Edmund Grześkowiak

Concomitant use of tramadol and venlafaxine – evaluation of antidepressant-like activity and other behavioral effects in rats

BACKGROUND The aim of this study was to evaluate antidepressant-like effect (Porsolt test), locomotor activity and motor coordination of joint administration of tramadol (TRM) and venlafaxine (VEN) in rats. METHODS The tests were performed on male Wistar rats after single and chronic treatment (7 and 14 days) with TRM intraperitoneally (ip) and VEN orally (po) administered once a day. The controls were given 0.5% carboxymethylcellulose (CMC) solution (0.5 ml per rat, ip and po). RESULTS It was found that combination of TRM (5 mg/kg ip) with VEN (20 mg/kg po) caused an increased antidepressant effect compared to TRM and VEN administered alone, with no effect on locomotor activity or motor coordination in rats, which may be of clinical significance. It was also observed that reduced time of active swimming of animals in Porsolt test with an increased dose (10 and 20 mg/kg) and time of administration (7 and 14 days) of TRM were correlated with a decreased locomotor activity in rats. It may indicate the development of tolerance to TRMs antidepressant effect in rats during chronic treatment with doses higher than 5 mg/kg. CONCLUSION It can be expected that combination of low doses of TRM and VEN could potentially be feasible and relatively safe in cases with acute pain with co-existing depression, however, further investigations are needed.

Pharmacokinetics and pharmacodynamics of propofol in patients undergoing abdominal aortic surgery

Available propofol pharmacokinetic protocols for target-controlled infusion (TCI) were obtained from healthy individuals. However, the disposition as well as the response to a given drug may be altered in clinical conditions. The aim of the study was to examine population pharmacokinetics (PK) and pharmacodynamics (PD) of propofol during total intravenous anesthesia (propofol/fentanyl) monitored by bispectral index (BIS) in patients scheduled for abdominal aortic surgery. Population nonlinear mixed-effect modeling was done with Nonmem. Data were obtained from ten male patients. The TCI system (Diprifusor) was used to administer propofol. The BIS index served to monitor the depth of anesthesia. The propofol dosing was adjusted to keep BIS level between 40 and 60. A two-compartment model was used to describe propofol PK. The typical values of the central and peripheral volume of distribution, and the metabolic and inter-compartmental clearance were V(C) = 24.7 l, V(T) = 112 l, Cl = 2.64 l/min and Q = 0.989 l/min. Delay of the anesthetic effect, with respect to plasma concentrations, was described by the effect compartment with the rate constant for the distribution to the effector compartment equal to 0.240 min(-1). The BIS index was linked to the effect site concentrations through a sigmoidal E(max) model with EC(50) = 2.19 mg/l. The body weight, age, blood pressure and gender were not identified as statistically significant covariates for all PK/PD parameters. The population PK/PD model was successfully developed to describe the time course and variability of propofol concentration and BIS index in patients undergoing surgery.

The significance of -786T > C polymorphism of endothelial NO synthase (eNOS) gene in severe preeclampsia.

Objective. Preeclampsia (PE) is believed to be induced by endothelial cell dysfunction in placenta. Highly polymorphic endothelial nitric oxide synthase (eNOS) activity belongs to the factors significantly influencing vaso-motor tone in placenta and PE susceptibility. The aim of this study was to evaluate prevalence of −786T/C polymorphism of eNOS gene in the groups of women with mild and severe PE. Study design. The study was performed in the group of 218 preeclamptic (including 136 with severe PE) and of 400 normotensive healthy women delivered normally after a healthy gestation. The eNOS −786T/C polymorphism was determined using PCR/RFLP assay. Additionally, detailed correlation between eNOS genotypes and clinical/laboratory data in the PE group has been analyzed. Results. The higher frequency of mutated homozygous CC genotypes (17.4% vs. 11.5% in controls, OR 1.62, n.s.) and of C alleles (allelic frequency 44.1 vs. 36.6%; OR 1.36, p = 0.012) in the group of PE has been determined. Furthermore, in the group of severe PE the overrepresentation of mutated CC genotypes (23.5% vs. 11.5%, OR 2.37, p = 0.0014) and mutated C alleles (47.8 vs. 36.6%, OR 1.58, p = 0.0016) has been found. Conclusions. The presence of mutated homozygous CC genotype and C allele of −786T/C polymorphism of eNOS gene influences the higher susceptibility to develop severe PE development.

