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Open access

Mirosław Jasiński, Magdalena Chrościńska-Krawczyk and Stanisław J. Czuczwar

Summary

Background. Adenosine is regarded as an endogenous anticonvulsant and its agonists have been proved to affect the anticonvulsant activity of a number of antiepileptic drugs (AEDs) in animal models of seizures.

Aim. To evaluate effects of adenosine agonists on carbamazepine (CBZ) and valproate (VPA) in mouse model of generalized tonic-clonic convulsions.

Methods. The following adenosine receptor agonists were used: A1 – cyclohexyladenosine, A2A – CGS 21 680, A3 – N6-benzyl-NECA and A1 (preferentially) and A2 – 2-chloroadenosine. Their possible anticonvulsant effects were studied in a threshold electroconvulsive test for maximal electroconvulsions. The protective activity of AEDs alone or in combinations with adenosine agonists was evaluated in the form of their respective ED50 values necessary to protect 50% of mice against tonic extension of the hind limbs, following maximal electroshock, delivered through ear electrodes. The specificity of interactions between AEDs and adenosine agonists was challenged with an adenosine receptor A1 and A2 antagonist, aminophylline (5 mg/kg). The effects of AEDs alone or with adenosine agonists were tested for the occurrence of adverse effects (AE) (impairment of motor coordination) in a chimney test. All combinations with an enhancement the protective activity of CBZ or VPA were verified with the free plasma or brain concentration of these AED.

Results. Adenosine receptor agonists (cycloheksyladenosine up to 4 mg/kg; CGS 21 680 – 8 mg/kg; N6-benzyl-NECA – 1 mg/kg; 2-chloroadenosine – 2 mg/kg) did not significantly affect the threshold for maximal electroconvulsions. Cycloheksyladenosine (1 mg/kg), N6-benzyl-NECA (0.5 and 1 mg/kg) and 2-chloroadenosine (1 mg/kg) potentiated the anticonvulsant activity of CBZ. Valproate’s protective action was enhanced by one adenosine agonist – cycloheksyladenosine (1 mg/kg). Only the combination of CBZ + N6-benzyl-NECA (1 mg/kg) was resistant to aminophylline (5 mg/kg). Pharmacokinetic interactions were evident in case of the combination of CBZ + N6-benzyl-NECA (1 mg/kg) and resulted in an increased free plasma concentration of this CBZ. Interestingly, total brain concentration of CBZ confirmed the pharmacokinetic interaction as regards CBZ + N6-benzyl-NECA (1 mg/kg).

Conclusion. The best profile was shown by the combination of CBZ + 2-chloroadenosine which involved no AE or a pharmacokinetic interaction. The remaining positive combinations in terms of anticonvulsant activity were associated with general profound AE and pharmacokinetic interactions in some of them.

Open access

Borys Kuzminov, Vira Turkina and Yuriy Кuzminov

Abstract

This article presents a retrospective review of data on side effects of drugs containing naphazoline and data on toxicity of the agent when entered the body via different pathways. Most publications on clinical signs of possible naphazoline-associated side effects are lacking thorough analysis of possible causes. Limited data on the pharmacokinetics and pharmacodynamics of the drug led to various complications after its administration. Therefore, further studies on naphazoline content dynamics or products of its biotransformation in biological substrates and determination of half-life of the agent must be conducted. This will allow establishingsafe levels for different exposure pathways and harmful levels of the naphazoline with respect to its material accumulation. It should be noted that scientific publications contain controversial data regarding allergenic potential of the agent. Possible side effects of the drug on the reproductionand development are not revealed. Determination of effects the products containing naphazoline may have on immune and reproductive system is an important part of the research.

Open access

M. Lis, M. Szczypka, A. Suszko, M. Świtała and B. Obmińska-Mrukowicz

References Adams PE, Varma KJ, Powers TE, Lamendola JF ( 1987 ) Tissue concentrations and pharmacokinetics of florfenicol in male veal calves given repeated doses. Am J Vet Res 48: 1725-1732. Afifi NA, Abo el-Sooud, KA ( 1997 ) Tissue concentrations and pharmacokinetics of florfenicol in broiler chickens. Brt Poult Sci 38: 425-428. Ali BH, Al-Qarawi AA, Hashaad M ( 2003 ) Comparative plasma pharmacokinetics and tolerance of florfenicol following intramuscular and intravenous

Open access

Sachin Kokil and Manish Bhatia

References Deeks SG, Bardicht CP, Lietman PS, Hwang F, Cundy KC, Rooney JF, et al. Safety, pharmacokinetics and anti-retroviral activity of intravenous 9-[2-(R)-(phosphonomethoxy)propyl]adenine, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults. Antimicrob Agents Chemother 1998; 42: 2380-4. Shaw JP, Sueoka CM, Oliyai R, Lee WA, Arimilli KM, Kim CU, et al. Metabolism and pharmacokinetics of novel oral prodrugs of 9-[(R)-2-phosphonomethoxypropyl] adenine (PMPA) in dogs. Pharm

