BPDC groups. However, this was observed in BPDC patients with both deciduous canines present and in most UPDC patients where the deciduous canine was present, compared with the control group, who had more permanent canines present.Conclusions:Patients with PDC had greater reduction in tooth size compared with the control group. The arch length and arch width were similar in patients with and without PDC.