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BACKGROUND: We developed a 13-mer locked nucleic acid (LNA) inhibitor of miR-221 (LNA-i-miR-221) with a full phosphorothioate (PS)-modified backbone. This agent downregulated miR-221, demonstrated anti-tumor activity against human xenografts in mice, and favorable toxicokinetics in rats and monkeys. Allometric interspecies scaling allowed us to define the first-in-class LNA-i-miR-221 safe starting dose for the clinical translation. METHODS: In this first-in-human, open-label, dose-escalation phase 1 trial, we enrolled progressive cancer patients (aged ≥ 18 years) with ECOG 0-2 into 5 cohorts. The treatment cycle was based on a 30-min IV infusion of LNA-i-miR-221 on 4 consecutive days. Three patients within the first cohort were treated with 2 cycles (8 infusions), while 14 patients were treated with a single course (4 infusions); all patients were evaluated for phase 1 primary endpoint. The study was approved by the Ethics Committee and Regulatory Authorities (EudraCT 2017-002615-33). RESULTS: Seventeen patients received the investigational treatment, and 16 were evaluable for response. LNA-i-miR-221 was well tolerated, with no grade 3-4 toxicity, and the MTD was not reached. We recorded stable disease (SD) in 8 (50.0%) patients and partial response (PR) in 1 (6.3%) colorectal cancer case (total SD + PR: 56.3%). Pharmacokinetics indicated non-linear drug concentration increase across the dose range. Pharmacodynamics demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets. Five mg/kg was defined as the recommended phase II dose. CONCLUSIONS: The excellent safety profile, the promising bio-modulator, and the anti-tumor activity offer the rationale for further clinical investigation of LNA-i-miR-221 (ClinTrials.Gov: NCT04811898).
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MicroARNs , Neoplasias , Humanos , MicroARNs/genética , MicroARNs/uso terapéutico , Neoplasias/tratamiento farmacológico , Oligonucleótidos/uso terapéuticoRESUMEN
Dipeptidyl-peptidase-4 (DPP-4) inhibitors are a relatively new class of non-insulin glucose-lowering agents, belonging to the incretin family, which are able to improve glycemic control with a favorable safety profile, since they are associated with a low risk of hypoglycemia, no weight gain, and good tolerability in patients with chronic renal failure. Some experimental and clinical studies suggest that these drugs may exert significant pleiotropic effects, in particular on chronic kidney disease (CKD) progression, but data from clinical trials are still controversial. In an effort to clarify the effects of DPP-4 inhibitors (DPP-4is) on diabetes-related renal damage, we performed a narrative review of available clinical trials and other experimental studies focusing on renal effects of DPP-4is. Currently, there is no conclusive evidence proving the usefulness of this drug class for improving diabetes-related renal damage. However, our literature review suggests that DPP-4is are safe and well tolerated in type 2 diabetes mellitus (T2DM) patients with CKD. More importantly, results from the reviewed studies indicate that DPP-4 inhibitor therapy may improve two major risk factors for diabetic nephropathy, such as hyperglycemia and albuminuria, resulting in potential renal benefits beyond glycemic control. Despite several limitations, the conclusions of our review corroborate previous evidence on the potential renal benefits of DPP-4is, highlighting the urgent need of future trials adequately powered and designed on hard renal outcomes to ascertain (or contradict) the therapeutic benefit of DPP-4is in T2DM and CKD patients.
