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1.
Cancers (Basel) ; 16(2)2024 Jan 11.
Article in English | MEDLINE | ID: mdl-38254816

ABSTRACT

Prostate cancer (PCa) is the fourth most frequently diagnosed cancer worldwide, accounting for 7.3% of all cancers. PCa mortality is the fifth most common cause of cancer death. Despite well-known factors influencing the development of PCa, such as age, race/ethnicity and family history, many researchers have raised the possibility of persistent infections with oncogenic viruses. Therefore, we aimed to assess the frequency of Epstein-Barr virus (EBV) DNA in tissue collected from PCa patients. Next, the frequency and the level of Epstein-Barr virus capsid antigen (EBVCA) and Epstein-Barr nuclear antigen 1 (EBNA1) antibodies in both IgA and IgG classes were measured. The antibody titer was also analyzed depending on the risk group, Gleason score (GS) and tumor, node, metastasis (TNM) classification. Serum samples were analyzed using the Microblot-Array EBV IgM, IgA and IgG test kits. The study group consisted of 115 patients diagnosed and histopathologically confirmed with PCa. In 49% of patients included in the study, EBV DNA was detected in the tumor tissue. The studies showed both higher seroprevalence and higher antibody titers in patients with EBV-positive PCa compared to patients with EBV-negative PCa. We also observed a dependence of antibody titer on pathological features, such as GS, risk group and T stage.

2.
Vaccines (Basel) ; 11(4)2023 Mar 30.
Article in English | MEDLINE | ID: mdl-37112682

ABSTRACT

Cancer is an important public health problem. Prostate cancer is one of the most common cancers among men. In Poland, the incidence of this type of cancer is constantly growing. Considering the appearance of a new coronavirus in December 2019 (SARS-CoV-2) and the fact that oncology patients, including those with prostate cancer, are particularly vulnerable to infection, it is recommended to get vaccinated against COVID-19. In our study, we determined the level and prevalence of antibodies against SARS-CoV-2 IgG in patients with prostate cancer compared to the control group and whether the patients' ages affected the level of antibodies. PCa patients and controls were divided into two age groups: 50-59 years and 60-70 years. We also analyzed the level of antibodies in patients belonging to the relevant risk groups for prostate cancer (the European Society of Urology risk group classification of prostate cancer). For the study, we used the Microblot-Array COVID-19 IgG test to detect antibodies against the three main SARS-CoV-2 antigens: NCP, RBD, and S2. Our results showed that prostate cancer patients had significantly lower levels of anti-SARS-CoV-2 IgG antibodies compared to controls. In addition, age also affected the decrease in the number of IgG antibodies. The level of antibodies in the intermediate/high-risk group was lower compared to the low-risk group.

3.
Antioxidants (Basel) ; 11(1)2022 Jan 11.
Article in English | MEDLINE | ID: mdl-35052650

ABSTRACT

Recent years have seen remarkable progress in research into free radicals oxidative stress, particularly in the context of post-ischemic recirculation brain injury. Oxidative stress in post-ischemic tissues violates the integrity of the genome, causing DNA damage, death of neuronal, glial and vascular cells, and impaired neurological outcome after brain ischemia. Indeed, it is now known that DNA damage and repair play a key role in post-stroke white and gray matter remodeling, and restoring the integrity of the blood-brain barrier. This review will present one of the newly characterized mechanisms that emerged with genomic and proteomic development that led to brain ischemia to a new level of post-ischemic neuropathological mechanisms, such as the presence of amyloid plaques and the development of neurofibrillary tangles, which further exacerbate oxidative stress. Finally, we hypothesize that modified amyloid and the tau protein, along with the oxidative stress generated, are new key elements in the vicious circle important in the development of post-ischemic neurodegeneration in a type of Alzheimer's disease proteinopathy.

