Differences in sex hormone levels in the menstrual cycle due to tobacco smoking - myth or reality?

INTRODUCTION: Tobacco smoke contains, among others, polycyclic aromatic hydrocarbons (PAHs), heterocyclic analogues, aromatic amines, N-nitrosamines, volatile hydrocarbons, aldehydes, phenols, miscellaneous organic compounds, metals, and inorganic compounds. Tobacco smoking can harm women's reproductive system and may reduce fertility. The objective of the study was to explore the effect of tobacco smoke on the menstrual cycle due to smoking and second-hand smoke-exposure. MATERIAL AND METHODS: The study was performed on 153 women of reproductive age, who received care at the Gynaecological-Obstetric Clinical Hospital of the Poznan University of Medical Sciences. They were divided into three treatment groups: non-smokers, secondhand smokers, and smokers. Comprehensive assessment of all hormone levels: follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17ß-oestradiol (E2), and progesterone (P), in the various phases of the menstrual cycle and with concomitant determinations of serum cotinine concentrations was performed. The menstrual cycle was observed with ultrasonography. RESULTS: Cigarette smoking may be an important factor in disrupting reproduction: 1. The increase in the oestradiol E2 level was accompanied by significantly lowered serum cotinine concentrations in tobacco smokers; 2. In smoking patients, the serum level of LH significantly increased on the first days of the menstrual cycle; 3. The higher levels of P (in the 14th and 21st days) were assumed to be the result of a longer menstrual cycle. CONCLUSIONS: Active and passive smoking may be an important contributor to reproductive health issues and deserves greater focus in health education programs directed towards women of reproductive age.

Pharmacokinetics of Levodopa and 3-O-Methyldopa in Parkinsonian Patients Treated with Levodopa and Ropinirole and in Patients with Motor Complications.

Parkinson's disease (PD) is a progressive, neurodegenerative disorder primarily affecting dopaminergic neuronal systems, with impaired motor function as a consequence. The most effective treatment for PD remains the administration of oral levodopa (LD). Long-term LD treatment is frequently associated with motor fluctuations and dyskinesias, which exert a serious impact on a patient's quality of life. The aim of our study was to determine the pharmacokinetics of LD: used as monotherapy or in combination with ropinirole, in patients with advanced PD. Furthermore, an effect of ropinirole on the pharmacokinetics of 3-OMD (a major LD metabolite) was assessed. We also investigated the correlation between the pharmacokinetic parameters of LD and 3-OMD and the occurrence of motor complications. Twenty-seven patients with idiopathic PD participated in the study. Thirteen patients received both LD and ropinirole, and fourteen administered LD monotherapy. Among 27 patients, twelve experienced fluctuations and/or dyskinesias, whereas fifteen were free of motor complications. Inter- and intra-individual variation in the LD and 3-OMD concentrations were observed. There were no significant differences in the LD and 3-OMD concentrations between the patients treated with a combined therapy of LD and ropinirole, and LD monotherapy. There were no significant differences in the LD concentrations in patients with and without motor complications; however, plasma 3-OMD levels were significantly higher in patients with motor complications. A linear one-compartment pharmacokinetic model with the first-order absorption was adopted for LD and 3-OMD. Only mean exit (residence) time for 3-OMD was significantly shorter in patients treated with ropinirole. Lag time, V/F, CL/F and tmax of LD had significantly lower values in patients with motor complications. On the other hand, AUC were significantly higher in these patients, both for LD and 3-OMD. 3-OMD Cmax was significantly higher in patients with motor complications as well. Our results showed that ropinirole does not influence LD or 3-OMD concentrations. Higher 3-OMD levels play a role in inducing motor complications during long-term levodopa therapy.

The GPR18 Agonist PSB-KD-107 Exerts Endothelium-Dependent Vasorelaxant Effects.