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Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Riñón/efectos de los fármacos , Animales , Humanos , Riñón/fisiologíaRESUMEN
Trabectedin (Yondelis(®)) is a potent marine-derived antineoplastic drug with high activity against various soft tissue sarcoma (STS) subtypes as monotherapy, and in combination with pegylated liposomal doxorubicin (PLD) for the treatment of patients with relapsed platinum-sensitive ovarian cancer. This article reviews the safety and pharmacokinetic profiles of trabectedin. Records were identified using predefined search criteria using electronic databases (e.g. PubMed, Cochrane Library Database of Systematic Reviews). Primary peer-reviewed articles published between 1 January 2006 and 1 April 2014 were included. The current safety and tolerability profile of trabectedin, based on the evaluation in clinical trials of patients treated with the recommended treatment regimens for STS and recurrent ovarian cancer, was reviewed. Trabectedin as monotherapy or in combination with PLD, was not associated with cumulative and/or irreversible toxicities, such as cardiac, pulmonary, renal, or oto-toxicities, often observed with other common chemotherapeutic agents. The most common adverse drug reactions (ADRs) were myelosuppression and transient hepatic transaminase increases that were usually not clinically relevant. However, trabectedin administration should be avoided in patients with severe hepatic impairment. Serious and fatal ADRs were likely to be related to pre-existing conditions. Doxorubicin or PLD, carboplatin, gemcitabine, or paclitaxel when administered before trabectedin, did not seem to influence its pharmacokinetics. Cytochrome P450 (CYP) 3A4 has an important role in the metabolism of trabectedin, suggesting a risk of drug-drug interactions with trabectedin used in combination with other CYP3A4 substrates. Trabectedin has a favorable risk/efficacy profile, even during extended treatment in pretreated patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dioxoles/efectos adversos , Neoplasias Ováricas/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Tetrahidroisoquinolinas/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Dioxoles/administración & dosificación , Interacciones Farmacológicas/efectos de la radiación , Femenino , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Tetrahidroisoquinolinas/administración & dosificación , TrabectedinaRESUMEN
Pharmacovigilance is responsible for monitoring the safety of medicines in normal clinical use and during clinical trials. In the light of the experience acquired and following an assessment by the Commission of the Union system of pharmacovigilance, it has become clear that it is necessary to take measures in order to improve the operation of Union law on the pharmacovigilance of medicinal products for human use. Regulation (EU) No 1235/2010 and Directive 2010/84/EU introduced new legislation on pharmacovigilance. The marketing authorization holder should be responsible for continuously monitoring the safety of its medicinal products for human use, for informing the authorities of any changes that might have an impact on the marketing authorization, and for ensuring that the product information is kept up-to-date. Marketing authorization holders (MAH) record all suspected adverse reactions occurring in the European Union or in the third countries, and which are brought to their attention spontaneously by the patients or their health care, or occurring in the context of post-authorization study. For all medicinal products is mandatory to maintain a pharmacovigilance system master file (PSMF). According to the Legislative Decree 219/2006 the MAH must submit to the competent authorities the information on suspected adverse reactions of a medicinal product, in form of a periodic safety update reports (PSURs).
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Hepatocellular carcinoma (HCC) remains a major global health problem and Calabria in the south of Italy is not an exception. Sorafenib is the first and only Food and Drug Administration approved drug for the treatment of advanced HCC and it is currently under intensive monitoring by the Health Authorities in Italy Agenzia Italiana del Farmaco. This general report has been developed with the aim of briefly reviewing the data found in the reports of adverse reactions (ADRs) collected in Calabria in 2012 for sorafenib treated patients. Extrapolated data have highlighted some differences between the adverse drug reactions reported in patients younger or older than 70 years and other important differences with the current approved leaflet. Several limitations might be present in data analysis form spontaneous reporting, however, the relevance of reporting ADRs (dermatitis, asthenia, vomiting, etc.) for the early identification of drug related signals has to be underlined.