Assessing circadian rhythms during prolonged midazolam infusion in the pediatric intensive care unit (PICU) children

BACKGROUND This study evaluates possible circadian rhythms during prolonged midazolam infusion in 27 pediatric intensive care unit (PICU) children under mechanical ventilation. METHODS Blood samples for midazolam and 1-OH-midazolam assay were collected throughout the infusion at different times of the day. The blood pressure, heart rate and body temperature were recorded every hour for the rhythms analysis. Population nonlinear mixed-effect modeling with NONMEM was used for data analysis. RESULTS A two-compartment model for midazolam pharmacokinetics and a one-compartment model for midazolam metabolite adequately described the data. The 24 h profiles of all monitored physiological parameters were greatly disturbed/abolished in comparison with the well-known 24 h rhythmic patterns in healthy subjects. There was no significant circadian rhythm detected with respect to midazolam pharmacokinetics, its active metabolite pharmacokinetics and all monitored parameters. CONCLUSIONS We concluded that the light-dark cycle did not influence midazolam pharmacokinetics in intensive care units children. Also, endogenous rhythms in critically ill and sedated children are severely disturbed and desynchronized. Our results confirmed that it is necessary to adjust the dose of midazolam to the patients body weight. The low value of midazolam clearances observed in our study was probably caused by mechanical ventilation, which was shown to decrease the cardiac output.

Influence of Time of Day on Propofol Pharmacokinetics and Pharmacodynamics in Rabbits

This study evaluates the administration time-of-day effects on propofol pharmacokinetics and sedative response in rabbits. Nine rabbits were sedated with 5 mg/kg propofol at three local clock times: 10:00, 16:00, and 22:00 h. Each rabbit served as its own control by being given a single infusion at the three different times of day on three separate occasions. Ten arterial blood samples were collected during each clock-time experiment for propofol assay. A two-compartment model was used to describe propofol pharmacokinetics, and the pedal withdrawal reflex was used as the sedation pharmacodynamic response. The categorical data comprising the presence or absence of pedal withdrawal reflex was described by a logistic model. The typical volume of the central compartment equaled 7.67 L and depended on rabbit body weight. The elimination rate constant depended on drug administration time; it was lowest at 10:00 h, highest at 16:00 h, and intermediate at 22:00 h. Delay of the anesthetic effect, with respect to plasma concentrations, was described by the effect compartment, with the rate constant for the distribution to the effector compartment equal to 0.335 min−1. Drug concentration had a large effect on the probability of anesthesia. The degree of anesthesia was largest at 10:00 h, lowest at 16:00 h, and intermediate at 22:00 h. In summary, both the pharmacokinetics and pharmacodynamics of propofol in rabbits depended on administration time. The developed population approach may be used to assess chronopharmacokinetics and chronopharmacodynamics of medications in animals and humans. (Author correspondence: agnbienert@op.pl)

Biopharmaceutical availability of sulphadicramide from ocular ointments in vitro

The effect of absorption promoters, i.e. sodium deoxycholate, lauryl ether polioxyethylene-9, and l-alpha-lysophosphatidylo choline, on the process of sulphadicramide dialysis through lipophilic synthetic membranes and animal cornea in vitro, was studied. Formulation of ophthalmic ointments containing sulphadicramide and the above promoters was proposed and biopharmaceutical evaluation of the ointments was performed.

Influence of demographic factors, basic blood test parameters and opioid type on propofol pharmacokinetics and pharmacodynamics in ASA I-III patients.

The aim of the study was to examine population pharmacokinetics (PK) and pharmacodynamics (PD) of propofol (CAS 2078-54-8) during total intravenous anesthesia monitored by spectral frequency index (SFx). Twenty-eight patients of ASA physical status I-III (ASA: American Society of Anesthesiologists) scheduled for laparoscopic cholecystectomy were included. In group I an anesthesia was induced with a bolus of propofol (2 mg/kg) and remifentanil (CAS 132875-61-7) (1.0 microg/kg), followed by a continuous infusion of remifentanil. In group II, an alfentanil (CAS 71195-58-9) (10 microg/kg) bolus dose was followed by a continuous infusion of alfentanil. The general anesthetic technique included propofol, opioid and muscle relaxant. During anesthesia, the propofol infusion rate (3-8 mg/kg/h) was adjusted to the SFx value. Venous blood samples were collected from the patients during 240 min after termination of the infusion. A two compartment model was used to describe propofol PK. A standard effect compartment model was used to describe the delay between the effect and the concentration of propofol. The SFx index was linked to the effect site concentrations through a sigmoidal Emax model. The influence of continuous (body weight, age, blood pressure, heart rate and blood oxygenation, serum protein, the erythrocyte count, hemoglobin and hematocrit, serum creatinine and creatinine clearance) and categorical (gender and the type of opioid) covariates on the pharmacokinetic and pharmacodynamic parameters was investigated. PK/PD analysis was performed using NONMEM. All the screened covariates did not influence propofol PK and PD, except of the opioid type. The central compartment volume of propofol was larger in the presence of remifentanil than in the presence of alfentanil.

