Real-space path integration is impaired in Alzheimer's disease and mild cognitive impairment.

INTRODUCTION: Path integration (PI) is an important component of spatial navigation that integrates self-motion cues to allow the subject to return to a starting point. PI depends on the structures affected early in the course of Alzheimer's disease (AD) such as the medial temporal lobe and the parietal cortex. OBJECTIVES: To assess whether PI is impaired in patients with mild AD and amnestic mild cognitive impairment (aMCI) and to investigate the role of the hippocampus, entorhinal and inferior parietal cortex in this association. METHODS: 27 patients with aMCI, 14 with mild AD and 18 controls completed eight trials of Arena Path Integration Task. The task required subjects with a mask covering their eyes to follow an enclosed triangle pathway through two previously seen places: start-place1-place2-start. Brains were scanned at 1.5T MRI and respective volumes and thicknesses were derived using FreeSurfer algorithm. RESULTS: Controlling for age, education, gender and Mini-Mental State Examination score the aMCI and AD subjects were impaired in PI accuracy on the pathway endpoint (p=0.042 and p=0.013) compared to controls. Hippocampal volume and thickness of entorhinal and parietal cortices explained separately 36-45% of the differences in PI accuracy between controls and aMCI and 28-31% of the differences between controls and AD subjects. CONCLUSIONS: PI is affected in aMCI and AD, possibly as a function of neurodegeneration in the medial temporal lobe structures and the parietal cortex. PI assessment (as a part of spatial navigation testing) may be useful for identification of patients with incipient AD.

[Serious sepsis treatment in intensive care departments in the Czech Republic -  EPOSS Project pilot results]. / Lécba tezké sepse na pracovistích intenzivní péce v Ceské republice -  pilotní výsledky projektu EPOSS.

INTRODUCTION: Severe sepsis is still associated with significant morbidity and mortality, which is however different, as well as its management, depending on the region. What is the situation in the Czech Republic and what is the character of patients with severe sepsis is currently not known. The aim of the project is to describe the processes of care, outcome and characteristics of patients with severe sepsis admitted to the intensive care department of the Czech Republic. METHODS: This is a multicentre and observational project with retrospective enrollment of patients who meet the criteria for severe sepsis before or within 24 hours after admission to selected intensive care units (ICU EPOSS). RESULTS: 394 patients were analyzed. Median age at admission was 66 (56- 76) years, males predominated (58.9%) and the median APACHE II score on admission was 25 (19- 32). Patients were predominantly medical (56.9%) and most were secondary admitted from other ICU (53.6%). Meeting the criteria of severe sepsis was most frequently within the period (± 4 hours) of admission the EPOSS ICU (77.6%). Median total fluid intake during the first 24 hours was 6,680 (4,840- 9,450) ml. Most patients required mechanical ventilation (58.4%). Compliance with the resuscitation bundle of severe sepsis in our group was very good and was associated with lower mortality of patients. Most frequently, the EPOSS ICU length of stay (LOS) was 7 (3- 15) days and median hospital LOS was 13 (8- 28) days. Hospital mortality in our cohort was 35.8%. CONCLUSION: Introducing the project, which in its first stage obtained valuable and internationally comparable data about patients with severe sepsis admitted to the involved ICU in the Czech Republic.

Collagenolytic potential of rat liver myofibroblasts.

Rat liver myofibroblasts (MFB) were isolated by repeated passaging of nonparenchymal liver cell fraction. They were cultured on polystyrene Petri dishes, on fibrin or on type I collagen gels for 5 days. Quantitative RT-PCR, Western blotting, zymography and immunocytochemistry were used to study differences in cell morphology and protein expression. MFB were large and spread on plastic substrate, with prominent alpha-smooth muscle (alpha-SMA) fibres. They turned much smaller and elongated on collagen which was accompanied by the rearrangement of the cytoskeleton and a decrease in alpha-SMA and beta-actin content. Collagen gel induced the expression of a group of metalloproteinases (MMP-2, -3, -9, -13), on mRNA and protein level which resulted in the degradation of the gel. This response was accompanied by changes in the mRNA expression of cytokines of TGF-beta family, CTGF and interleukin-6, as well as of osteopontin and thrombospondin-2 that are involved in metalloproteinases (MMPs) regulation. The expression of MMPs substrates, collagen types I, IV and XII did not change or decreased. The effects of fibrin gels on MFB were milder than those of collagen. MFB assumed to deposit collagen and other ECM components in fibrotic liver, besides hepatic stellate cells, also possess a great collagenolytic potential.