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Aripiprazole (APZ) is regarded as a first-line atypical antipsychotic used for the treatment of first and multiple episodes of schizophrenia to improve positive- and negative-symptoms. Its therapeutic indications were extended to acute manic and mixed episodes associated with bipolar disorder. In addition, APZ was approved as an adjunct therapy for major depressive disorder in 2007. Compared to other antipsychotic drugs, APZ has a unique pharmacological profile. It is a partial agonist at D2 dopamine receptors and serotonin 5-HT(1A) and 5-HT7 receptors, whereas it is an antagonist at serotonin 5-HT(2A) and 5-HT6 receptors. Since epilepsy is often accompanied with neurological comorbidities such as depression, anxiety and cognitive deficits caused by both the disease and/or drug treatment, we wished to examine the effects of a sub-chronic treatment (>14 consecutive days) with APZ (0.3, 1 and 3 mg/kg; i.p.) on both absence seizures and WAG/Rij rat's behavior using different standard paradigms: Open field (OF) test, elevated plus maze (EPM) test, forced swimming (FS) test, sucrose consumption (SC) test and Morris water maze (MWM). WAG/Rij rats represent a validated genetic animal model of absence epilepsy with mild-depression comorbidity, also including other behavioral alterations. APZ treatment showed some anti-absence properties and regarding the behavioral comorbidity in this rat strain, we observed that APZ possesses clear antidepressant effects in the FS and SC tests also increasing memory/learning function in the Morris water maze test. In the two anxiety models used, APZ showed only minor effects. In conclusion, our results indicate that APZ might actually have a potential in treating absence seizures or as add-on therapy but more interestingly, these effect might be accompanied by positive modulatory actions on depression, anxiety and memory which might be also beneficial in other epileptic syndromes. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
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Anticonvulsivantes/uso terapéutico , Antidepresivos/uso terapéutico , Trastornos del Conocimiento/prevención & control , Depresión/tratamiento farmacológico , Epilepsia Tipo Ausencia/tratamiento farmacológico , Nootrópicos/uso terapéutico , Piperazinas/uso terapéutico , Quinolonas/uso terapéutico , Animales , Aripiprazol , Conducta Animal/efectos de los fármacos , Cognición/efectos de los fármacos , Trastornos del Conocimiento/etiología , Depresión/complicaciones , Depresión/fisiopatología , Modelos Animales de Enfermedad , Epilepsia Tipo Ausencia/complicaciones , Ratas , Ratas EndogámicasRESUMEN
OBJECTIVE: To assess both clinical and biological efficacy and toxicity of sorafenib in patients with metastatic renal cell carcinoma (mRCC) previously treated with an anti-angiogenic vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. METHODS: Sorafenib is an orally active multikinase inhibitor approved for the treatment of mRCC. Drug-focused translational research on tissues (i.e. B-RAF) and plasma (VEGFR-α, circulating endothelial cells, endothelial progenitor cells) was performed to define biological predictive and prognostic markers and their related kinetics. Patients with mRCC pretreated with an anti-angiogenic treatment, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 and adequate organ function were eligible. Patients received sorafenib 400 mg twice a day continuously in 4-week cycles. Patients with no progressive disease at 12 weeks continued to receive sorafenib at the standard dose, whereas progressing patients received an increased dose (600 mg twice a day) with early disease restaging after 4 weeks. Patients who progressed at 600 mg twice a day went off study. Efficacy (overall tumour control) was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS: In all, 19 patients were entered. The baseline characteristics were as follows: ECOG PS 0-1 94.8%; median (range) age 62 (41-81) years; nephrectomy 100%; surgery for metastatic disease 26.4%; clear cell 79.1%; papillary cell 15.7%; sarcomatoid/high grade 5.2%; two or more metastatic sites 84%. Overall, 11 patients (58%) had disease control at 6 months without significant correlation between response to prior therapy and hypertension. Progression-free survival (PFS) of 8.3 months was observed. Of six patients for whom the dose was escalated due to early progression, three benefitted with PFS of >3 months. Three (15.7%) of 19 patients had a V600E mutation and one had a K601E mutation; PFS appeared to be substantially shorter in these patients compared with 15 patients with wild-type B-RAF (2.5 vs 9.1 month, P < 0.05). The most common toxicity (National Cancer Institute Common Toxicity Criteria, NCIC 3.0, all patients) was grade ≥1 diarrhoea and grade 2-3 hand-foot syndrome in 11 patients. Grade 3 mucositis was observed in one patient. CONCLUSIONS: Sorafenib at doses of 400-600 mg twice a day continuously results in acceptable and well tolerated salvage treatment after VEGFR tyrosine kinase inhibitor failure. In progressive patients, treatment with a higher dose could be a valid option and B-RAF mutations may be an interesting predictive marker to be studied in a larger randomized trial.