GPR18 is an orphan GPCR that is activated by the cannabinoid tetrahydrocannabinol (THC). Emerging evidence indicates its involvement in the control of cardiovascular functions, including heart rate, contractility, vascular tone, as well as blood pressure. Therefore, we investigated the effects of selective GPR18 receptor ligands, namely PSB-KD-107 (agonist) and PSB-CB-92 (antagonist), on blood pressure, electrocardiogram (ECG), and vascular dilatation in vitro and in vivo, as well as their anti-oxidative potential in in vitro ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate free radical (DPPH) assays. Our results clearly show that PSB-KD-107 dilates blood vessels. This effect is related to its activation of GPR18 as it can be blocked by the GPR18 antagonist PSB-CB-92. Moreover, our finding confirms the presence of GPR18 in blood vessels. The mechanism of the vasorelaxant activity of PSB-KD-107 is mainly related to endothelial nitric oxide generation; however, we cannot exclude additional nitric oxide-independent mechanisms or a direct influence on K+ channels. PSB-KD-107 may affect blood pressure and heart function after a single administration; however, this effect was no longer observed after repeated administrations once daily for eight days. PSB-KD-107 does not affect platelet aggregation-an important feature considering the safety of its administration. PSB-KD-107 also shows a significant anti-oxidant effect and further studies of its antioxidant activity in vivo are justified.

MH-76, a Novel Non-Quinazoline α1-Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats.

BACKGROUND: Quinazoline α1-adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on AntiHypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, they are no longer recommended as a first line therapy of hypertension. Recent studies have shown that quinazoline-based α1-adrenoceptors antagonists (prazosin, doxazosin) induce the apoptosis and necrosis, which may be responsible for ALLHAT outcomes; however, these effects were proven to be independent of α1-adrenoceptor blockade and were associated with the presence of quinazoline moiety. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α1-adrenoceptor antagonist which, in fructose-fed rats, exerted antihypertensive effect, and, contrary to prazosin, reduced insulin resistance and abdominal adiposity. In this study we aimed to further investigate and compare the effects of MH-76 and prazosin on inflammation in adipose tissue of fructose-fed rats. METHODS: Abdominal adipose tissue was collected from four groups of fructose-fed rats (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical, histopathological and immunohistochemical studies. Moreover, selected tissue distribution studies were performed. RESULTS: Treatment with MH-76 but not with prazosin improved endothelial integrity, reduced adipose tissue inflammation and infiltration by immune cells, resulting in lowering leptin, MCP-1, IL-6, TNF-α and PAI-1 levels. In adipose tissue from Fructose + MH-76 animals, a higher amount of eosinophils accompanied with higher IL-4 concentration was observed. Treatment with MH-76 but not with prazosin markedly reduced phosphorylation of IRS-1 at Ser307. CONCLUSION: MH-76 may improve insulin signaling in adipose tissue by reducing the pro-inflammatory cytokine production and inhibiting the inflammatory cells recruitment. In contrast, in adipose tissue from animals treated with prazosin, the inflammatory effect was clearly enhanced.

The non-compartmental steady-state volume of distribution revisited.

The lack in the literature of a simple, yet general and complete derivation of the widely used equation for non-compartmental calculation of steady-state volume of distribution is pointed out. It is demonstrated that the most frequently cited references contain an overly simplified explanation. The logical gap consists in doubly defining the same quantities without a proof the definitions are equivalent. Two alternative solutions are proposed: analytical derivation and hydrodynamic analogy. It is shown, that the problem can be analyzed in a purely macroscopic framework by utilizing the integral mean value of the function, without the need to resort to statistical distributions.

Effects of structural modification of the daunosamine moiety of anthracycline antibiotics on pKa values determined by capillary zone electrophoresis.

The thermodynamic acid dissociation constants (pKa1 and pKa2) of 16 anthracycline antibiotics, including doxorubicin (DOX) and daunorubicin (DAU), their epimers, epidoxorubicin (EDOX) and epidaunorubicin (EDAU), as well as novel anthracycline derivatives containing piperidine (FPIP), morpholine (FMOR) and hexamethylenoimine (FHEX) rings in the formamidine group of the daunosamine moiety were determined by analysis of the dependence between measured electrophoretic mobility and the pH of the buffer using the capillary zone electrophoresis method. The results obtained confirmed the ampholytic character of anthracyclines with at least two ionization states. The determined values were in the range of 8.36-9.28 and 9.38-11.48 for pKa1 and pKa2 arising from ionization of amino and phenolic groups, respectively. Structural modifications in the daunosamine moiety of the studied anthracyclines affected their pharmacological properties, such as antiproliferative activity.