Clinical activity of patupilone in patients with pretreated advanced/metastatic colon cancer: results of a phase I dose escalation trial.

BACKGROUND: New agents that are active in patients with metastatic colorectal cancer are needed. Patupilone (EPO906; epothilone B) is a novel microtubule-stabilising agent. METHODS: Patients with advanced colon cancer who progressed after prior treatment regimens received intravenous patupilone (6.5-10.0 mg m(-2)) once every 3 weeks by a 20-min infusion (20MI), 24-h continuous infusion (CI-1D) or 5-day intermittent 16-h infusion (16HI-5D). Adverse events (AEs), dose-limiting toxicities (DLTs), pharmacokinetics and anti-tumour activity were assessed. RESULTS: Sixty patients were enrolled. The maximum tolerated dose (MTD) was not reached in the 20MI arm (n=31), as no DLTs were observed. Three patients in the CI-1D arm (n=26) experienced 1 DLT each at 7.5, 8.0 and 9.0 mg m(-2), but MTD was not reached. However, the prolonged 16HI-5D arm was terminated at 6.5 mg m(-2) after two of the three patients developed a DLT. Diarrhoea was the most common AE and DLT, with increased severity at the higher doses (9.0 and 10.0 mg m(-2)). Grade 3 or 4 diarrhoea was observed in 11 (35%) of the patients in the 20MI arm, 4 (15%) of the patients in the CI-1D arm and 2 (67%) of the patients in the 16HI-5D arm. Patupilone activity was observed in the 20MI arm with a disease control rate of 58%, including four confirmed partial responses. The disease control rate in CI-1D arm was 39%. CONCLUSION: Patupilone given once every 3 weeks as a 20-min infusion had promising anti-tumour activity and manageable safety profile at doses that demonstrated therapeutic efficacy.

[Disturbance of synthesis of cholesterol and its precursors in clinically serious conditions]. / Porucha syntézy cholesterolu a jeho prekurzoru u klinicky závazných stavu.

OBJECTIVE: The aim of the study was to elucidate the role and importance of hypocholesterolemia in clinically serious conditions. It was a monocentric, prospective clinical study. MATERIAL AND METHODS: Two groups of patients were recruited to the study--one group were patients with coronary heart disease (CHD), who underwent miniinvasive cardiosurgical operation without extracorporeal circulatio (n = 17) and one group of patients, who sustain polytrauma (n = 19). Thirty six patients were recruited into the study. We performed the determination of sterols (total cholesterol, HDL-cholesterol, LDL-cholesterol, triacylglycerols), and their precursors (beta-sitosterol, campesterol, lathosterol, skvalen), interleukin IL-6 and cortisol in the blood serum. The short version of ACTH stimulation test was performed. The oxidative burst of granulocytes was evaluated. The blood samples were taken on the day of admission, the first, the fourth and the eighth post-operative and post-traumatic day. RESULTS: There was a significant decline of total cholesterol (TC) and LDL-cholesterol level with full recovery during observed period. There was a decline of cholesterol synthesis (lathosterol and lathosterol/cholesterol ratio) together with a decline of total cholesterol. There was a significantly negative correlation between IL-6 level and total cholesterol. Despite no confirmation of disturbance of adrenal function, there was a significantly positive correlation between lathosterol/cholesterol ratio (a de novo cholesterol synthesis marker) and cortisol level after the ACTH stimulation test. There was a significant breakdown of bactericidal function of granulocytes along with a decline of cholesterol level. CONCLUSION: There was decline of endogenous cholesterol synthesis in clinically serious conditions. The cholesterol synthesis rate is negatively influenced by IL-6 level. The rate of endogenous cholesterol synthesis positively correlated with cortisol production by the adrenals and with bactericidal function of granulocytes.