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Bencenosulfonatos/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/patología , Diarrea/inducido químicamente , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Síndrome Mano-Pie/etiología , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Mucositis/inducido químicamente , Metástasis de la Neoplasia , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Pronóstico , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Terapia Recuperativa/métodos , Sorafenib , Resultado del TratamientoRESUMEN
In the present study, we provide evidences for a differential effect of perinatal alcohol exposure with a direct correlation to the genetic background on the development of seizures. Ethanol (EtOH) is a widely used psychoactive substance that exerts its action by affecting multiple targets in the central nervous system. EtOH is known to interact with almost all identified neurotransmitters although its effects on excitatory and inhibitory amino acid neurotransmissions are considered to be particularly important in the mediation of its behavioural effects. Prenatal exposure to alcohol is associated with a wide variety of offspring's abnormalities which lead to the so called foetal alcohol syndrome (FAS), which is also related to a higher susceptibility to convulsions. In our study, a rat strain of convulsive epilepsy, the GEPRs rats, displayed an increase of seizure susceptibility after foetal exposure to this teratogenic drug, while a non-convulsive rat strain of absence epilepsy, the WAG/Rij rat, did not fully develop its characteristic features. However, when all groups of rat where tested for pentyletetrazole-induced convulsion, animals perinatally treated with ethanol were less responsive in comparison to their respective controls. These results are in agreement with previous reports showing how the genetic background can directly influence the teratogenic effects of alcohol, and this can be strictly related to the variability in the observation of offspring anomalies in humans which has lead to a 5-category classification system for individuals exposed to alcohol in uterus.
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Trastornos del Sistema Nervioso Inducidos por Alcohol/fisiopatología , Epilepsia/inducido químicamente , Epilepsia/genética , Etanol/toxicidad , Trastornos del Espectro Alcohólico Fetal/fisiopatología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , Encéfalo/anomalías , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Depresores del Sistema Nervioso Central/toxicidad , Convulsivantes/farmacología , Modelos Animales de Enfermedad , Epilepsia/fisiopatología , Femenino , Predisposición Genética a la Enfermedad/genética , Inmunidad Innata/genética , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratas , Ratas Mutantes , Especificidad de la EspecieRESUMEN
N-Acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (THIQ-10c) is a noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist that has been demonstrated to antagonize generalized tonic-clonic seizures in different animal models of epilepsy. In the study described here, we tested the potential effect of such a compound alone or co-administered with ethosuximide in a genetic animal model of absence epilepsy, the WAG/Rij rat. The intraperitoneal or intracerebroventricular microinjection of THIQ-10c alone was unable to significantly modify the number and duration of spike-and-wave discharges (SWDs). In contrast, intracerebroventricular administration of AMPA induced a dose-dependent increase in the number of SWDs. THIQ-10c dose-dependently antagonized this effect. Furthermore, co-administration of THIQ-1c with ethosuximide (50mg/kg, intraperitoneally) was able to significantly increase the efficacy of the anti-absence drug. In conclusion, although noncompetitive AMPA receptor antagonists alone might not be useful in the treatment of absence epilepsy because of their low therapeutic index, combining them with ethosuximide might be helpful in controlling absence seizures in patients not tolerating this drug or in refractory patients.