4.
Eur J Cancer Prev ; 24(2): 122-7, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25187206

ABSTRACT

A number of single nucleotide polymorphisms (SNPs) in the human genome have been associated with increased risk of prostate cancer. Recently, a single SNP in the region of chromosome 8q24 (rs188140481) has been associated with a three-fold increased risk of prostate cancer in Europe and North America. To establish whether rs188140481 is associated with the risk of prostate cancer in Poland, we genotyped 3467 men with prostate cancer and 1958 controls. The A allele of rs188140481 was detected in 44 of 3467 (1.3%) men with prostate cancer and in seven of 1958 (0.4%) controls (odds ratio=3.6; 95% confidence interval 1.6-7.9; P=0.0006). The allele was present in eight of 390 (2.1%) men with familial prostate cancer (odds ratio=5.8; 95% confidence interval 2.1-16.2; P=0.001). A positive family history of cancers at sites other than the prostate was observed in 27% of men who carried the rs188140481 risk allele and in 44% of noncarriers (P=0.04). No cancer at a site other than the prostate was more common in first-degree or second-degree relatives of carriers of the rs188140481 risk allele than relatives of noncarriers. The rs188140481 polymorphism in the 8q24 region confers a moderate increase in the risk of prostate cancer in Polish men. The SNP does not appear to be associated with susceptibility to cancers of other types.


Subject(s)
Chromosomes, Human, Pair 8/genetics , Prostatic Neoplasms/genetics , White People/genetics , Adult , Aged , Aged, 80 and over , Case-Control Studies , Gene Frequency , Genetic Predisposition to Disease , Genotype , Heterozygote , Humans , Male , Middle Aged , Pedigree , Poland , Polymorphism, Single Nucleotide
5.
Pharmacol Rep ; 66(3): 399-403, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24905515

ABSTRACT

BACKGROUND: Identification of new molecular targets as well as the new models recapitulating different aspects of pathophysiology of status epilepticus (SE) in humans might prove essential for the breakthrough in the efforts against pharmacoresistance in epilepsy. Recently, we described a new model of generalized convulsive SE induced with orphenadrine (ORPH) in rats with unique characteristics [5]. The current study was aimed at assessing the efficacy of a new generation antiepileptic drugs (AEDs) and some of the experimental agents in suppressing ORPH-evoked seizures in rats. METHODS: ORPH was administered intraperitoneally (ip) in the dose of 80 mg/kg in male Wistar rats. The latency to first seizure, the number of seizure episodes and the duration of overt SE, as well as the incidence of deaths was scored with simultaneous electroencephalographic (EEG) recordings. RESULTS: ORPH induced seizures in 100% of animals at a dose of 80 mg/kg, associated with low mortality and good behavioural outcome. Among new generation AEDs: felbamate, levetiracetam, topiramate, lamotrigine and progabide did not affect the seizure incidence. Among the experimental drugs, only dizocilpine, the non-competitive NMDA antagonist, dose-dependently affected the occurrence of the SE (p<0.001). However, CGP-39551 competitive NMDA antagonist, the same as scopolamine and mecamylamine (muscarinic and nicotinic receptors antagonists, respectively) showed no effect. CONCLUSIONS: Based on the above findings, one may speculate that NMDA activation is partly involved in the proconvulsant activity of orphenadrine but may not be the primary pathomechanism. ORPH-induced seizures may provide an interesting option for studying novel targets for pharmacological interventions in status epilepticus.


Subject(s)
Dizocilpine Maleate/pharmacology , N-Methylaspartate/antagonists & inhibitors , Orphenadrine/pharmacology , Status Epilepticus/chemically induced , Status Epilepticus/drug therapy , 2-Amino-5-phosphonovalerate/analogs & derivatives , Animals , Anticonvulsants/pharmacology , Electroencephalography/methods , Hippocampus/drug effects , Hippocampus/metabolism , Male , N-Methylaspartate/metabolism , Rats , Rats, Wistar , Seizures/drug therapy , Seizures/metabolism , Status Epilepticus/metabolism
6.
Int J Cancer ; 134(5): 1139-46, 2014 Mar 01.
Article in English | MEDLINE | ID: mdl-24037955

ABSTRACT

Several single nucleotide polymorphisms (SNPs) have been associated with an elevated risk of prostate cancer risk. It is not established if they are useful in predicting the presence of prostate cancer at biopsy or if they can be used to define a low-risk group of men. In this study, 4,548 men underwent a prostate biopsy because of an elevated prostate specific antigen (PSA; ≥4 ng/mL) or an abnormal digital rectal examination (DRE). All men were genotyped for 11 selected SNPs. The effect of each SNP, alone and in combination, on prostate cancer prevalence was studied. Of 4,548 men: 1,834 (40.3%) were found to have cancer. A positive association with prostate cancer was seen for 5 of 11 SNPs studied (rs1800629, rs1859962, rs1447295, rs4430796, rs11228565). The cancer detection rate rose with the number of SNP risk alleles from 29% for men with no variant to 63% for men who carried seven or more risk alleles (OR = 4.2; p = 0.002). The SNP data did not improve the predictive power of clinical factors (age, PSA and DRE) for detecting prostate cancer (AUC: 0.726 vs. 0.735; p = 0.4). We were unable to define a group of men with a sufficiently low prevalence of prostate cancer that a biopsy might have been avoided. In conclusion, our data do not support the routine use of SNP polymorphisms as an adjunct test to be used on the context of prostate biopsy for Polish men with an abnormal screening test.