Open access

Renata Rezonja Kukec, Iztok Grabnar, Tomaz Vovk, Ales Mrhar, Viljem Kovac and Tanja Cufer

Abstract

Background. Chemotherapy with platinum agent and etoposide for small-cell lung cancer (SCLC) is supposed to be associated with intermediate risk (10-20%) of febrile neutropenia. Primary prophylaxis with granulocyte colonystimulating factors (G-CSFs) is not routinely recommended by the treatment guidelines. However, in clinical practice febrile neutropenia is often observed with standard etoposide/platinum regimen. The aim of this analysis was to evaluate the frequency of neutropenia and febrile neutropenia in advanced SCLC patients in the first cycle of standard chemotherapy. Furthermore, we explored the association between severe neutropenia and etoposide peak plasma levels in the same patients.

Methods. The case series based analysis of 17 patients with advanced SCLC treated with standard platinum/etoposide chemotherapy, already included in the pharmacokinetics study with etoposide, was performed. Grade 3/4 neutropenia and febrile neutropenia, observed after the first cycle are reported. The neutrophil counts were determined on day one of the second cycle unless symptoms potentially related to neutropenia occurred. Adverse events were classified according to Common Toxicity Criteria 4.0. Additionally, association between severe neutropenia and etoposide peak plasma concentrations, which were measured in the scope of pharmacokinetic study, was explored.

Results. Two out of 17 patients received primary GCS-F prophylaxis. In 15 patient who did not receive primary prophylaxis the rates of both grade 3/4 neutropenia and febrile neutropenia were high (8/15 (53.3%) and 2/15 (13.3%), respectively), already in the first cycle of chemotherapy. One patient died due to febrile neutropenia related pneumonia. Neutropenic events are assumed to be related to increased etoposide plasma concentrations after a standard etoposide and cisplatin dose. While the mean etoposide peak plasma concentration in the first cycle of chemotherapy was 17.6 mg/l, the highest levels of 27.07 and 27.49 mg/l were determined in two patients with febrile neutropenia.

Conclusions. Our study indicates that there is a need to reduce the risk of neutropenic events in chemotherapy treated advanced SCLC, starting in the first cycle. Mandatory use of primary G-CSF prophylaxis might be considered. Alternatively, use of improved risk models for identification of patients with increased risk for neutropenia and individualization of primary prophylaxis based on not only clinical characteristics but also on etoposide plasma concentration measurement, could be a new, promising options that deserves further evaluation.

Open access

I. Hodorova, J. Mihalik, J. Vecanova, M. Dankova and S. Rybarova

Renal Ontogeny of P-Glycoprotein/MDR1 in Rat

BACKGROUND: P-glycoprotein (Pgp/MDR1) is an ATP-dependent, integral plasma-membrane efflux pump that is constitutively expressed on adult apical brush-border epithelium of renal proximal tubules. This Pgp/MDR1 tissue distribution and localization affects the absorption, distribution, metabolism, and excretion of Pgp/MDR1 substrates. The ontogeny of rat Pgp/MDR1 is still doubtful, and such knowledge may be helpful in understanding age-related pharmacokinetics. The purpose of this study was to determine, whether Pgp/MDR1 expression is altered during development.

METHODS: Postnatal expression of Pgp was determined using immunohistochemical method. Tissue from Wistar rat were isolated on the 1st day (D1), 7th day (D7), 14th day (D14), 21st day of life (D21) and from adult animals (60 days old; Ad).

RESULTS: Our ontogeny study illustrated that expression of Pgp was relatively constant from birth to adulthood.

CONCLUSIONS: Knowledge of the ontogeny of transport proteins involved in distribution and elimination of drugs is important for adequate interpretation of the results of toxicity studies in juvenile animals.

Open access

José Pimentel

SUMMARY

Background. Monotherapy is the choice regimen to treat newly diagnosed epilepsies. However, if it fails, several strategies may be followed.

Aim. To discuss the treatment options when an initial monotherapy regimen fails.

Methods. We reviewed the relevant literature on the topic by using PubMed.