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Anticonvulsivantes/administración & dosificación , Modelos Animales de Enfermedad , Electroencefalografía/efectos de los fármacos , Epilepsia Tipo Ausencia/tratamiento farmacológico , Epilepsia Tipo Ausencia/genética , Etosuximida/administración & dosificación , Receptores AMPA/antagonistas & inhibidores , Animales , Corteza Cerebral/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos , Tetrahidroisoquinolinas/administración & dosificación , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/administración & dosificaciónRESUMEN
The study aimed to assess the efficacy and safety of brostallicin, a new DNA minor groove binder, at a dose of 10mg/m2, intravenous (i.v.) every three weeks, in patients with advanced or inoperable soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST) failing first line therapy. Two groups were recruited: (1) GIST following treatment with imatinib; (2) other STS following treatment with single agent doxorubicin or ifosfamide or a single line of combination therapy. The primary end-point was overall response rate (ORR) as defined by response evaluation criteria in solid tumours (RECIST). Progression free survival (PFS) was a secondary end-point. In the GIST group, a Simon two step design was planned: first step 18 patients, total 32 patients (p1=20% p0=5% alpha=beta=0.1). In the non-GIST group, planned sample size was 40 in a standard Fleming one-step design (p0=10%, p1=25%, alpha=beta=0.1). Forty-three patients with non-GIST and 21 patients with GIST were recruited. In general, the drug was well tolerated. Common Toxicity Criteria (CTC) grade 3 or grade 4 toxicity was granulocytopenia: 70% of patients, 50% of cycles; fatigue: 25% of patients, 8% of cycles; febrile neutropenia: 14% of patients, 4% of cycles. There was one confirmed toxic death due to neutropenic septicaemia. Three patients had clinically significant allergic reactions in 249 cycles delivered. In the GIST group, no patients had a confirmed response and recruitment was discontinued at the first step. In the non-GIST group, there were two confirmed partial responses. The 3 month PFS was 46% in the non-GIST group and 33% in the GIST group. In the non-GIST group, this PFS is in the range of other agents considered active in STS, and may predict for more substantial first line activity. Further investigation in STS other than GIST appears warranted.
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Antineoplásicos/administración & dosificación , Tumores del Estroma Gastrointestinal , Guanidinas/administración & dosificación , Pirroles/administración & dosificación , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Progresión de la Enfermedad , Femenino , Guanidinas/efectos adversos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Pirroles/efectos adversos , Sarcoma/mortalidad , Neoplasias de los Tejidos Blandos/mortalidad , Neoplasias de los Tejidos Blandos/secundario , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
CFM-2 [1-(4-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one] and THIQ-10c [N-acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline], are two non-competitive 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) receptor antagonists, which demonstrated to antagonize generalized tonic-clonic seizures in different animal models. We have evaluated the effects of such compounds in a genetic animal model of absence epilepsy, the WAG/Rij rat. Animals were focally microinjected into specific brain areas of the cortico-thalamic circuit in order to evaluate the effects of these compounds on the number and duration of epileptic spike-wave discharges (SWDs) and better characterize the role of AMPA neurotransmission in this animal model. The focal microinjection of the two AMPA antagonists into some thalamic nuclei (ventralis posteromedialis (VPM), reticularis (NRT), ventralis posterolateralis (VPL) and the primary somatosensory forelimb region (S1FL)) was, generally, not able to significantly modify the occurrence of SWDs. Whereas, both compounds were able to reduce the number and duration of SWDs dose-dependently when microinjected into the peri-oral region of the primary somatosensory cortex (S1po). These findings suggest that AMPA receptor antagonists might play a role in absence epilepsies and that it might depend on the involvement of specific neuronal areas.