Subject(s)
Polymorphism, Single Nucleotide , Prostate/pathology , Prostatic Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , Alleles , Area Under Curve , Biopsy , Digital Rectal Examination , Humans , Male , Middle Aged , Prostate-Specific Antigen/blood , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology
7.
Gene ; 532(2): 173-6, 2013 Dec 15.
Article in English | MEDLINE | ID: mdl-24096176

ABSTRACT

BACKGROUND: Germline mutations of BRCA2 and NBS1 genes cause inherited recessive chromosomal instability syndromes and predispose to prostate cancer of poor prognosis. Mutations of the BLM gene cause another chromosomal instability clinical syndrome, called Bloom syndrome. Recently, a recurrent truncating mutation of BLM (Q548X) has been associated with a 6-fold increased risk of breast cancer in Russia, Belarus and Ukraine, but its role in prostate cancer etiology and survival has not been investigated yet. METHODS: To establish whether the Q548X allele of the BLM gene is present in Poland, and whether this allele predisposes to poor prognosis prostate cancer, we genotyped 3337 men with prostate cancer and 2604 controls. RESULTS: Q548X was detected in 13 of 3337 (0.4%) men with prostate cancer compared to 15 of 2604 (0.6%) controls (OR=0.7; 95% CI 0.3-1.4). A positive family history of any cancer in a first- or second-degree relative was seen only in 4 of the 13 (30%) mutation positive families, compared to 49% (1485/3001) of the non-carrier families (p=0.3). The mean follow-up was 49months. Survival was similar among carriers of Q548X and non-carriers (HR=1.1; p=0.9). The 5-year survival for men with a BLM mutation was 83%, compared to 72% for mutation-negative cases. CONCLUSIONS: BLM Q548X is a common founder mutation in Poland. We found no evidence that this mutation predisposes one to prostate cancer or affect prostate cancer survival. However, based on the observed 0.6% population frequency of the Q548X allele, we estimate that one in 100,000 children should be affected by Bloom syndrome in Poland.


Subject(s)
Codon, Nonsense , Prostatic Neoplasms/genetics , RecQ Helicases/genetics , Adult , Aged , Aged, 80 and over , Case-Control Studies , DNA Mutational Analysis , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Prostatic Neoplasms/mortality , Risk Factors , Survival Analysis , Young Adult
8.
Prostate ; 73(5): 542-8, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23334858

ABSTRACT

BACKGROUND: The G84E mutation in the HOXB13 gene has been associated with a high lifetime risk of prostate cancer in North America (about 20-fold). The geographical and ethnic extent of this recurrent allele has not yet been determined. METHODS: We assayed for the presence of the G84E mutation in 3,515 prostate cancer patients and 2,604 controls from Poland and estimated the odds ratio for prostate cancer associated with the allele. RESULTS: The G84E mutation was detected in 3 of 2,604 (0.1%) individuals from the general population in Poland and in 20 of 3,515 (0.6%) men with prostate cancer (Odds ratio [OR] = 5.0; 95% CI: 1.5-16.7; P = 0.008). The allele was present in 4 of 416 (1.0%) men with familial prostate cancer (OR = 8.4, 95% CI: 1.9-37.7; P = 0.005). CONCLUSIONS: The G84E mutation predisposes to prostate cancer in Poland, but accounts for only a small proportion of cases. We expect that the G84E founder mutation might be present in other Slavic populations.


