GENETIC VARIABILITY OF PHARMACOKINETICS AND PHARMACODYNAMICS OF ANALGESICS (LAYERED MEDICINE)

Pain therapy, the most widely spread disorder, tends more as other diseases, to administration of drug molecules targeted to the affected tissue at the right dose, or to the patient or patient groups (personalized medicine). A decisive determinant of this strategy is the genetic one, which is to some extent the basis of the variability of pharmacokinetic and pharmacodynamic response to analgesics in the patient population. The differences in action and response to analgesics are due in these cases to hyperfunctional or nonfunctional uni-nucleotide gene polymorphisms encoding enzyme-modified transport proteins or receptors involved in the biotransformation and dynamics of analgesics. Genomic testing increases therapeutic efficacy and avoids adverse effects especially in patients with long-term therapies.   &nbsp

GENETIC VARIABILITY OF PHARMACOKINETICS AND PHARMACODYNAMICS OF ANALGESICS (LAYERED MEDICINE)

Pain therapy, the most widely spread disorder, tends more as other diseases, to administration of drug molecules targeted to the affected tissue at the right dose, or to the patient or patient groups (personalized medicine). A decisive determinant of this strategy is the genetic one, which is to some extent the basis of the variability of pharmacokinetic and pharmacodynamic response to analgesics in the patient population. The differences in action and response to analgesics are due in these cases to hyperfunctional or nonfunctional uni-nucleotide gene polymorphisms encoding enzyme-modified transport proteins or receptors involved in the biotransformation and dynamics of analgesics. Genomic testing increases therapeutic efficacy and avoids adverse effects especially in patients with long-term therapies.   &nbsp

THE IMPORTANCE OF OXIDATIVE AND NITROSATIVE STRESS ON ANGIOTENSIN II-INDUCED AMNESTIC EFFECTS IN RAT

The renin-angiotensin system (RAS) is one of the most important neuropeptide systems in the brain and it isknown now that in addition to the regulation of blood pressure, RAS is also implicated in the modulation of somesuperior functions involving the emotional responses, pain or cognitive functions. However, in the last few years variousstudies regarding the modulatory effects of Ang II on learning and memory showed conflicting results, with both positiveand negative reports. In addition, the effects of Ang II on oxidative stress and its relations to the cognitive processes arenot very well understood.We report here the amnesic effects of Ang II icv 0.1μg/kg b.w administration in rats, as showed by decreasedspontaneous alternation in Y-maze. Also, we noticed a significant correlation between the behavioral deficits in Y-mazeand the levels of some oxidative stress markers. This could also have a possible therapeutic importance, since thereduction in blood pressure via manipulation of RAS can results in enhanced cognitive effects. Also, both oxidative andnitrosative stress seems to play an important part in the aforementioned aspects

NEW MOLECULES USEFUL IN THE MIGRAINE TREATMENT

Migraine is a neurovascular condition characterized by episodes of severe headache with inter-individual variability. Inflammation of neurogenic origin contributes to the mechanism of occurrence of migraine and other primary headaches. Neurovascular headache is a condition in which neural events have as a result dilation of blood vessels and the appearance of painful sensation. CGRP (calcitonin-gene-related peptide) is a neuropeptide widespread both in the central and peripheral nervous system, being one of the most potent vasodilator substances with important role in controlling blood pressure in both normal and abnormal conditions. The releasing of perivascular peptides relaxes cerebral arteries while stimulating cAMP accumulation or release of EDRF (endothelium derived relaxing factor). An alternative to acute treatment of migraine used so far is the CGRP receptor blockade with selective antagonists. They represent potential therapeutic molecules with superior advantages to triptans and a longer duration of action

Synergistic interaction between trimetazidine and ketoprophen in mice

Recent studies have demonstrated the antinociceptive, anti-inflammatory, and gastric protective effects of trimetazidine (TDZ) on various models in rats. The present study proposes to demonstrate the antinociceptive action in mice, evaluated in conditions of inflammatory pain, together with the determination of the type of pharmacodynamic interaction between trimetazidine and ketoprofen (KETO). In this study we used as experimental model of nociception the abdominal constrictive response (writhing test), induced with Zymosan A in mice, and for the study of the interaction we used as quantitative evaluation method the method of binary combinations in fixed proportions. The experimental results allowed the demonstration of the ED 50 for ketoprofen (DE50 = 0.606 ± 0.108 mg/kg) and the demonstration of the synergism for the associated substances. (Zadd = 1.818 ± 0.326 mg/kg, Zmix = 0. 458 ± 0.101 mg/kg, γ = 0.251, Tc = 4.928, Tt = 3.84, P< 0.05). The results demonstrate that for the same level of activity (50%), smaller doses of each substance can be used, compared to the doses of the substances administered alone, which might contribute to a reduction in the number or severity of adverse effects. on the other side, the demonstration of the synergism might contribute to the clarification of the action mechanisms. The experiments presented below were made in agreement with the rules and regulations concerning the work with lab animals