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Anticonvulsivantes , Encéfalo/fisiología , Epilepsia Tipo Ausencia/fisiopatología , Epilepsia Generalizada/fisiopatología , Antagonistas de Aminoácidos Excitadores/farmacología , Receptores AMPA/antagonistas & inhibidores , Animales , Benzodiazepinonas/administración & dosificación , Benzodiazepinonas/farmacología , Encéfalo/efectos de los fármacos , Electrofisiología , Epilepsia Tipo Ausencia/tratamiento farmacológico , Epilepsia Generalizada/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Inmunohistoquímica , Masculino , Microinyecciones , Ratas , Ratas Endogámicas , Corteza Somatosensorial/fisiopatología , Transmisión Sináptica/efectos de los fármacos , Núcleos Talámicos/efectos de los fármacos , Núcleos Talámicos/fisiologíaRESUMEN
Neurosteroids are synthesized in the brain and have been demonstrated to modulate various cerebral functions. Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), a naturally occurring neurosteroid, and ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a synthetic derivative, are two neurosteroids acting as positive allosteric modulators of the GABA(A) receptor complex acting on a specific steroid recognition site. Both agents antagonize generalized tonic-clonic seizures in various animal models of epilepsy. Pregnenolone sulphate (3beta-hydroxy-5alpha-pregnen-20-one 3-sulphate; PS) is a negative allosteric modulator of GABA(A) receptors and a positive modulator of the NMDA receptors. We have evaluated the effects of such compounds in a genetic animal model of absence epilepsy, the WAG/Rij rat. Animals were chronically implanted with five frontoparietal cortical electrodes for electrocorticogram (EEG) recordings and bilateral guide cannulae into specific brain areas of the cortico-thalamic circuit in order to evaluate the effects of these compounds on the number and duration of epileptic spike-wave discharges (SWDs). The focal and bilateral microinjection of the two GABA(A) positive modulators into some thalamic nuclei (nucleus ventralis posteromedialis, nucleus reticularis thalami, nucleus ventralis posterolateralis was usually able to significantly worsen the occurrence of SWDs in WAG/Rij rats. Whereas both compounds were able to reduce the number and duration of SWDs when microinjected into the peri-oral region of the primary somatosensory cortex. The effects of PS were more complex depending on both the dose and the site of administration, generally, at low doses in thalamic nuclei and cortex, PS induced an increase of absence activity and a reduction at higher doses. These findings suggest that neurosteroids might play a role in absence epilepsies and that it might depend on the involvement of specific neuronal areas.
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Epilepsia Tipo Ausencia/tratamiento farmacológico , Pregnanolona/análogos & derivados , Pregnanolona/administración & dosificación , Pregnenolona/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Electroencefalografía/métodos , Epilepsia Tipo Ausencia/fisiopatología , Masculino , Microinyecciones/métodos , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
Inducible nitric oxide synthase knock-out (iNOS(-/-)) mice are valid models of investigation for the role of iNOS in patho-physiological conditions. There are no available data concerning neuroactive amino acid levels of iNOS(-/-) mice and their behaviour in response to pentylenetetrazole (PTZ). We found no significant differences in the convulsive dose 50 (CD(50)) between iNOS(-/-) and control (iNOS(+/+)) mice, however, iNOS(-/-) mice reach the kindled status more slowly than control, suggesting that in basal condition the GABA-benzodiazepine inhibitory inputs are unaltered by iNOS mutation. Clear differences between iNOS(+/+) and iNOS(-/-) mice amino acid concentrations were evident both in basal conditions and after kindling. Our results show that aspartate was significantly lower in all brain areas studied except the brain stem whereas glutamate and glutamine were significantly higher in the cortex, hippocampus and brain stem. GABA was slightly and not significantly higher in the cortex, hippocampus and brain stem, whereas taurine was significantly higher in all areas except diencephalon and glycine was significantly lower in the diencephalon and cerebellum. In this context, the inability of iNOS(-/-) mice to increase the NO levels following PTZ administrations indicate that NO might play a pro-epileptogenic role in the genesis and development of some types of epilepsy. Since there is no correlation between neurotransmitter levels and the development of kindling, it is possible to exclude that the difference between the two strains is due to an imbalance between the considered neurotransmitters, and it is then possible that this difference is due to the presence of iNOS, which might be involved in long term plasticity of the brain.