Subject(s)
Homeodomain Proteins/genetics , Point Mutation/genetics , Prostatic Neoplasms/ethnology , Prostatic Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Genetic Predisposition to Disease/ethnology , Genetic Predisposition to Disease/genetics , Genotype , Humans , Male , Middle Aged , Odds Ratio , Pedigree , Poland/epidemiology , Risk Factors , White People/genetics , White People/statistics & numerical data
9.
Cent European J Urol ; 66(2): 159-62, 2013.
Article in English | MEDLINE | ID: mdl-24579018

ABSTRACT

Small cell carcinomas of the urinary bladder originating from the neuroendocrine cells are extremely rare. We present a case of a 76-year-old patient with small cell carcinoma of the urinary bladder. The patient had hematuria and cystoscopy revealed a tumor located in a urinary bladder diverticulum. Partial resection of the bladder wall with diverticulectomy was performed. Microscopic examination established the diagnosis of neuroendocrine carcinoma, which was confirmed by immunohistochemistry. Three-month follow-up showed no recurrent disease. Patient refused further chemotherapy and radiotherapy.

10.
Amino Acids ; 43(4): 1663-70, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22349835

ABSTRACT

Kidneys possess a complex enzyme system which plays a major role in tryptophan metabolism. Taking into account a considerably high concentration of one of the tryptophan metabolites, kynurenic acid (KYNA) in this organ and previously reported antiproliferative activity against colon cancer cells in vitro, we measured its content in human normal and tumour kidney tissue. KYNA concentration was considerably higher in normal renal tissue (379.7 ± 39.7 pmol/g wet weight) than in renal cell carcinomas (115.5 ± 20.8 pmol/g wet weight). In in vitro experiments, KYNA in higher micro- and millimolar concentrations significantly inhibited proliferation, DNA synthesis and migration of renal cancer Caki-2 cells. Our results suggest that KYNA may affect cell cycle regulators and signalling pathways through overexpression of p21 Waf1/Cip1 and inhibition of phosphorylation of Rb protein and p38 MAPK. In conclusion, KYNA may be suggested as an endogenous agent, controlling the growth of tumour, or a chemopreventive agent.


Subject(s)
Carcinoma, Renal Cell/chemistry , Kidney Neoplasms/chemistry , Kidney/chemistry , Kynurenic Acid/metabolism , Kynurenic Acid/pharmacology , Adult , Aged , Biopsy , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Chromatography, High Pressure Liquid , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Female , Gene Expression/drug effects , Humans , Kidney/pathology , Kidney Neoplasms/pathology , Male , Middle Aged , Retinoblastoma Protein/genetics , Retinoblastoma Protein/metabolism , Signal Transduction/drug effects , p21-Activated Kinases/genetics , p21-Activated Kinases/metabolism , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolism
11.
Pharmacol Rep ; 63(3): 690-6, 2011.
Article in English | MEDLINE | ID: mdl-21857079

ABSTRACT

Nefopam is a centrally acting non-opioid analgesic with a mechanism of action that is not completely understood. Adverse effects associated with the therapeutic use and overdose of nefopam are mainly associated with the central nervous system, such as hallucinations, cerebral edema and convulsions. The aim of this study was to assess the effect of nefopam on the electrical threshold and its influence on the protective activity of antiepileptic drugs in the maximal electroshock test in mice. A 5 mg/kg dose of nefopam significantly elevated the electric seizure threshold, while a dose of 1 mg/kg failed to protect mice against electroconvulsion. At a subthreshold dose of 1 mg/kg, nefopam significantly enhanced the anticonvulsant activity of valproate against electroconvulsions. The protective activity of phenobarbital and phenytoin was significantly enhanced by co-administration of nefopam at the 5 mg/kg dose, but this same dose of nefopam failed to affect the protective activity of carbamazepine. In conclusion, nefopam exerts an anticonvulsive effect when given alone and significantly enhances the protective activity of certain antiepileptic agents against electroconvulsions induced in mice.


Subject(s)
Analgesics, Non-Narcotic/pharmacology , Anticonvulsants/pharmacology , Nefopam/pharmacology , Seizures/prevention & control , Analgesics, Non-Narcotic/administration & dosage , Animals , Dose-Response Relationship, Drug , Drug Synergism , Electroshock , Male , Mice , Nefopam/administration & dosage
12.
Brain Res Bull ; 84(6): 389-93, 2011 Apr 05.
Article in English | MEDLINE | ID: mdl-21272614