The pharmacokinetics and hypoglycaemic effect of sunitinib in the diabetic rabbits.

BACKGROUND Diabetes is one of the most common metabolic diseases in the world, which may influence changes in the pharmacokinetics and pharmacodynamics of drugs. Sunitinib is a tyrosine kinase inhibitor (TKI) broadly used for treatment of numerous cancers, which exhibits the side hypoglycaemic effect. The aim of the study was a comparison of concentrations and pharmacokinetics of sunitinib after a single administration in rabbits with hyperglycaemia and normoglycaemia (control group). Additionally, the effect of sunitinib on glucose levels was investigated. METHODS The research was carried out on a control group (n=6) and a group of rabbits with diabetes (n=6). The rabbits were treated with sunitinib in the oral dose of 25mg. Plasma concentrations of sunitinib and its metabolite (SU12662) were measured with validated HPLC method with UV detection. RESULTS The comparison of the sunitinib Cmax and AUC0-∞ in the diabetic group with the control group gave the ratios of 1.63 [90% confidence interval (CI) [1.59; 1.66] and 2.03 [1.97; 2.09], respectively. Statistically significant differences between the analyzed groups were revealed for Cmax (p=0.006), AUC0-∞ (p=0.0088), and AUCkel (p=0.009). The maximum glycaemia drop of 14.4-69.6% and 15.4-33.5% was observed in the diabetic animals and in the control group, respectively. The glycaemia values returned to the initial values in 24h after the administration of the drug. CONCLUSIONS The research proved the significant influence of diabetes on the pharmacokinetics of sunitinib and it confirmed the hypoglycaemic effect of the TKI in diabetic rabbits and in normoglycaemia.

Pharmacokinetics of sufentanil during long‐term infusion in critically ill pediatric patients

The aim of this study was to develop a population pharmacokinetic model of sufentanil and to assess the influence of covariates in critically ill children admitted to a pediatric intensive care unit. After institutional approval, 41 children were enrolled in the study. Blood samples for pharmacokinetic (PK) assessment were collected from routinely placed arterial catheters during and after discontinuation of infusion. Population nonlinear mixed‐effects modeling was performed using NONMEM. A 2‐compartment model described sufentanil PK sufficiently. Typical values of the central and peripheral volume of distribution and the metabolic and intercompartmental clearance for a theoretical patient weighing 70 kg were VC = 7.90 l, VT = 481 L, Cl = 45.3 L/h, and Q = 38.3 L/h, respectively. High interindividual variability of all PK parameters was noted. Allometric/isometric principles to scale sufentanil PK revealed that to achieve the same steady‐state sufentanil concentrations in plasma for pediatric patients of different body weights, the infusion rate should follow the formula (infusion rate for a 70‐kg adult patient, μg/h) × (body weight/70 kg)0.75. Severity of illness described by PRISM score, the monitored physiological and laboratory parameters, and coadministered drugs such as vasopressors were not found to be significant covariates.

The physical and chemical stability of cisplatin (Teva) in concentrate and diluted in sodium chloride 0.9

Aim of the study The subject of study was the stability of cisplatin in concentrate in glass vials and diluted in polyethylene (PE) bags stored at 15–25°C for up to 30 days. Material and methods Original vials of cisplatin injection (1 mg/ml, Teva) were stored at room temperature and subjected to re-piercing after 1, 2, 3, 7, 14, 21, 28 and 30 days following the initial piercing. Cisplatin infusions at nominal concentrations of 0.1 mg/ml were prepared in 0.9% sodium chloride (1000 ml) in PE bags. Chemical stability was measured by means of a stability-indicating high-performance liquid chromatography (HPLC) assay. Physical stability was assessed by visual inspection in normal light. Results The concentration of cisplatin at each sampling time in the analysed solutions remained within 92.0–100.7% of initial concentration, regardless of the container. No changes in colour or turbidity were observed in any of the vials or prepared solutions. Conclusions Cisplatin, both undiluted in glass containers and diluted with NaCl 0.9% in PE bags, remains stable (< 10% degradation) for at least 30 days at room temperature when protected from light.