Biochemical and pharmacological effects of mitoxantrone and acetyl-L-carnitine in mice with a solid form of Ehrlich tumour.

BACKGROUND: Dysfunction of the carnitine system in non-tumour tissue following anticancer therapy has been reported. In this setting, supplementation with carnitine derivatives might increase the general metabolic activity of normal cells so that they might better withstand the adverse effects of chemotherapy aimed at tumour cells. Here we investigated the effect of acetyl-L-carnitine (ALC) alone and in combination with the antineoplastic agent mitoxantrone (MX) in an animal cancer model. METHODS: The effects of MX and MX-ALC were assessed based on gain or loss of body weight and on local growth of a solid form of Ehrlich tumour inoculated into mice. We also performed biochemical analyses like serum activities of some enzymes signalling the functioning of the liver, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Total protein, albumin and bilirubin were also determined in serum. Under favourable conditions, the Ehrlich tumour readily forms metastases, and this is the reason why we performed histological studies of samples of both the liver and heart in order to identify changes that may have mediated the observed effect of the treatment. In addition to those studies, the survival time of treated animals against controls was also noted. RESULTS: MX monotherapy was associated with lower body weight gain, fewer metastases, smaller tumour size, and lower dissemination. ALC alone promoted survival, but had no potentiating effect on MX therapy in terms of survival. Serum biochemistry changes associated with MX-ALC treatment consisted of a significant (p < 0.05) increase in AST with MX at 6 or 9 mg·kg(-1) plus ALC 200 mg·kg(-1) and a significant (p < 0.05) reduction in total protein compared to the corresponding MX group; serum albumin and bilirubin remained unchanged. CONCLUSION: ALC in combination with MX, regardless of the dose of MX, led to higher occurrences of metastases with dissemination to the kidneys, lungs, heart, and mediastinum compared to MX treatment alone. These histological findings indicate that ALC is inappropriate to combine with MX in the treatment of a solid cancer. The protective effect of ALC in combination therapy with the cytostatic drug MX was not supported in this study by our findings that the agent did not improve the therapeutic outcomes of MX therapy.

[Case report: fat embolism syndrome--grave handicap after traumatic long-bones fractures]. / Syndrom tukové embolie--prehled problematiky a kazuistika: závazný prubeh po traumatu dlouhých kostí.

Embolism of fat and bone marrow tissue is quite often due to bone fractures but it is seldom with signs of systemic involvement as a fat embolism syndrome. The main forming factor is late stabilization of fractures and hypovolemia too. Clinical image of fat embolism syndrome results from lung and systemic microembolism which leads to activation of inflammatory and thrombogenic cascades. We present a case report of a 24-year-old male after bike accident in low speed suffering from isolated thighbone fracture--osteosynthesis was applied in 6 hours after injury. The very first day the organ failure and coma with negative CT occurred, then ARDS, petechiae into the skin of chest and conjunctiva, also embolic closure of a. centralis retinae. Treatment interventions included anticoagulation, steroids, artificial ventilation for 17 days. After 3 weeks from injury he was still unconscious (with GCS 10) so that we tried a hyperbaric oxygen therapy. The patient regained consciousness after 3 months after injury. One year later he is able to walk alone, he has no visual failure, but he is still quadruspastic although able to manipulate with a mobile phone. We discuss diagnostic criteria and treatment. We also point out need of volumetherapy in prevention of fat embolism syndrome--this was underrated here because of primary missed out diagnose of co-existing tibia fracture at the same time (this was stabilised 18 hours after injury).

Effect of somatostatin on repair of ionizing radiation-induced DNA damage in pituitary adenoma cells GH3.

