Safety and activity of the first-in-class locked nucleic acid (LNA) miR-221 selective inhibitor in refractory advanced cancer patients: a first-in-human, phase 1, open-label, dose-escalation study.

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.

Safety profile of biologic drugs for psoriasis in clinical practice: An Italian prospective pharmacovigilance study.

Psoriasis is an inflammatory and chronic skin disorder associated with physical and psychological burden impairing patients' quality of life. In the last decade, biologic drugs have widely changed treatment of moderate-severe psoriasis and their number is increasing overtime. To early identify expected/unexpected adverse events (AEs) with biologic treatments, pharmacovigilance programs are needed.

Safety profiles of biologic agents for inflammatory bowel diseases: a prospective pharmacovigilance study in Southern Italy.

Introduction: Inflammatory bowel diseases (IBDs) are a public health issue with over 3.5 million patients in Europe, but the advent of several biologic agents has completely changed their management. Pharmacovigilance is needed to early detect expected/unexpected adverse events (AEs) to assess the safety of drugs in a real-world setting.

Perampanel chronic treatment does not induce tolerance and decreases tolerance to clobazam in genetically epilepsy prone rats.

Tolerance to some therapeutic effects of antiepileptic drugs may account for the development of pharmacoresistance in patients with epilepsy. In the present study, following oral acute pretreatment with the new antiepileptic drug perampanel (0.1, 0.

Exploring the effects of DPP-4 inhibitors on the kidney from the bench to clinical trials.

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.

The Anticonvulsant Activity of a Flavonoid-Rich Extract from Orange Juice Involves both NMDA and GABA-Benzodiazepine Receptor Complexes.

The usage of dietary supplements and other natural products to treat neurological diseases has been growing over time, and accumulating evidence suggests that flavonoids possess anticonvulsant properties. The aim of this study was to examine the effects of a flavonoid-rich extract from orange juice (OJe) in some rodent models of epilepsy and to explore its possible mechanism of action. The genetically audiogenic seizures (AGS)-susceptible DBA/2 mouse, the pentylenetetrazole (PTZ)-induced seizures in ICR-CD1 mice and the WAG/Rij rat as a genetic model of absence epilepsy with comorbidity of depression were used.

A comprehensive safety evaluation of trabectedin and drug-drug interactions of trabectedin-based combinations.

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.

Nexavar(®)-related adverse reactions: Calabrian (Italy) experience for sorafenib exposition in 2012.

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.

Pharmacovigilance in pharmaceutical companies: An overview.

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.

Pazopanib a tyrosine kinase inhibitor with strong anti-angiogenetic activity: a new treatment for metastatic soft tissue sarcoma.

Soft tissue sarcomas (STS) are rare tumors with mesenchymal origin, accounting for 1% of all human cancer. Local control of STS can be obtained through the use of surgery and radiotherapy. In about 40% of these patients, disease will recur at distant sites, and of these more than 90% will die because of this aggressive malignancy.

Pharmacodynamic potentiation of antiepileptic drugs' effects by some HMG-CoA reductase inhibitors against audiogenic seizures in DBA/2 mice.

It is known that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are effective in both the primary and the secondary prevention of ischemic heart disease. Increasing evidence indicates that statins have protective effects in several neurological diseases including stroke, cerebral ischemia, Parkinson disease, multiple sclerosis, traumatic brain injury and epilepsy. The aim of the present research was to evaluate the effects of some HMG-CoA reductase inhibitors (i.

An open-label, dose-finding study of the combination of satraplatin and gemcitabine in patients with advanced solid tumors.

Purpose: Satraplatin is a third generation oral platinum, which has demonstrated antitumor activity. The aim of this phase I study was to determine the maximum tolerated dose (MTD) of the combination of satraplatin and gemcitabine in patients previously treated with chemotherapy and in patients without prior chemotherapy.

Patients And Methods: Two separate MTDs were planned in two different patient groups (those with and without prior chemotherapy treatment).

Ameliorating effects of aripiprazole on cognitive functions and depressive-like behavior in a genetic rat model of absence epilepsy and mild-depression comorbidity.

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.

Phase II escalation study of sorafenib in patients with metastatic renal cell carcinoma who have been previously treated with anti-angiogenic treatment.

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.

Fosinopril and zofenopril, two angiotensin-converting enzyme (ACE) inhibitors, potentiate the anticonvulsant activity of antiepileptic drugs against audiogenic seizures in DBA/2 mice.

The renin-angiotensin system (RAS) exists in the brain and it may be involved in pathogenesis of neurological and psychiatric disorders including seizures. The aim of the present research was to evaluate the effects of some angiotensin-converting enzyme inhibitors (ACEi; captopril, enalapril, fosinopril and zofenopril), commonly used as antihypertensive agents, in the DBA/2 mice animal model of generalized tonic-clonic seizures. Furthermore, the co-administration of these compounds with some antiepileptic drugs (AEDs; carbamazepine, diazepam, felbamate, gabapentin, lamotrigine, phenobarbital, phenytoin, topiramate and valproate) was studied in order to identify possible positive interactions in the same model.

Novel 3-carboxy- and 3-phosphonopyrazoline amino acids as potent and selective NMDA receptor antagonists: design, synthesis, and pharmacological characterization.

The design and synthesis of new N1-substituted 3-carboxy- and 3-phosphonopyrazoline and pyrazole amino acids that target the glutamate binding site of NMDA receptors are described. An analysis of the stereochemical requirements for high-affinity interaction with these receptors was performed. We identified two highly potent and selective competitive NMDA receptor antagonists, (5S,alphaR)-1 and (5S,alphaR)-4, which exhibit good in vitro neuroprotective activity and in vivo anticonvulsant activity by i.

Effects of ethanol on the development of genetically determined epilepsies in rats.

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.

Enhancement of anti-absence effects of ethosuximide by low doses of a noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist in a genetic animal model of absence epilepsy.

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).

Influence of levetiracetam on the anticonvulsant efficacy of conventional antiepileptic drugs against audiogenic seizures in DBA/2 mice.

Levetiracetam (LEV, [S]-alpha-ethyl-2-oxo-1-pyrrolidine acetamide) is a new antiepileptic that has been used as adjunctive therapy to treat patients with intractable epilepsy. Systemic administration of levetiracetam (2.5-30 mg/kg, intraperitoneally (i.

Amino acid levels in some brain areas of inducible nitric oxide synthase knock out mouse (iNOS-/-) before and after pentylenetetrazole kindling.

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.

Brostallicin, an agent with potential activity in metastatic soft tissue sarcoma: a phase II study from the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

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.

Effects of non-competitive AMPA receptor antagonists injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy.

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.

Effects of some neurosteroids injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy.

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.

Amino acid levels in some lethargic mouse brain areas before and after pentylenetetrazole kindling.

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.

Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour: a retrospective population pharmacokinetic study over time. EORTC Soft Tissue and Bone Sarcoma Group.

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.