ABSTRACT

The current study was aimed to assess the convulsant potency of orphenadrine (ORPH) in rats together with a screen of different conventional antiepileptic drugs (AEDs) on their efficacy to suppress it. ORPH was administered intraperitoneally (i.p.) in doses of 50-80 mg/kg in male Wistar rats. The latency to first seizure, the number of seizure episodes and the duration of overt status epilepticus (SE) as well as the incidence of deaths was scored with simultaneous electroencephalographic (EEG) recordings. Subsequently, the effects of conventional AEDs on ORPH-evoked (80 mg/kg) seizure incidence were studied. ORPH dose-dependently induced seizures in increasing number of animals, reaching 100% at a dose of 80 mg/kg, associated with low mortality and no drug-related neurotoxicity. Epileptic attacks started as complex partial fits consisting of stereotyped behavior, limb movements, head shaking and myoclonic twitches of the body. Subsequently, an overt generalized convulsive SE appeared, lasting for approximately 2h. Among conventional AEDs: carbamazepine, ethosuximide and phenytoin had no effect while valproate (p<0.001), diazepam (p<0.01), and phenobarbital (p<0.001) dose-dependently suppressed seizure activity. All the above characteristics make the new model, a useful, easy to perform experimental tool to study the pathophysiology of SE as well as the effects of new AEDs.


Subject(s)
Orphenadrine/adverse effects , Status Epilepticus/chemically induced , Animals , Anticonvulsants/therapeutic use , Antiparkinson Agents/adverse effects , Dose-Response Relationship, Drug , Electroencephalography , Humans , Male , Random Allocation , Rats , Rats, Wistar , Status Epilepticus/drug therapy
13.
Epilepsy Res ; 88(2-3): 269-74, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20015615

ABSTRACT

In this study we investigated the effectiveness of two antiepileptic drugs: riluzole and topiramate against pilocarpine-induced seizures, which are considered to be a model of intractable epilepsy commonly used to investigate the antiepileptic effect of drugs and mechanisms of epileptogenesis. Seizures and status epilepticus were induced by pilocarpine in adult male Wistar rats. Riluzole (1-4mg/kg) administered intraperitoneally before pilocarpine dose-dependently protected rats against seizures with the anticonvulsant ED(50) value (50% effective anticonvulsant dose) of 1.8 (1.3-2.6)mg/kg. In contrast, riluzole at 8 and 12mg/kg administered after the onset of pilocarpine-induced seizures affected neither status epilepticus nor mortality of rats. Topiramate significantly enhanced convulsive action of pilocarpine, lowering the convulsant CD(50) value (50% effective convulsant dose) of pilocarpine from 350.8 (329.2-373.8) to 246.4 (218.6-278.2)mg/kg. Riluzole (4mg/kg) lowered plasma and brain concentration of pilocarpine administered at a dose of 400mg/kg from 168.0+/-8.6 to 75.3+/-19.9microg/ml and from 193.7+/-6.6 to 97.0+/-26.1microg/g, respectively. Topiramate (200mg/kg) increased plasma and brain concentration of pilocarpine administered at a dose of 300mg/kg from 78.1+/-2.9 to 106.0+/-6.8microg/ml and from 138.4+/-5.0 to 155.2+/-5.1microg/g, respectively. It seems that both anticonvulsant effect exerted by riluzole and proconvulsant effect exerted by topiramate in pilocarpine model of seizures are due to a pharmacokinetic interaction. Therefore, we postulate that the concentration of pilocarpine should be measured routinely whenever the anticonvulsant effect of drugs is determined in the pilocarpine model of seizures.


Subject(s)
Fructose/analogs & derivatives , Pilocarpine/pharmacokinetics , Riluzole/pharmacokinetics , Seizures/chemically induced , Status Epilepticus/chemically induced , Animals , Anticonvulsants/pharmacokinetics , Brain/drug effects , Brain/metabolism , Chromatography, High Pressure Liquid , Convulsants/pharmacokinetics , Drug Interactions , Fructose/pharmacokinetics , Male , Rats , Rats, Wistar , Seizures/drug therapy , Seizures/metabolism , Status Epilepticus/drug therapy , Status Epilepticus/metabolism , Topiramate
14.
Pharmacol Rep ; 61(4): 732-6, 2009.
Article in English | MEDLINE | ID: mdl-19815957