Differential effects of liver steatosis on pharmacokinetic profile of two closely related hepatoselective NO-donors; V-PYRRO/NO and V-PROLI/NO.

PURPOSE: To analyze the effect of liver steatosis and obesity on pharmacokinetic profile of two structurally-related liver-selective NO-donors - V-PYRRO/NO and V-PROLI/NO. METHODS: C57BL/6 mice were fed control or high-fat diet for 15 weeks to induced liver steatosis and obesity (HFD mice). Pharmacokinetics and renal elimination studies were conducted in vivo following iv dosing of V-PYRRO/NO and V-PROLI/NO (0.03mmol/kg). Hepatic clearance was evaluated ex vivo in the isolated perfused mice liver and in vitro with the use of liver microsomes. RESULTS: V-PYRRO/NO and V-PROLI/NO, despite similar structure, displayed different pharmacokinetic properties. V-PYRRO/NO was uptaken and metabolized by the liver, while V-PROLI/NO was eliminated unchanged with urine. In HFD mice, despite increased CYP450 metabolism of V-PYRRO/NO the elimination rate was slower most likely due to the impairment of hepatic microcirculation caused by liver fat accumulation. In turn, in HFD mice renal clearence of V-PROLI/NO was accelerated and volume of distribution was increased most likely due to additional intracellular water in HFD mice. CONCLUSIONS: The pharmacokinetics of V-PROLI/NO, the novel proline-based analog of V-PYRRO/NO with additional single carboxylic acid moiety, attached to the molecule of V-PYRRO/NO to improve the water solubility, was differently affected by liver steatosis and obesity as compared with the parent compound V-PYRRO/NO.

Population pharmacokinetic modelling of valproic acid and its selected metabolites in acute VPA poisoning.

BACKGROUND: Valproic acid (VPA) is a first-line antiepileptic drug. It is used in the treatment of many different types of partial and generalized epileptic seizures. Though the clinical pharmacokinetics of VPA has been well defined, information about pharmacokinetics after overdoses is rare. The aim of this study was to try to build a population pharmacokinetic model that would describe the time course of VPA and its selected metabolites when the drug is ingested in an overdose situation. METHODS: Blood samples were collected during admission to the hospital and several times during treatment for poisoning (10 men and 10 women). The concentration of VPA and its metabolites were determined by liquid chromatography coupled with mass spectrometry. For population pharmacokinetic evaluation of VPA and its metabolites, the two-compartment-model was applied. RESULTS: The estimated doses of VPA taken ranged from 6 to 65g, while the time after ingestion ranged from 1 to 30h. Results showed that the ß-oxidation process exhibited Michaelis-Menten kinetics becoming saturated during acute intoxication. The same could not be said for the desaturation route. VPA therapy increased the Vmax for ß-oxidation by 59% while decontamination appeared to be of moderate efficacy lowering the F value by 34% on the average. CONCLUSIONS: None of the models perfectly described the experimental data. Important factors like the variable degree of protein binding by VPA could not be included in the models. The small number of subjects used in the study made the analysis of more covariates impossible.

PHARMACOKINETICS OF DICLOFENAC SODIUM AND PAPAVERINE HYDROCHLORIDE AFTER ORAL ADMINISTRATION OF TABLETS TO RABBITS.

Non-compartmental pharmacokinetic analysis of diclofenac sodium (DIC) and papaverine hydrochloride (PAP) after oral administration of composed tablets to rabbits was developed. HPLC method for determination of DIC and PAP in rabbit plasma was developed and validated. Chromatographic separation of DIC, PAP and the IS was achieved on a Zorbax SB C18 5-µm column (150 mm x 4.6 mm) using methanol-water (55:45, v/v) as mobile phase at a flow rate of 0.8 mL/min. Pharmacokinetic analysis showed that oral administration of a tablet composed of DIC and PAP do not change the pharmacokinetic parameters such as MRT, MAT, Cl and bioavailability of the active substances compared with single administration of DIC and PAP after single dose.