Ionizing radiation and somatostatin analogues are used for acromegaly treatment to achieve normalization or reduction of growth hormone hypersecretion and tumor shrinkage. In this study, we investigated a combination of somatostatin (SS14) with ionizing radiation of (60)Co and its effect on reparation of radiation-induced damage and cell death of somatomammotroph pituitary cells GH3. Doses of gamma-radiation 20-50 Gy were shown to inhibit proliferation and induce apoptosis in GH3 cells regardless of somatostatin presence. It has been found that the D(0) value for GH3 cells was 2.5 Gy. Somatostatin treatment increased radiosensitivity of GH3 cells, so that D(0) value decreased to 2.2 Gy. We detected quick phosphorylation of histone H2A.X upon irradiation by the dose 20 Gy and its colocalization with phosphorylated protein Nbs-1 in the site of double strand break of DNA (DSB). Number of DSB decreased significantly 24 h after irradiation, however, clearly distinguished foci persisted, indicating non repaired DSB, after irradiation alone or after combined treatment by irradiation and SS14. We found that SS14 alone triggers phosphorylation of Nbs1 (p-Nbs1), which correlates with antiproliferative effect of SS14. Irradiation also increased the presence of p-Nbs1. Most intensive phosphorylation of Nbs1 was detected after combined treatment of irradiation and SS14. The decrease of the number of the DSB foci 24 h after treatment shows a significant capacity of repair systems of GH3 cells. In spite of this, large number of unrepaired DSB persists for 24 h after the treatment. We conclude that SS14 does not have a radioprotective effect on somatomammotroph GH3 cells.

Cryptococcosis--a review of 13 autopsy cases from a 54-year period in a large hospital.

From 1952 to 2005, 13 cases of cryptococcosis confirmed by postmortem examination were diagnosed in autopsy material from the University Hospital in Hradec Králové, the Czech Republic. Histologically, Cryptococcus was found in multiple organs (brain and spinal cord, lungs, lymph nodes, spleen, bone marrow, liver, kidneys and adrenal glands). The lungs and CNS were the organs most often involved. Only in two cases was the diagnosis of cryptococcal infection established during the patient's lifetime, in both presenting clinically as meningitis, with positive result of CSF cultivation. Data and issues of diagnostics and treatment of cryptococcosis are discussed.

Fulminant course of metastatic liposarcoma after delivery--case report.

Abdominal liposarcoma is a rare tumor of uncertain prognosis. Radical surgery is possible in about two-thirds of the patients, and the prognosis of patients with inoperable tumors is dismal. Only a few cases of liposarcoma complicating pregnancy have been documented. We report a case of a patient who was diagnosed with metastatic abdominal liposarcoma during the third trimester of the pregnancy. After induced vaginal delivery, palliative surgery was performed and one cycle of systemic combination chemotherapy was administered. Despite the multimodality treatment the patient died of progressive disease within one month after diagnosis. Autopsy revealed high-grade pleomorphic liposarcoma arising from the retroperitoneum with liver and lung metastases.

Diurnal variation of 6beta-hydroxycortisol in cardiac patients.

The 24-hour urinary excretion of 6-beta-hydroxycortisol (6beta-OHC) and the urinary ratio of 6beta- hydroxycortisol/cortisol (6beta-OHC/UFC) have been proposed as noninvasive probes for human cytochrome P450 3A4 isoform (CYP3A4). In this study, we evaluated within- and between-day variability of 6beta-OHC excretion and 6beta-OHC/UFC ratio in nine Caucasian men with cardiac disease. Each study participant was asked to collect 24-hour urine specimens during four consecutive days in five standardized time intervals. Concentrations of UFC and 6beta-OHC were determined by immunoassay and the high-performance liquid chromatographic (HPLC) method, respectively. The HPLC method was accurate and precise, as indicated by the recovery rate of 96.5-103.3 % and less than 5.2 % and 6.3 % of the coefficient of variation for within-run and between-run assay, respectively. In patients, diurnal variations in UFC and 6beta-OHC excretion were parallel. Consequently, 6beta-OHC/UFC ratio remained stable during the day. Both, 6beta-OHC excretion and 6beta-OHC/UFC ratio showed significant relationship between 24-hour value and values measured in corresponding collection periods with best correlations obtained from night interval (22.00-06.00, r = 0.86-0.91). These results indicated that urinary 6beta-OHC excretion and 6beta-OHC/UFC ratio measured in overnight/morning urine could precisely reflect 24-hour values even in severely ill patients. In addition, a simple and sensitive HPLC method was described for determination of 6beta-OHC in urine.