ABSTRACT

Orphenadrine is an anticholinergic drug used in the treatment of Parkinson's disease, and is also known to exert nonspecific antagonistic activity at the phencyclidine binding site of the N-methyl-D-aspartate (NMDA) receptor. The aim of this study was to assess the anticonvulsant properties of orphenadrine and to evaluate its effect on the anticonvulsant activity of antiepileptic drugs against maximal electroshock-induced seizures in mice. Orphenadrine given at a dose of 5.65 mg/kg elevated the electrical seizure threshold from 5.7 (5.4-6.1) to 6.8 (6.3-7.3) mA, while a dose of 2.8 mg/kg was ineffective. The ED(50) values of orphenadrine administered 10, 30 and 120 min before maximal electroshock-induced convulsions were 16.8 (11.3-25.1), 17.8 (15.7-20.0) and 25.6 (23.3-28.3) mg/kg, respectively. Orphenadrine at a sub-threshold dose of 2.8 mg/kg significantly enhanced the anticonvulsant activity of valproate by reducing its ED(50) value from 315.8 (270.0-369.4) to 245.9 (207.1-292.0) mg/kg without affecting the free plasma levels of valproate. However, orphenadrine failed to enhance the protective activity of carbamazepine, phenytoin, phenobarbital, lamotrigine, topiramate, or oxcarbazepine against maximal electroshock-induced seizures.


Subject(s)
Anticonvulsants/therapeutic use , Electroshock , Neuroprotective Agents/therapeutic use , Orphenadrine/therapeutic use , Seizures/prevention & control , Animals , Anticonvulsants/blood , Drug Synergism , Electroshock/methods , Male , Mice , Neuroprotective Agents/blood , Orphenadrine/blood , Random Allocation , Seizures/blood
15.
Ann Neurol ; 64(4): 434-45, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18991352

ABSTRACT

OBJECTIVE: Sedative and anticonvulsant drugs, which inhibit N-methyl-D-aspartate receptor-mediated excitation or enhance GABA-mediated action, may cause apoptotic neurodegeneration in the developing mammalian brain. Here we explored whether such agents influence early postnatal neurogenesis. METHODS: The N-methyl-D-aspartate antagonist MK801 and the GABA subtype A agonists phenobarbital and diazepam were administered to infant rats, and cell proliferation and neurogenesis were studied in the brain using 5-bromo-2'-deoxyuridine and doublecortin immunohistochemistry and stereology. Using confocal microscopy, we quantified neurogenesis in the dentate gyrus on postnatal day 15 (P15) after treatment with MK801 or phenobarbital on P6 to P10. Learning and memory were assessed at the age of 6 months after early postnatal treatment with phenobarbital. RESULTS: MK801, phenobarbital, and diazepam reduced numbers of newly born cells in the brain. We found no evidence that these agents caused apoptosis of 5-bromo-2'-deoxyuridine-positive cells. In the dentate gyrus, many of the newly formed cells differentiated toward a neuronal phenotype. Phenobarbital and MK801 reduced numbers of newly formed neurons in the dentate gyrus. At the age of 6 months, phenobarbital-treated rats had fewer neurons in the dentate gyrus and performed worse than saline-treated littermates in water maze learning and memory task. INTERPRETATION: These findings show that blockade of N-methyl-D-aspartate receptor-mediated excitation and enhancement of GABA subtype A receptor activation impair cell proliferation and inhibit neurogenesis in the immature rat brain. Because many sedative and antiepileptic drugs used in pediatric medicine act via these mechanisms, our findings raise concerns about their potential impact on human brain development.


Subject(s)
Anticonvulsants/pharmacology , Hypnotics and Sedatives/pharmacology , Neurogenesis/drug effects , Age Factors , Analysis of Variance , Animals , Animals, Newborn , Apoptosis/drug effects , Behavior, Animal/drug effects , Bromodeoxyuridine/metabolism , Cell Count/methods , Cell Proliferation/drug effects , Doublecortin Protein , Female , Hippocampus/anatomy & histology , Male , Maze Learning/drug effects , Rats , Rats, Wistar , Time Factors
16.
Pol J Pharmacol ; 56(1): 67-72, 2004.
Article in English | MEDLINE | ID: mdl-15047979

ABSTRACT

Allopurinol, an inhibitor of xanthine oxidase, is indicated in the management of patients with elevated serum and urinary uric acid levels. It was also reported to be beneficial in patients with epilepsy when added to traditional antiepileptic drug. Here, we investigated the effect of allopurinol upon the electrical seizure threshold and its effect on the protective efficacy of common antiepileptic drugs, carbamazepine (CBZ) and valproate (VPA) against maximal electroshock (MES)-induced convulsions in mice. We found that allopurinol administered at doses of 5, 15 or 45 mg/kg, did not affect electrical seizure threshold. When administered acutely or for a prolonged period of time (5 times every 24 h), it did not affect anticonvulsant activity of CBZ and VPAin MES. Free plasma concentration of both anticonvulsants was not affected by allopurinol given at a dose of 45 mg/kg for 5 days. Thus, our results did not support suggestions that allopurinol can be beneficial as add-on drug in the management of epilepsy at least in patients treated with CBZ or VPA.