Influence of tobacco smoke exposure on pharmacokinetics of ethyl alcohol in alcohol preferring and non-preferring rats.

BACKGROUND: A vast majority of people who abuse alcohol are also defined as "heavy smokers". Tobacco smokes induces CYP1A1, CYP1A2, CYP2A6 isoenzymes, but on the other hand, ethanol activates CYP2E1, which can be important during combined, chronic use of both of them. The aim of the study was to evaluate the influence of tobacco smoke xenobiotics on ethanol pharmacokinetics and the level of its metabolites in alcohol preferring and non-preferring rats. METHODS: Ethanol, acetaldehyde, methanol, n-propanol and n-butanol were determined in whole blood by means of gas chromatography. Cotinine in serum was determined by LC-MS/MS. A non-compartmental analysis (cotinine, acetaldehyde) and Widmark equation (ethanol) were used for pharmacokinetic parameters calculation. RESULTS: Ethanol levels were lower in animals exposed to tobacco smoke compared to rats receiving this xenobiotic, without a prior exposure to tobacco smoke. Lower values of the studied pharmacokinetic parameters were observed in the alcohol preferring males compared to the non-alcohol preferring rats. Both n-propanol and n-butanol had higher values of the pharmacokinetic parameters analyzed in the animals exposed to tobacco smoke and ethanol compared to those, which ethanol was administered only once. CONCLUSIONS: An increase in maximum concentration and the area under concentration-time curve for ethanol after its administration to rats preferring alcohol and exposed to tobacco smoke are accompanied by a decrease in the volume of distribution. The changes in the volume of distribution may be caused by an increase in the first-pass effect, in the intestinal tract and/or in the liver. The acetaldehyde elimination rate constant was significantly higher in alcohol-preferring animals.

Classification models based on the level of metals in hair and nails of laryngeal cancer patients: diagnosis support or rather speculation?

The etiology of cancer is complex, and the disturbances in toxic and essential metals homeostasis are among many of the factors that lead to the development of malignancy. The aim of this study is to investigate the relationship between cancer risk and element status as well as cancer risk and external factors, such as diet, smoking and drinking habits, in order to support diagnosis of cancer. The samples of hair and nails obtained from patients with larynx cancer and healthy subjects were analyzed. Essential elements (Ca, Cr, Mg, Zn, Cu, Mn, and Fe), besides toxic metals (Cd, Co, and Pb), were determined using inductively coupled plasma atomic emission spectrometry (ICP-OES) and mass spectrometry (ICP-MS) techniques. The concentration of essential elements was from 1.5- (Zn) to 4.7-fold (Fe) higher in hair and from 2.4- to 3.3-fold higher in the nails of the control group compared to the patients, while the opposite trend was observed for the heavy metals. The differences between two groups in the level of metals (except for Zn) were statistically significant (p < 0.05). The association of cancer with metals and other factors was evaluated using various statistical methods, for which the best predictions were obtained using logistic regression, artificial neural networks and canonical discriminant analysis. The classifiers constructed using the data from a survey of diet and lifestyle, and analysis of elements in hair and nails, can be useful tools for estimating cancer risk and early screening of the disease.

Abnormal olanzapine toxicokinetic profiles--population pharmacokinetic analysis.

CONTEXT: Olanzapine is widely used in the treatment of schizophrenia and it is becoming more frequently responsible for overdoses. Standard pharmacokinetic models do not fit to the toxic concentration data. OBJECTIVE: The aim of present study is to investigate the reasons for an abnormal olanzapine plasma concentration time curve in the range of toxic concentrations. Two hypotheses were verified: entering the enterohepatic cycle, and drug deposition and its desorption from activated charcoal used for gastrointestinal decontamination. MATERIALS AND METHODS: One-hundred thirty-five plasma concentration data from 21 patients hospitalized for acute olanzapine poisoning were analyzed with the use of the population pharmacokinetic approach. A non-linear mixed-effects modeling approach with Monolix 4.3.1 was employed. RESULTS: A model assuming gallbladder emptying at irregular intervals was developed. Also, a model that describes desorption of olanzapine from the charcoal surface, in which the dose is divided into two absorbed fractions, was constructed. The analysis has found gastrointestinal decontamination and previous olanzapine treatment, as the significant covariates for toxicokinetic parameters of olanzapine. CONCLUSION: Our study provides interesting models for investigation of toxic concentration of olanzapine, which may also be used as the basis for further model development for other drugs as well. The investigated population was not large enough to reliably confirm any of the proposed models. It would be well worth continuing this study with more substantial data. Also, any additional information about olanzapine metabolite concentration could be vital.