Evaluation of the antineoplastic activity of mitoxantrone-L-carnitine combination therapy on an experimental solid form of ehrlich tumour in mice.

We have commenced a series of experiments to evaluate the effect of carnitine derivatives on the antineoplastic activity of mitoxantrone (MX) on various animal cancers. This report describes the therapeutic effect of MX in combination with l-carnitine (LCAR) on the growth of a solid form of Ehrlich tumour inoculated into mice. LCAR was administered subcutaneously at doses of either 200 or 100mgkg(-1) on day 6 and 13 after tumour inoculation, 1h prior to the treatment with MX. Mitoxantrone was administered intravenously at doses of 3 or 6mgkg(-1). We found that LCAR had no potentiating effect on the efficacy of MX, in terms of either slowing tumour growth or increasing the survival of mice. Nevertheless, therapeutic effects can be assumed at higher doses of both drugs based on values calculated from an index of relative hazards.

[A cell and genotoxic stress: a reaction to double strand breaks of DNA]. / Bunka a genotoxický stres: reakce na dvojité zlomy DNA.

Double strand breaks (DSB) of DNA represent a major impact on the genome integrity. Cells have developed complex set of reactions for prevention of genotoxic damage and cellular dysfunction. The quickly reacting proteins of human cells include proteinkinases from the family of phophatidylinositol-3-kinase related proteinkinases: ataxia-teleangiectasia mutated (ATM), ataxia-teleangiectasia and Rad3-related (ATR) and catalytic subunit of DNA-dependant proteinkinase (DNA-PKcs). Activated ATM phosphorylates other targets, including proteins p53, Mdm2, Chk1, Chk2, Brca1, Nbs1 and cAb1. This article discusses the molecular response to DSB in detail.

[Possibilities of medical treatment in acromegaly]. / Moznosti medikamentózni lécby akromegalie.

Active acromegaly deteriorates the quality of life and shortens the life expectancy. Surgery is the first-line therapy in the majority of patients, followed by radiotherapy in unsuccessful cases. The surgery cure rate is only one half in the case of macroadenomas and it takes years before radiotherapy normalizes GH and IGF-I levels. In the interim, medical therapy is necessary. Second-generation dopamine agonists (cabergoline) are successful in about one third of patients, especially in those with lower basal IGF-I levels and with adenomas co-secreting prolactin. Somatostatin analogues octreotide and lanreotide are the gold standard of medical treatment - both are available in a form applicable as once-monthly injections. They successfully control disease activity in the majority of patients and induce tumour shrinkage in part of adenomas. Surgical debunking of macroadenomas improves the results of therapy with somatostatin analogues and it is not necessary to discontinue this therapy before radiotherapy. The potential of higher efficiency represent new analogues, binding not only to somatostatin receptor subtype 2, but also to subtype 5 and "dopastatins" that are able to bind both to the somatostatin and the dopamine D2 receptors. The advent of the GH receptor antagonist pegvisomant provides the possibility to normalise IGF-I in virtually every patient. Combined treatment with somatostatin analogues probably enables reduction from daily to weekly injections.

Combined effect of sodium selenite and campthotecin on cervical carcinoma cells.