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Aminoácidos/metabolismo , Encéfalo/enzimología , Antagonistas del GABA/farmacología , Excitación Neurológica , Óxido Nítrico Sintasa de Tipo II/metabolismo , Animales , Encéfalo/fisiopatología , Convulsivantes , Antagonistas de Receptores de GABA-A , Ratones , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo II/genética , Pentilenotetrazol , Convulsiones/tratamiento farmacológico , Convulsiones/fisiopatología , Taurina/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Genetic animal models have contributed significantly to our understanding of epilepsy causes. Lethargic mice are considered a valid model of absence epilepsy, which have been shown to possess behavioral, electrographic and pharmacological profiles similar to those of humans with absence epilepsies. Single gene mutations that comprise the beta4 subunit of voltage-sensitive Ca2+ channels underlie the spontaneous discharges of the absence, non-convulsive seizures of lethargic mice. There are no available data concerning how the mutant channels actually behave at terminals in response to chemical activation by subconvulsant stimulation with pentylenetetrazole. In this study, we found no significant difference in the convulsive dose 50 between lethargic and control mice. Lethargic mice showed a more rapid development of kindling to pentylenetetrazole than control animals. No significant differences were observed between the groups of mice rechallenged with pentylenetetrazole 30 or 60 days after the end of the chronic treatment. Marked differences in brain amino acid levels were found between the two strains of mice in basal conditions and after kindling. In conclusion, our results indicate that lethargic mice show a range of biochemical and behavioral changes, correlated in particular with a higher susceptibility to develop kindled seizures.
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Aminoácidos/metabolismo , Encéfalo/metabolismo , Excitación Neurológica/metabolismo , Pentilenotetrazol/toxicidad , Convulsiones/metabolismo , Fases del Sueño/fisiología , Animales , Encéfalo/efectos de los fármacos , Excitación Neurológica/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , Convulsiones/inducido químicamente , Fases del Sueño/efectos de los fármacosRESUMEN
Imatinib pharmacokinetics (PK) may be affected by a number of factors that are related to the disease being treated and to the response of that disease to imatinib. Patients in the phase I and phase II trials conducted by the EORTC in patients with gastrointestinal stromal tumours (GISTs) and other sarcomas had detailed blood sampling for imatinib PK on day 1 and on day 29. Patients with GISTs also had repeat sampling, using a limited sampling strategy, after approximately 12 months on therapy. This population PK study was carried out to examine what covariates affected imatinib PK in GIST patients and what PK changes occurred over time. In the model producing the best fit, low clearance (CL) correlated with low body weight and high granulocyte count, whereas low haemoglobin correlated with low volume of distribution. For a patient with 77% of the median body weight or with 1.87 times the median granulocyte count, the apparent CL is 6.53 l/h, about 70% of the typical apparent CL of 9.33 l/h; for a patient of 84% of the typical haemoglobin level, the volume of distribution is about 70%. Total white blood cell count correlated closely with granulocyte count and there was a moderate correlation between haemoglobin and albumin (r = 0.454). There was a trend towards increased imatinib clearance after chronic exposure over 12 months. The typical apparent CL increased 33% from day 1. Nevertheless, the approximate 95% confidence interval of the increase of the typical apparent CL was 33 +/- 34.6%, which contains zero. It is not yet clear whether this is a significant factor in the amelioration of imatinib toxicity that occurs with time or is related to disease control, and further work is required to confirm this observation.
Asunto(s)
Antineoplásicos/farmacocinética , Tumores del Estroma Gastrointestinal/metabolismo , Piperazinas/farmacocinética , Pirimidinas/farmacocinética , Benzamidas , Peso Corporal , Femenino , Granulocitos , Hemoglobinas/metabolismo , Humanos , Mesilato de Imatinib , Recuento de Leucocitos , Masculino , Estudios Retrospectivos , Sarcoma/metabolismo , Factores de TiempoRESUMEN
Interleukin-6-deficient (IL-6(-/-)) mice and their normal littermate (WT) were studied to evaluate their susceptibility to seizures induced by electroshock and audiogenic stimuli at different ages. No significant changes in maximal electroshock susceptibility were evidenced between the two strains, while audiogenic seizures (AGS) can be induced only in IL-6(-/-) mice. The effects of age and genetic condition on AGSs were evaluated. The behavioural and electrocortical changes during audiogenic stimulus were observed. In addition, the levels of neurotransmitter amino acids in five brain areas (of both strains) were measured at 60 days of age. Aspartate level significantly increased in the brain stem (BS) and hippocampus (HI), while it decreased in the diencephalon (DE) of IL-6(-/-) mice. Glutamate content significantly decreased in the cerebellum (CB), DE and HI. GABA levels significantly decreased in all the areas studied. Glycine significantly decreased in the BS, CB and DE, while taurine decreased only in the DE. The levels of glutamine significantly decreased in all the areas examined, except in the cortex (CX). The changes of neuroactive amino acid levels, particularly in the BS, might explain the characteristic of high propensity to AGS of IL-6(-/-) mice. The present data support the validity of IL-6(-/-) mice as a novel epileptic model for the study of the pathophysiology and pharmacology of epilepsy.