Searching for an optimal AUC estimation method: a never-ending task?

An effective method of construction of a linear estimator of AUC in the finite interval, optimal in the minimax sense, is developed and demonstrated for five PK models. The models may be given as an explicit C(t) relationship or defined by differential equations. For high variability and rich sampling the optimal method is only moderately advantageous over optimal trapezoid or standard numerical approaches (Gauss-Legendre or Clenshaw-Curtis quadratures). The difference between the optimal estimator and other methods becomes more pronounced with a decrease in sample size or decrease in the variability. The described estimation method may appear useful in development of limited-sampling strategies for AUC determination, as an alternative to the widely used regression-based approach. It is indicated that many alternative approaches are also possible.

Tobacco smoke exposure and endothelial dysfunction in patients with advanced coronary artery disease.

INTRODUCTION:  Exposure to tobacco smoke is associated with a higher cardiovascular risk, especially in patients with coronary artery disease (CAD).  OBJECTIVES:  The aim of the study was to evaluate the effect of active and passive tobacco smoking on the activity of endothelial markers in advanced atherosclerosis. PATIENTS AND METHODS:  We studied 181 consecutive patients with advanced CAD (53 women and 128 men) aged 60 ±8 years, including 102 active self­declared smokers (56.3%). We determined plasma asymmetric dimethylarginine (ADMA), thrombomodulin (TM), and plasminogen activator inhibitor­1 (PAI­1) levels, along with serum cotinine concentrations as a marker of tobacco smoking.  RESULTS:  Plasma ADMA levels were higher in active smokers compared with nonsmokers (0.60 ±0.09 µmol/l vs. 0.49 ±0.08 µmol/l, P <0.001). There were similar intergroup differences in TM (4.60 ±2.11 ng/ml vs. 3.0 ±1.7 ng/ml, P <0.0001) and PAI­1 levels (30.3 ±12.4 ng/ml vs. 23.6 ±11.3 ng/ml, P <0.0001). We observed positive correlations between cotinine and ADMA (r = 0.71, P <0.0001), TM (r = 0.53, P <0.0001), and PAI­1 (r = 0.58, P <0.0001). In 21 patients (26.6%) who declared to be nonsmokers, cotinine levels (mean, 6.30 ±22.5 ng/ml) significantly correlated with ADMA, TM, and PAI­1 (all P <0.001). A multivariate regression analysis showed that cotinine was an independent predictor of ADMA, TM, and PAI­1 in the whole patient group.  CONCLUSIONS:  Despite long­lasting endothelial injury in advanced CAD, continued cigarette smoking is able to further enhance endothelial damage by increasing ADMA levels and resultant inhibition of fibrinolysis.

How to combine non-compartmental analysis with the population pharmacokinetics? A study of tobacco smoke's influence on the bioavailability of racemic citalopram in rats.

BACKGROUND: Citalopram (CIT) is an antidepressant drug from the group of selective serotonin reuptake inhibitors in which it is the most potent selective inhibitor of serotonin uptake currently available. Patients treated with CIT are often heavy cigarette smokers. Individual pharmacokinetic parameters cannot be directly estimated if full pharmacokinetic profiles are not available for each subject. Sparse sampling is common to experiments using small animals, such as the case that our study is concerned with. METHODS: The aim of the study was to demonstrate how the two (non-compartmental analysis (NCA) and nonlinear mixed-effect (NLME)) approaches, used simultaneously, can help overcome specific limitations of these separate methods whilst at the same time preserve their respective benefits. RESULTS: Despite the ultra-sparse design, the NLME approach enabled us to develop a pharmacostatistic model with the required covariate--exposition to the tobacco smoke. CONCLUSIONS: A tobacco smoke slows down the absorption of the CIT and at the same time makes it more effective. The consistency of results obtained both with NCA and NLME decreased the risk of model misspecification and increased confidence in the final conclusions. Combining NLME with NCA may therefore be recommended for investigating pharmacokinetic properties of the drug in the sparse designs.