Review and Discussion. Approximately 64% of people with epilepsy (PWE) de novo are free of seizures with the first appropriate antiepileptic drug (AED) in monotherapy. The type (first versus second generation) of the first AED to use depends on the physician's personal choice provided that it is a first-line AED. There is a tendency to prefer a substitution rather than a combination of a failed first AED when it was produced associated with an idiosyncratic reaction, was poorly tolerated at a moderate dose, or produced no improvement in seizure control. In contrast, there is some evidence to prefer secondary polytherapy whenever the PWE tolerate its first AED but with a suboptimal response. In this case, and particularly mainly if a first generation AED was used as a first-line treatment, I prefer to choose a new generation AED given their more favourable pharmacokinetic and pharmacodynamic profiles. A very often used strategy is transitional polytherapy between two regimens of monotherapy.

Conclusion. Any therapeutic decision should take into account factors such as seizure type or syndrome, possibility of drug side effects, comorbidities, comedications, age, teratogenic potential, and compliance. Whatever the option to be taken, the PWE, his family or the caregivers should take part in the decision making.

Open access

Isidora Stojic, Vladimir Zivkovic, Ivan Srejovic, Nevena Jeremic, Vladimir Jakovljevic, Dragan Djuric and Slobodan Novokmet

Abstract

To date, numerous platinum (II) complexes have been successfully used in the treatment of different types of cancer. Therapeutic platinum complexes are different in terms of their structure, chemical reactivity, solubility, pharmacokinetics and toxicity. The aim of our research was the evaluation of cardiotoxicity of dichloro-(ethylendiamine) platinum (II) in a model of isolated rat heart using the Langedorff technique. Oxidative stress was assessed by determination of superoxide anion radical, hydrogen peroxide, Thiobarbituric Acid Reactive Substances and nitric oxide levels from coronary venous effluent. All reagents were perfused at increasing concentrations from 10-8 to 10-4 M for 30 minutes. In this paper, we report that substances administered at higher doses did not induce dose-dependent effects on oxidative stress markers. The results of this research may be of great interest for future studies in this area. There are many novel platinum compounds that had previously demonstrated antitumour activity, and these types of experiments in our study can assist in the examination of their cardiotoxicity. These results could be helpful for understanding dose-dependent side effects of existing and novel platinum compounds

Open access

Daniela Košťálová, Lýdia Bezáková, Lucia Račkovác, Silvia Mošovská and Ernest Šturdík

Abstract

Extensive research over the past half century has shown that curcumin (diferuloylmethane), a polyphenolic compound of turmeric (Curcuma longa L.), can modulate multiple cell signaling pathways. Extensive clinical trials have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in human. Curcumin, known for thousand years as a subject of Ayurvedic medicine, has undergone in recent times remarkable transformation into a drug candidate with prospective multipotent therapeutic application. Characterized by high chemical reactivity, resulting from an extended conjugated double bond system prone to nucleophilic attack, curcumin has been shown to interact with a plethora of molecular targets, in numerous experimental observations. In clinical trials, has been used either alone or in combination with other agent. However, its clinical advance has been limited by its short biological half-life, fast metabolism and poor systemic bioavailability after oral administration. To mitigate the above limitations, recently various formulation of curcumin, including nanoparticles, micelles, liposomes, phytosomes delivery system has been examined. The present review has been devoted towards better understanding of the phytonutraceutic properties of curcumin and turmeric based on their disease specific indications and enhancing their prophylactic and therapeutic nutraceutical qualities. The article deals with the biological activity, mode of action, toxicity and forthcoming application of these leads.

Open access

P. Hnilicova and D. Dobrota

Nuclear Magnetic Resonance as a Diagnostic Tool in Breast Cancer

The early detection and treatment of breast cancer is of direct benefit to patients. Magnetic resonance imaging (MRI) is a promising modality for detection, diagnosis, and staging of breast cancer. MRI enables two methods: the diffusion-weighted MRI (DW MRI) and the dynamic contrast enhanced MRI (DCE MRI). DW MRI reflects the diffusion of water molecules in the extracellular fluid space and allows the estimation of cellularity and tissue structure. The value of the diffusion of water in tissue is called the apparent diffusion coefficient (ADC). ADC values in malignant lesions are smaller than in benign tissue. DCE MRI yields appropriate pharmacokinetic data of physiological parameters that relate to tissue perfusion, microvascular vessel wall permeability and extracellular volume fraction. Gadolinium based contrast agent is usually used in breast DCE MRI diagnostics. Changes in the post-contrast signal intensity help to distinguish lesions according to characteristically enhanced accumulation of contrast agent. Malignant lesions are characterized by a faster and stronger signal enhancement than benign lesions which relate to their neoangiogenesis. Over the last few years, there has been appreciable interest in the use of magnetic resonance spectroscopy (MRS) for the non-invasive analysis of breast tisue metabolites. One of the spectroscopic hallmarks of the neoplastic process appears to be the presence of total choline signal in the in vivo spectrum. Despite the fact that MRI and MRS achieve excellent results, they are still not so frequently used in comparison to mammography and breast ultrasound.