Subject(s)
Allopurinol/therapeutic use , Anticonvulsants/therapeutic use , Carbamazepine/therapeutic use , Electroshock/methods , Seizures/etiology , Valproic Acid/therapeutic use , Allopurinol/pharmacology , Animals , Body Weight/drug effects , Carbamazepine/blood , Drug Administration Schedule , Drug Evaluation, Preclinical/methods , Injections, Intraperitoneal , Male , Mice , Poland , Seizures/drug therapy , Seizures/physiopathology , Time Factors , Valproic Acid/blood , Xanthine Oxidase/antagonists & inhibitors , Xanthine Oxidase/therapeutic use
17.
Pharmacol Biochem Behav ; 75(2): 319-27, 2003 May.
Article in English | MEDLINE | ID: mdl-12873622

ABSTRACT

Tiagabine (TGB), a new potent gamma-aminobutyric acid (GABA) uptake inhibitor, is widely applied in adjunctive treatment of partial seizures in humans. Although, polytherapy is not an initial method of epilepsy treatment, clinicians often combine TGB with other antiepileptics as add-on therapy for assuring the anticonvulsant protection in patients with refractory seizures. To evaluate the character of pharmacological interactions between TGB and some antiepileptics, the isobolographic analysis was used as a suitable method for determining the exact types of interactions. Determination of an influence of TGB on the protective effects of diphenylhydantoin (DPH), carbamazepine (CBZ), valproate (VPA), phenobarbital (PB), lamotrigine (LTG), topiramate (TPM), and felbamate (FBM) in maximal electroshock-induced seizures was essential for this study. To exclude or confirm a pharmacokinetic character of observed interactions, the free plasma and brain concentrations of antiepileptic drugs (AEDs) studied were evaluated by using the immunofluorescence or high-pressure liquid chromatography (HPLC).TGB (up to 2.5 mg/kg) remained ineffective upon the electroconvulsive threshold, whilst the drug in doses of 5 and 10 mg/kg significantly raised the electroconvulsive threshold in mice. According to the isobolography, TGB appears to act synergistically with VPA. The remaining combinations tested exerted additive interactions. A pharmacokinetic character of interaction between TGB and VPA was evidently corroborated either in plasma or brains. Moreover, TGB significantly reduced the plasma and brain concentrations of DPH; however, pharmacokinetic events were not accompanied by any changes in anticonvulsant activity of the latter. Finally, the isobolographic analysis revealed that combinations of TGB with VPA exerted synergistic (supra-additive) interaction resulting from a pharmacokinetic interaction.


Subject(s)
Anticonvulsants/pharmacology , Electroshock , Nipecotic Acids/pharmacology , Seizures/prevention & control , Animals , Anticonvulsants/blood , Brain/metabolism , Chromatography, High Pressure Liquid , Data Interpretation, Statistical , Drug Synergism , Fluorescent Antibody Technique , Male , Mice , Motor Activity/drug effects , Nipecotic Acids/blood , Psychomotor Performance/drug effects , Spectrophotometry, Ultraviolet , Tiagabine
18.
Epilepsia ; 44(8): 1003-13, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12887431