The effects of selenite, campthotecin and their combination were investigated in cervical carcinoma cell line Hep-2 HeLa during 24h. The measured parameters included morphological changes, proliferation, oxidative stress, mitochondrial status, caspase-3 activation and nuclear fragmentation. Selenite at all but lowest concentrations inhibited cell growth and proliferation and induced cell death characterized by membrane blebbing, oxidative stress and mitochondrial damage, occurring in the absence of caspase-3 activation and nuclear fragmentation. Campthotecin at all concentrations induced gradual apoptosis including all measured morphological and molecular parameters with exception of oxidative stress. A combination of selenite and campthotecin induced both antagonistic and synergistic effects on cervical carcinoma cells. While low selenium concentration slightly reduced cytotoxicity and proapoptotic effects of campthotecin, moderate and higher concentrations of selenium enhanced them, changing simultaneously apoptosis into more necrosis-like death. These results show importance of selenium as a potential modulator and enhancer of campthotecin-based anticancer therapy in nonovarian malignancies.

[A relationship between dehydroepiandrosterone sulphate and insulin resistance in obese men and women]. / Vztah mezi dehydroepiandrosteron-sulfátem a inzulinovou rezistencí u obézních muzu a zen.

UNLABELLED: The aim of our study was to investigate if there is any significant relationship between adrenal steroid hormone dehydroepiandrosterone-sulphate (DHEAS) and insulin resistance, as there are some previous signs in the literature suggesting such relationship but the results are not conclusive. METHODS: In our study participated 50 obese women and 20 obese men both with BMI over 27 kg/m2. Insulin resistance was calculated using HOMA insulin resistance index (HOMA-IR) that is based on fasting glycaemia and basal insulin levels. RESULTS: The negative correlation between DHEAS and HOMA-IR was found in the whole group of obese women but close behind statistical significance (r = -0.27, p = 0.055). But the group of obese women does not seem to be homogenous in correlation between DHEAS and insulin resistance. The significant negative correlation between DHEAS and insulin resistance was found in the subgroup (n = 21) of obese type 2 diabetic women (r = -0.55, p = 0.01) but no correlation was found in the subgroup (n = 29) of obese non-diabetic women (r = -0.06, p = 0.77). The relationship between DHEAS and glycaemia homeostasis was also confirmed by significant negative correlation between DHEAS and glycated haemoglobin (HbA1c) both in the subgroup of type 2 diabetic women (r = -0.51, p = 0.03) and in the subgroup of non-diabetic women (r = -0.70, p = 0.001). There was not found any significant correlation between DHEAS and insulin resistance neither in the whole group (n = 20) of obese men (r = 0.04, p = 0.87) nor in the subgroup (n = 11) of obese type 2 diabetic men (r = 0.55, p = 0.08) or in the subgroup (n = 9) of obese non-diabetic men (r = -0.42, p = 0.26). CONCLUSIONS: Significant negative correlation between DHEAS and HOMA-IR was found in the group of obese type 2 diabetic women but not in obese non-diabetic women suggesting that low DHEAS level might be connected to the development of insulin resistance and type 2 diabetes mellitus in obese women.

Inhibition of hormone secretion in GH-secreting pituitary adenomas by receptor-subtype specific somatostatin analogues in vitro.

The aim of the study was to determine the inhibitory effects of somatostatin analogues with relative specificity to somatostatin receptor subtype 2 (SSTR2) (BIM-23197), subtype 5 (SSTR5) (BIM-23268), and their combination on GH and PRL secretion in acromegalic adenomas in vitro. Three types of answer were observed: 1. In one resistant adenoma no inhibition was achieved. 2. The GH secretion in six adenomas was suppressed significantly more (p < 0.01 or p < 0.001 using Mann-Whitney U-test in concentration range of 10(-12) to 10(-8) mol/l) with SSTR2 specific analogue BIM-23197 with no additive effect of compounds combination. 3. In three adenomas the potency of BIM-23197 and BIM-23268 was almost equal and the combination of these SSTR2 and SSTR5 specific compounds had statistically significant additive effect (p < 0.05 or p < 0.01 in concentration range of 10(-12) to 10(-8) mol/l). PRL secretion of five adenomas was more suppressed with SSTR5 specific BIM-23268 (statistically significant in concentrations 10(-10) to 10(-8) mol/l). In conclusion the somatostatin analogue BIM-23268 had an additive effect on suppression of GH secretion in a subset of adenomas, where both SSTR2 and SSTR5 were involved. This effect was not observed in the majority of tumours, where the inhibitory effect seems to be mediated via SSTR2 only.