Asunto(s)
Estimulación Acústica/métodos , Encéfalo/metabolismo , Epilepsia Refleja/genética , Epilepsia Refleja/metabolismo , Predisposición Genética a la Enfermedad , Interleucina-6/deficiencia , Interleucina-6/genética , Neurotransmisores/biosíntesis , Factores de Edad , Animales , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Neurotransmisores/genéticaRESUMEN
In the present study, the susceptibility of knockout interleukin-6 (IL-6(-/-)) mice to various convulsant stimuli has been evaluated and compared with other three related mice strains. Animals were treated with chemical convulsants impairing the gamma-aminobutyric acid neurotransmission [pentylenetetrazole (PTZ), picrotoxin, bicuculline, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), methyl-beta-carboline-3-carboxylate (beta-CCM)], enhancing glutamatergic neurotransmission [N-methyl-d-aspartate (NMDA), alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainic acid (KA)] or a K(+)channel blocker [4-aminopyridine (4-AP)]. The behavioural changes of such convulsant stimuli on IL-6(-/-) were observed and compared with those observed in C57, IL-6(+/+) and DBA/2 mice. The occurrence of clonic and/or tonic seizures was scored and statistically analysed to observe possible differences on seizure susceptibility. The IL-6(-/-) mice exhibited significantly higher seizure susceptibility to PTZ, beta-CCM, DMCM, NMDA, AMPA and KA than did the other mice strains, with the exception of DBA/2 mice. This study demonstrates that IL-6(-/-) mice possess an increased susceptibility to some convulsant stimuli. In particular, the major convulsant effects produced by NMDA, AMPA and KA suggest that the excitatory amino acid system is more active in the central nervous system (CNS) of IL-6(-/-) mice. The present data suggest that IL-6(-/-) mice might be a valid novel epileptic model for the study of pathophysiology and pharmacology of epileptic seizures.
Asunto(s)
Convulsivantes/toxicidad , Interleucina-6/deficiencia , Interleucina-6/genética , Convulsiones/inducido químicamente , Animales , Susceptibilidad a Enfermedades/inmunología , Aminoácidos Excitadores/genética , Aminoácidos Excitadores/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Convulsiones/genética , Convulsiones/metabolismoRESUMEN
The two enantiomers of propranolol antagonize generalized tonic-clonic seizures in DBA/2 mice with the (-)-enantiomer being about 1.5 times more potent than the (+)-enantiomer. Metoprolol was less active and atenolol was unable to affect audiogenic seizures. In combination with conventional antiepileptic drugs, both propranolol enantiomers tested in doses not affecting the occurrence of audiogenic seizures increased the anticonvulsant activity of diazepam, phenobarbital, valproate and lamotrigine and tended to increase that of carbamazepine and phenytoin. The effect was more pronounced with the (-)-enantiomer. This increase was associated with an enhancement of motor impairment, however, the therapeutic index of combined treatment of the antiepileptic drugs with both propranolol enantiomers was more favourable than the combination with saline alone. Metoprolol was also able to decrease the ED(50) values of the antiepileptic drugs, whereas atenolol showed no effects. Since neither enantiomer of propranolol significantly influenced the total and free plasma levels of the antiepileptics, pharmacokinetic interactions are not likely. In addition, (+)- and (-)-propranolol did not significantly affect the hypothermic effects of the antiepileptics tested. In conclusion, both enantiomers of propranolol and metoprolol showed an additive anticonvulsant effect when co-administered with some conventional antiepileptic drugs, most notably diazepam, phenobarbital, lamotrigine and valproate, implicating a possible therapeutic relevance of such drug combinations.