Single- vs Multiple-Dose Pharmacokinetics of Clozapine in Psychiatric Patients

Clozapine plasma levels were monitored in 16 patients during a series of three consecutive treatments (single dose-multiple dose-single dose). Each patient received a single 75-mg dose (3 x 25 mg) with clozapine tablets, and serial plasma samples were collected over 48 hr after the dose. At 48 hr, a multiple-dose regimen was started, consisting of an initial dose escalation period followed by dosing at a constant regimen for at least 6 days. After the last dose, serial plasma samples were again obtained over 72 hr. Drug was then withheld for at least 7 days, a final single 75-mg dose was given, and plasma sampling was repeated. A subset of the patient population (N = 7) was used to test for a food effect during the single-dose treatments. The pharmacokinetic parameters between the initial and the final single dose periods were not significantly different. Similarly, there were no differences within patients when given the dose after fasting (fed 1 hr after dose) or with a meal. In contrast, the terminal elimination rate differed between the single-dose and the multiple-dose treatments (t1/2 m3 = 7.9 hr single dose and 14.2 hr multiple dose) (P less than 0.05) and the dose-normalized area under the plasma concentration/time curves increased 27% with multiple dosing. Since a previous study in patients (Choc et al., Pharm. Res. 4:402-405, 1987) showed dose proportionality of clozapine plasma concentrations during multiple-dose regimens, the present results cannot be described by Michaelis-Menten kinetics.     

Properties of a copper-containing cytochrome c1aa3 complex: a terminal oxidase of the extreme thermophile Thermus thermophilus HB8.

From the plasma membrane of Thermus thermophilus HB8 we have partially purified a detergent-solubilized complex of cytochromes a and c1 that actively catalyzes the transfer of electrons from ascorbate via a redox dye to oxygen. The complex is composed of two types of polypeptides, with molecular weights of approximately 55,000 and 33,000. Quantitative analysis revealed the presence of heme a, heme c, and copper in a ratio of 2:1:2, with the heme a being present at 10 +/- 1.3 nmol/mg of protein. The heme c was shown to be associated with the molecular weight 33,000 peptide and is suggested to be of the c1 type. The optical and electron paramagnetic resonance properties of this complex were found to be similar to those of eukaryotic cytochrome oxidase, suggesting the following arrangement of chromophores: a magnetically isolated cytochrome c1 and an oxygen-reducing functional unit consisting of two heme a groups and two copper ions associated with one or more larger peptides.     

Single dose kinetics of thioridazine and its two psychoactive metabolites in healthy humans: a dose proportionality study

Dose proportionality in some pharmacokinetic parameters for thioridazine and its two active metabolites (mesoridazine and sulforidazine) was investigated in 11 healthy human subjects following oral administration of three single doses (25, 50, and 100 mg) of thioridazine hydrochloride separated in each case by an interval of two weeks. Also, after a further two weeks, another 100-mg dose of thioridazine (divided as 5 mg every 0.5 h) was administered to all the volunteers to investigate the effect of a slow rate of dosage input on the pharmacokinetic parameters of this drug. An HPLC method was used to measure concentrations of thioridazine, mesoridazine, and sulforidazine in plasma samples collected up to 72 h following each dose. Dose proportionality for the three single doses of thioridazine was observed for all three analytes in the area under the plasma concentration versus time curves (AUC infinity 0 or AUCt0) and the maximum plasma concentration (Cmax) in that the relationships between the dose and these parameters were each describable by an equation for a straight line (r2 greater than or equal to 0.8). However, the mean apparent distribution and elimination rate constants for thioridazine and mesoridazine and the mean apparent oral clearance for thioridazine decreased significantly with increasing dose. This suggests nonlinear trends in the elimination kinetics at high doses of thioridazine. When a 100-mg divided oral dose of thioridazine was administered, no statistically significant differences between single and divided doses were observed in the mean AUC infinity 0 or AUCt0 for thioridazine or sulforidazine. A significant decrease in the mean AUC infinity 0 or AUCt0 was observed for mesoridazine after the administration of the divided dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Giant hemangioma with thrombocytopenia and osteolysis successfully treated with prednisone

A 6-week-old girl with a hemangioma with thrombocytopenia, consumption coagulopathy, extensive bleeding, disappearance of the right pubic bone, and destruction of part of the right iliac bone was successfully treated with prednisone. Treatment lasted 30 weeks. Bleeding ceased within a few days; bone rebuilding was first observed at 30 days and was extensive at the end of treatment. When the child was 3 years old, pelvic films were normal. The occurrence of Kasabach-Merritt syndrome associated with complete osteolysis as in our patient is rare and bone reconstruction is unusual.     