Acute CO poisoning is associated with impaired fibrinolysis and increased thrombin generation.

Carbon monoxide (CO) poisoning is a leading cause of unintentional poisoning deaths in many countries. In ex vivo studies, CO released from carbon monoxide-releasing molecules has been shown to attenuate fibrinolysis via increased alpha-2-antiplasmin activity. Hypofibrinolysis is associated with coronary ischaemia, which is also commonly observed in CO poisoning. We examined fibrin clot properties in acutely poisoned CO patients. Ex vivo plasma fibrin clot permeability, turbidimetry and efficiency of fibrinolysis were investigated in 48 patients and controls matched for age and sex. CO-poisoned patients had 11.6% longer clot lysis time than the controls (p < 0.0001). No intergroup differences in clot permeability or turbidimetric variables were observed. Plasma tissue-type plasminogen antigen (tPA), plasminogen activator inhibitor-1 (PAI-1) antigen and activity and F1.2 prothrombin fragments were higher in the patients than in the controls (all p < 0.0001). Plasma tPA activity was lower in the CO-poisoned group. Multiple linear regression showed that a thrombin generation marker, F1.2, is the strongest predictor of clot lysis time, followed by PAI-1 activity and carboxyhaemoglobin levels. In conclusion, this report is the first to demonstrate that acute CO poisoning in human beings is linked to increased thrombin generation and impaired fibrinolysis, which might contribute to ischaemic complications.

Binding of 1-[3-(4-tert-butyl-phenoxy)propyl]piperidine, a new non imidazole histamine H3 receptor antagonist to bovine serum albumin.

The degree of binding of a drug to plasma proteins has a significant effect on its distribution, elimination, and pharmacological effect since only the unbound fraction is available for distribution into extra-vascular space. The binding of DL76 (1-[3-(4-tert-butyl-phenoxy)propyl]piperidine) to bovine serum albumin (BSA) was studied in viitro by equilibrium dialysis at 37 degrees C and pH 7.4 over the concentration range of 0.32-317.18 microM and at a physiological protein concentration of 602 microM. Drug concentrations were determined by validated LC/MS/MS method. Nonlinear regression analyses of the data pointed to a single class of binding sites (m = 1) with a dissociation constant of DL76 equal 49.20 microM. Scatchard plot concave-down curve might indicate positive cooperativity, which was confirmed by the Hill plot with the slope higher than one.

[Laboratory investigations in acute olanzapine poisonings]. / Badania laboratoryjne w ostrych zatruciach olanzapina.

BACKGROUND: Olanzapine is an atypical antipsychotic with multireceptor affinity and different pharmacological effects, which can result with abnormalities in laboratory investigations. AIM OF THE STUDY: To assess the nature and frequency of laboratory tests abnormalities in patients with an acute olanzapine poisoning. MATERIAL: 26 adult cases (mean age 37.7 +/- 15.3 years) of an acute olanzapine poisoning (serum level above 100 ng/mL). Group consisted of 11 men and 13 women, but 1 man and 1 woman were poisoned twice. METHODS: Prospective analysis of the following laboratory parameters: complete blood count (CBC), coagulation tests (APTT, INR), serum concentration of sodium, potassium, chlorides, glucose, BUN, creatinine and bilirubin, serum activity of AST, ALT, GGTP and CPK, urinalysis. RESULTS: The most common laboratory abnormalities in the study group were: hyperglycaemia (96%), hyper-prolactinaemia (83%), elevated CPK (80%), hypokalaemia (75%), hyperbilirubinaemia (60%), leukocytosis (55%). Less frequent parameters were: elevated AST (20%), hyponatraemia (15%), elevated ALT(10%) and thrombocytopenia (5%). The onset of some parameters was as follows: 1st day of hospitalization hyperglycaemia, leukocytosis and hypokalaemia, 2nd - hyperbilirubinaemia and elevated CPK, and 3rd - hyperprolactinaemia. CONCLUSIONS: In acute olanzapine poisonings: (1) muscle and liver injury, serum glucose and electrolytes abnormalities, and changes in CBC can be present; (2) the valuable parameters for the monitoring of the course of poisonings are: serum activity of CPK and transaminases (AST, ALT), serum level of bilirubin, glucose, potassium and sodium, and CBC; (3) hyperprolactinaemia probably lacks of practical importance, but the further investigations are needed in this area.