ABSTRACT

PURPOSE: The study investigated the types of interactions between lamotrigine (LTG) and first-generation antiepileptic drugs (AEDs) or topiramate (TPM) with isobolographic analysis. METHODS: Anticonvulsant and adverse-effect profiles of combinations of LTG with other AEDs, at fixed ratios of 1:3, 1:1, and 3:1, were evaluated in the maximal electroshock (MES)-induced seizures and the chimney test (motor performance) in mice, which allowed the determination of benefit indices (BIs) for individual combinations. RESULTS: Combinations of LTG with TPM or valproate (VPA), at fixed ratios of 1:1, were significantly supraadditive (synergistic) in the MES test and, simultaneously, subadditive (antagonistic) in the chimney test, showing the best profile for AED combinations. In contrast, combinations between LTG and carbamazepine (CBZ), in terms of antiseizure protection against MES, were subadditive (antagonistic) and additive in the chimney test, resulting in unfavorable AED combinations. Moreover, the combination of LTG with phenobarbital (PB), at a fixed ratio of 1:1, despite synergy in the MES test, also was synergistic in the chimney test, resulting in a modest BI for AED combination. LTG combined with phenytoin was additive in both the MES and chimney tests in mice. The remaining combinations, at fixed ratios not mentioned earlier, also showed an average BI for AED combinations. Furthermore, LTG combined with all studied AEDs did not affect long-term memory in mice. None of the AEDs influenced the free plasma level of LTG, whereas LTG slightly reduced the free plasma concentration of PB. CONCLUSIONS: Interactions between LTG and TPM or LTG and VPA at a fixed ratio of 1:1 might be profitable from a preclinical point of view, displaying the most optimal BI.


Subject(s)
Anticonvulsants/toxicity , Epilepsy/physiopathology , Fructose/analogs & derivatives , Fructose/toxicity , Triazines/toxicity , Animals , Anticonvulsants/pharmacokinetics , Dose-Response Relationship, Drug , Drug Interactions , Electroshock , Epilepsy/blood , Fructose/pharmacokinetics , Lamotrigine , Male , Mice , Motor Skills/drug effects , Topiramate , Triazines/pharmacokinetics
19.
Pol J Pharmacol ; 55(5): 799-802, 2003.
Article in English | MEDLINE | ID: mdl-14704477

ABSTRACT

Nicotine administered acutely at subconvulsive dose of 4 mg/kg, significantly decreased the protective activity of valproate, carbamazepine, diphenylhydantoin, phenobarbital, topiramate and lamotrigine against maximal electroshock-induced tonic convulsions in mice. The obtained data may suggest that interaction between nicotine and antiepileptic drugs should be carefully considered as a cause of the therapeutic failure in epileptic patients.


Subject(s)
Anticonvulsants/antagonists & inhibitors , Fructose/analogs & derivatives , Nicotine/administration & dosage , Nicotine/adverse effects , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/pharmacokinetics , Carbamazepine/administration & dosage , Carbamazepine/antagonists & inhibitors , Carbamazepine/pharmacokinetics , Dose-Response Relationship, Drug , Drug Interactions , Electroshock , Fructose/administration & dosage , Fructose/antagonists & inhibitors , Fructose/pharmacokinetics , Humans , Injections, Intraperitoneal , Lamotrigine , Mice , Nicotine/pharmacokinetics , Phenobarbital/administration & dosage , Phenobarbital/antagonists & inhibitors , Phenobarbital/pharmacokinetics , Phenytoin/administration & dosage , Phenytoin/antagonists & inhibitors , Phenytoin/pharmacokinetics , Seizures/chemically induced , Seizures/physiopathology , Seizures/prevention & control , Topiramate , Triazines/administration & dosage , Triazines/antagonists & inhibitors , Triazines/pharmacokinetics , Valproic Acid/administration & dosage , Valproic Acid/antagonists & inhibitors , Valproic Acid/pharmacokinetics
20.
Pol J Pharmacol ; 55(5): 803-6, 2003.
Article in English | MEDLINE | ID: mdl-14704478

ABSTRACT

Gabapentin and baclofen at doses not affecting motor performance, produced dose-dependent inhibition of both phases in the formalin test in mice. Isobolographic analysis revealed an additive interaction between the studied drugs in the second phase of the formalin test. Gabapentin given at doses effective in both phases of the formalin test significantly potentiated baclofen-induced motor impairment.


Subject(s)
Acetates/pharmacokinetics , Amines , Baclofen/pharmacokinetics , Cyclohexanecarboxylic Acids , Drug Synergism , Pain Measurement/drug effects , gamma-Aminobutyric Acid , Acetates/administration & dosage , Acetates/therapeutic use , Animals , Baclofen/administration & dosage , Baclofen/adverse effects , Dose-Response Relationship, Drug , Gabapentin , Injections, Intraperitoneal , Mice , Movement Disorders/physiopathology , Pain Measurement/methods
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