Decompressive surgery for malignant supratentorial infarction remains underutilized after guideline publication

Decompressive surgery <48 h from stroke onset reduces the prevalence of mortality and morbidity from malignant supratentorial infarction. We investigated if utilization of decompressive surgery changed in the Czech Republic (CZ) after the release of new guidelines regarding treatment of malignant brain infarction. The volume of decompressive surgery in 2009 in all centers in the CZ was assessed using the same methodology as in 2006. All neurosurgery departments in the CZ were asked to complete a questionnaire and asked to identify all cases of decompressive surgery for malignant brain infarction through a combination of discharge codes for "brain infarction" and "decompressive surgery" from electronic hospital charts. Data for 56 patients were obtained from 15 of the 16 neurosurgery departments in the CZ. The average age was 53 ± 13; number of males 20; median time to surgery was 48 h (range 24-62); median NIHSS score was 25 (IQR, 20-30); median infarct volume was 300 cm(3) [interquartile (IQR, 250-350)]; mean shift on CT was 10.6 ± 3.6 mm and size of hemicraniectomy was 125 cm(2) (IQR, 110-154). A favorable outcome was achieved in 45% of the patients. The number of procedures increased from 39 in 2,006 to 2,056 in 2009. Based on data from one stroke center, 10% suffered from malignant supratentorial infarction and 2.3% met the criteria for decompressive surgery. In 2009, as compared to 2006, the volume of decompressive surgery carried out moderately increased. However, procedures remained underutilized because only ~10% of those who needed decompressive surgery underwent surgery.     

Osteoplastic decompressive craniotomy--an alternative to decompressive craniectomy

Background  

In spite of various degrees of brain expansion, decompressive surgery is usually carried out using decompressive craniectomy (DC). After craniectomy it is necessary to perform cranioplasty, which prolongs hospitalization and is not always without complications. Hence, in situations when cranial decompression is indicated, but DC would be too radical, we do not remove the bone flap, and we perform so-called osteoplastic decompressive craniotomy (ODC). The technique is detailed.     

Launois-Bensaude Syndrome: An Unusual Localization of Obesity Disease

Background  Launois-Bensaude syndrome is a rare pathology consisting of adipose masses symmetrically distributed mainly in the superior part of the body. Men are especially affected between age of 30 and 60 as well as chronic alcohol abusers. Etiopathogenesis is attributable to mutations or deletions of mitochondrial DNA, and alcohol is a possible cofactor. Methods  The current treatment of the disease is described based on the authors’ experience. Four cases treated in our department are retrospectively reviewed regarding comorbidities and type of surgery performed. Results  A relevant and long-lasting reduction of fat bulges has been obtained in all cases with no major complications except for a mild anemia. Conclusion  Launois-Bensaude syndrome causes a functional rather than esthetic concern due to the peculiar localization of fat bulges. Currently, the only effective therapy is surgery, through lipectomy or liposuction of adipose bulges.     

Diffusion tensor magnetic resonance imaging of glial brain tumors

Aim

To evaluate the author's experience with the use of diffusion tensor magnetic resonance imaging (DTI) on patients with glial tumors.

Methods

A retrospective evaluation of a group of 24 patients with glial tumors was performed. There were eight patients with Grade II, eight patients with Grade III and eight patients with Grade IV tumors with a histologically proven diagnosis. All the patients underwent routine imaging including T2 weighted images, multidirectional diffusion weighted imaging (measured in 60 non-collinear directions) and T1 weighted non-enhanced and contrast enhanced images. The imaging sequence and evaluation software were produced by Massachusetts General Hospital Corporation (Boston, MA, USA). Fractional anisotropy (FA) maps were calculated in all patients. The white matter FA changes were assessed within the tumorous tissue, on the tumorous borderline and in the normally appearing white matter adjacent to the tumor. A three-dimensional model of the white matter tract was created to demonstrate the space relationship of the tumor and the capsula interna or corpus callosum in each case using the following fiber tracing parameters: FA step 0.25 and a tensor declination angle of 45 gr. An additional assessment of the tumorous tissue enhancement was performed.

Results

A uniform homogenous structure with sharp demargination of the Grade II tumors and the wide rim of the intermedial FA in all Grade III tumors respectively, were found during the evaluation of the FA maps. In Grade IV tumors a variable demargination was noted on the FA maps. The sensitivity and specificity for the discrimination of low- and high-grade glial tumors using FA maps was revealed to be 81% and 87% respectively. If the evaluation of the contrast enhancement was combined with the evaluation of the FA maps, both sensitivity and specificity were 100%.

Conclusion

Although the evaluation of the fractional anisotropy maps is not sufficient for glioma grading, the combination of the contrast enhancement pattern and fractional anisotropy maps evaluation improves the possibility of distinguishing low- and high-grade glial tumors. Three-dimensional models of the white matter fibers in the corpus callosum and the internal capsule may be used in the presurgical planning.     

Dynamic protein structures: infrared evidence for four discrete rapidly interconverting conformers at the carbon monoxide binding site of bovine heart myoglobin.

Infrared spectra for the carbon monoxide complex with myoglobin isolated as the oxygenyl species from bovine heart muscle were carefully examined in the C--O stretch region as either the pH or the temperature was varied. Deconvolutions of these spectra into bands of Gaussian shape suggest the presence of four bands near 1938(I), 1944(II), 1954(III), and 1965(IV) cm-1 with halfband widths of about 18, 9, 9, and 10 cm-1, respectively. The relative intensities of the four bands varied with changes in pH or temperature. 13C NMR spectra and other evidence indicate that the four C--O stretch bands arise from four discrete rapidly interconverting conformers: CI, CII, CIII, and CIV. Under conditions of physiological pH and temperature, the relative stabilities are CI approximately CII much greater than CIII approximately CIV. The delta H and delta S values for conformer interconversions are estimated to range from -8 to 34 kJ/mol and -27 to 87 J.mol-1 K-1, respectively; therefore the structures of the conformers may be expected to vary significantly. These findings provide evidence for a highly flexible, dynamic structure at the ligand-binding site of bovine myoglobin, even when ligands are bound.