[The clinical picture of acute olanzapine poisonings]. / Obraz kliniczny ostrych zatruc olanzapina.

BACKGROUND: Olanzapine is a second generation antipsychotic of thienobenzodiazepin group, which is used in the treatment of schizophrenia, bipolar disorder, and others, mainly psychiatric. Its multireceptor action (antagonism to dopaminergic D1, D2, D4, serotoninergic 5-HT2A, 5-HT2C, histaminergic H1, cholinergic M1-5, and a1--adrenergic receptors) results in multiple clinical symptoms in the course of acute poisoning. AIM OF THE STUDY: Evaluation of incidence and intensity of clinical symptoms in patients with of acute olanzapine intoxication. The pathophysiological mechanisms of particular symptoms are also described. MATERIAL: 26 patients (mean age 37.7 +/- 15.3 years) hospitalized in 2005-2008 in toxicological centers in Krakow and Gdansk because of acute olanzapine poisoning (all patients had the toxic serum level of olanzapine above 100 ng/mL). The study group consisted of 11 men (29.3 +/- 8.5 years) and 13 women (44.9 +/- 16.4 years); 1 man and 1 woman were poisoned twice. METHODS: Prospective analysis (using descriptive statistics) of data taken from medical anamnesis and results of physical examination, considering the following ones: consciousness disturbances (Glasgow Coma Scale, Matthew's scale, qualitative disturbances), vital signs (arterial blood pressure, heart rate, breathing rate, temperature), neurological findings (muscular tension, tendon reflexes, extrapyramidal symptoms, pupils) and others (oral and bronchial secretion, Poisoning Severity Score). RESULTS: The mean dose of ingested olanzapine in the study group was 352.5 +/- 220.0 mg, while the mean time since ingestion to hospital admission was 4.4 +/- 3.5 h. The half of the patients took other medicines together with olanzapine, and 23% consumed alcohol, as well. The following intensity of quantitative consciousness disturbances according to Matthew's scale were observed: grade 0 - 8%, I - 15%, II - 23%, III - 50%, and IV - 4%. The minimal and maximal values of blood pressure were: 102/63 +/- 16/14 and 163/ 97 +/- 27/18 mmHg, respectively; heart rate: 77 +/- 15 and 138 +/- 22 beats/min; temperature: 36.3 +/- 0.5 and 37.9 +/- 0.8 degrees C; breathing rate in non-intubated patients: 14 +/- 2 and 22 +/- 7 breaths/min. The mean duration of consciousness disturbances, endotracheal intubation and mechanical ventilation were: 44.9 +/- 31.3; 22.0 +/- 33.3 and 7.0 +/- 25.9 h, respectively. The study revealed tachycardia (85%), psychomotor agitation (81%), hypertension (73%), miosis (65%), and coma (54%) as the most common symptoms of poisoning. The hospitalization of poisoned patients lasted on average 5.7 +/- 3.6 days and the half of them were poisoned severely (PSS 3). CONCLUSIONS: In the course of acute olanzapine poisoning: (1) the prevailing symptoms come from circulatory and central nervous systems; (2) some symptoms are mutually opposed, eg.: coma - psychomotor agitation, hypertension - hypotension, tachycardia - bradycardia, hyperthermia - hypothermia, miosis - mydriasis; (3) rarely consciousness disturbances may persist for up to 6 days after olanzapine overdose; (4) the course of poisoning can be severe, sometimes complicated, but fatal outcomes are rare.