Influence of amiodarone on urinary excretion of 6beta-hydroxycortisol in humans.

The present study was undertaken to evaluate the use of cortisol 6beta-hydroxylation in defining the effect of amiodarone on cytochrome CYP3A activity. To accomplish this goal, the in vivo activity of CYP3A was estimated by measuring the 24-hour urinary excretion of 6beta-hydroxycortisol (6beta-OHC) and by calculating 24-hour ratio of 6beta-hydroxycortisol to urinary free cortisol (6beta-OHC/UFC ratio). Nine cardiac patients scheduled for amiodarone treatment were recruited to participate in this study. Urine was collected over a 24-hour period from each subject before the first amiodarone administration and during the third day of oral administration of amiodarone (200 mg four times daily as a loading dose). Three days of amiodarone treatment caused a significant decrease (p<0.05) in both the 6beta-OHC/UFC ratio and the 24-hour urinary excretion of 6beta3-OHC. These results suggest that amiodarone is an inhibitor of CYP3A activity.

Light-induced photoactivation of hypericin inhibits cellular growth in pituitary adenoma cell line AtT20/D16v-F2 (hypericin inhibits cellular growth of AtT20/D16v-F2).

Cultivation with 4-8 mumol/l hypericin (specific proteinkinase C inhibitor) activated by light induced high inhibition of the rate of HL-60 cell growth. When hypericin treated cells were not exposed to light growth inhibition was insignificant. Cultivation with light activated hypericin in concentration 16 mumol/l slightly inhibited growth rate of AtT20/D16v-F2 cells. AtT20/D16v-F2 cells did not proliferate in presence of light activated 32 mumol/l hypericin. Evidence of apoptosis was found in HL-60 cells treated with 1-8 mumol/l light activated hypericin, with maximum of apoptotic cells detected after 8 mumol/l light activated hypericin. Light activated hypericin induces both apoptosis and necrosis in dose and time dependent manners in HL-60 cells, but causes only necrosis in AtT20/D16v-F2 cells.

Influence of CYP3A metabolizer status on the pharmacokinetics and pharmacodynamics of amiodarone.

UNLABELLED: The present work was designed to determine whether the individual differences in pharmacokinetics and pharmacodynamics of amiodarone and its N-desethyl metabolite are related to cytochrome CYP3A metabolizer status. METHODS: 12 cardiac patients with inducible ventricular tachyarrhythmias during the baseline electrophysiologic study were enrolled in this study. Urinary 24-hour excretion of 6 beta-hydroxycortisol (6 beta-OHC and the ratio of 6 beta-hydroxycortisol to urinary free cortisol (6 beta-OHC/UFC) were measured before the first amiodarone administration. Trough plasma concentrations of amiodarone and N-desethylamiodarone (N-DEA) were measured after 79 +/- 11 days (2nd period) and after 182 +/- 25 days (3rd period). Electrophysiologic effects of amiodarone therapy were established with serial electrophysiologic studies in 9 of these patients at the baseline and after 79 +/- 11 days (during the second period). RESULTS: Both the 6 beta-OHC excretion and 6 beta-OHC/UFC ratio varied approximately 6-fold between the patients. We found significant inverse correlation between the 6 beta-OHC excretion and the trough plasma concentrations of amiodarone at the time of the 3rd period (rs = -0.58, p < 0.05). Similarly, there was correlation between the 24-hour urinary 6 beta-OHC excretion and trough plasma concentrations of amiodarone during the 3rd period (rs = -0.64, p < 0.025). We were unable to detect any association between CYP3A activity and amiodarone pharmacodynamics. CONCLUSION: This study points toward important information value of CYP3A metabolizer status in the context of therapeutic drug monitoring of amiodarone.