Current aspects of the interactions between dementia, the brain renin-angiotensin system and oxidative stress

There is increased interest in the interactions between vascular disorders and Alzheimer’s disease (AD). While initially these interactions were explained by the fact that these are both very common disorders, particularly later in life, recently, the possibility that these deficiencies might actually coexist is increasingly being questioned. This review attempts to present modern aspects and current reports regarding the interactions between AD, the renin-angiotensin system (RAS) and hypertension, while also describing the relevance of antihypertensive drug use acting via the RAS in the treatment and prevention of AD, as well as the importance of oxidative stress, the alteration of the balance between antioxidants and pro-oxidants, in the interaction between AD and the RAS

The dynamics of some oxidative stress markers in 3, 6 and 12-months alcohol abstinent patients: possible relevance for the usage of antioxidants in alcohol withdrawal / Dinamica unor markeri ai stresului oxidativ la 3, 6 şi 12 luni de abstinenţă de la alcool: posibila relevanţă a utilizării de antioxidanţi

În prezentul articol am fost interesaţi să studiem relevanţa stresului oxidativ în cadrul proceselor legate de abstinenţa de la alcool, având în vedere în special faptul că literatura de specialitate este extrem de controversată în acest domeniu de cercetare. Astfel, am determinat nivelul unor markeri specifici ai stresului oxidativ la pacienţii selectaţi după 3, 6 şi 12 luni de abstinenţă de la alcool. 62 de pacienţi de sex masculin au fost selectaţi pentru studiu. În cadrul studiului s-au prezentat 33 de pacienţi pentru determinările bazale, 14 pacienţi la 3 luni, 14 pacienţi la 6 luni şi 15 pacienţi la 12 luni de abstinenţa de la alcool, în timp ce lotul control a inclus 32 de persoane sănătoase, potrivite ca vârstă si sex-ratio cu celelalte grupuri de studiu. Astfel, în ceea ce priveşte rezultatele, în cazul superoxid dismutazei (SOD) am observat o diferenţă semnificativă între cele trei loturi de studiu (p<0.0001), precum şi o creştere semnificativă din punct de vedere statistic a valorilor SOD la pacienţii aflaţi la 3 luni (p<0.0001), 6 luni (p<0.0001) şi respectiv 12 luni (p<0.0001) de abstinenţa de la alcool, faţă de determinările bazale. De asemenea, în cazul glutation peroxidazei, am observat o diferenţă semnificativă din punct de vedere statistic între grupuri (p=0.0003), plus creşteri importante la 6 luni (p=0.03) şi 12 luni (p=0.006), faţă de determinările bazale. În ceea ce priveşte malondialdehida (MDA), ca şi principal marker al proceselor de peroxidare lipidică, am putut observa de asemenea diferenţe semnificative între grupurile de studiu (p<0.0001). Mai mult, în cazul tuturor celor 3 grupe de pacienţi s-au putut observa scăderi semnificative ale concentraţiei de MDA, în comparaţie cu determinările bazale (p=0.003 pentru 3 luni, p=0.01 pentru 6 luni şi p=0.0002 pentru 12 luni). În concluzie, aceste date confirmă un stress oxidativ crescut la pacienţii consumatori cronici de alcool şi, mai important decât atât, demonstrează o scădere semnificativă şi progresivă a statusului stresului oxidativ la 3, 6 şi 12 luni de abstinenţa de la alcool, aşa cum am putut observa din creşterea progresivă a activităţii specifice a enzimelor antioxidante determinate şi scăderea nivelelor de peroxidare lipidică

Inflammasome Molecular Insights in Autoimmune Diseases

Autoimmune diseases (AIDs) emerge due to an irregular immune response towards self- and non-self-antigens. Inflammation commonly accompanies these conditions, with inflammatory factors and inflammasomes playing pivotal roles in their progression. Key concepts in molecular biology, inflammation, and molecular mimicry are crucial to understanding AID development. Exposure to foreign antigens can cause inflammation, potentially leading to AIDs through molecular mimicry triggered by cross-reactive epitopes. Molecular mimicry emerges as a key mechanism by which infectious or chemical agents trigger autoimmunity. In certain susceptible individuals, autoreactive T or B cells may be activated by a foreign antigen due to resemblances between foreign and self-peptides. Chronic inflammation, typically driven by abnormal immune responses, is strongly associated with AID pathogenesis. Inflammasomes, which are vital cytosolic multiprotein complexes assembled in response to infections and stress, are crucial to activating inflammatory processes in macrophages. Chronic inflammation, characterized by prolonged tissue injury and repair cycles, can significantly damage tissues, thereby increasing the risk of AIDs. Inhibiting inflammasomes, particularly in autoinflammatory disorders, has garnered significant interest, with pharmaceutical advancements targeting cytokines and inflammasomes showing promise in AID management