Dependencia a los relajantes musculares- Tizanidina: reporte de un caso / Dependency on muscle relaxants- Tizanidine: a case report

Alrededor del mundo hay un abuso creciente de diferentes sustancias en nuestro medio, incluidos medicamentos de uso diario. La Tizanidina es un derivado de la imidazolina y hace parte de la familia de los relajantes musculares. Se utiliza para reducir el tono muscular asociado con la espasticidad causada por una lesión cerebral o de la médula espinal. Se presenta el caso de una mujer de 21 años con un cuadro clínico de cuatro años de evolución de consumo en patrón de dependencia y adicción de este medicamento con fines ansiolíticos. En la literatura científica no hay reportes sobre el consumo abusivo y dependencia a este fármaco, sin embargo, hay un factor de riesgo al tener efectos sedativos y se debe tener en cuenta en los trastornos por abuso de otras sustancias. (AU)

Around the world there is an increasing abuse of different substances, including daily use medicines. Tizanidine is a derivative of imidazoline and is part of the family of muscle relaxants. It is used to reduce muscle tone associated with spasticity caused by brain or spinal cord injuries. We present the case of a 21-year-old woman with a clinical history of four years of evolution of consumption in a pattern of dependency and addiction of this medicine for anxiolytic purposes. In the scientific literature there are no reports on abusive consumption and dependence on this drug, however, there is a risk factor because of its sedative effects. This risk should be considered in disorders due to abuse of other substances. (AU)

Tolerance and cross-tolerance to the antinociceptive effects of oxycodone and the imidazoline I2 receptor agonist phenyzoline in adult male rats.

RATIONALE: Emerging evidence suggests the potential utility of combining opioids with imidazoline I2 receptor agonists for chronic pain. However, chronic pain management requires prolonged pharmacotherapy, and the consequence of such combination therapy remains unclear. OBJECTIVE: This study examined the anti-hyperalgesic effect of the opioid oxycodone, the selective I2 receptor agonist phenyzoline, alone and in combination, during prolonged treatment. METHODS: Von Frey filament test was used to examine the anti-hyperalgesic effect of drugs in complete Freund's adjuvant (CFA)-induced inflammatory pain or chronic constriction injury (CCI)-induced neuropathic pain in rats. Twice-daily treatment with oxycodone and phenyzoline, alone or in combination, was continued until the development of significant tolerance (oxycodone) or as long as 19 days passed (phenyzoline). RESULTS: In rats receiving CFA or CCI manipulation, mechanical hyperalgesia was dose-dependently reversed by oxycodone and phenyzoline. Twice-daily treatment with 2 × ED50 dose of oxycodone for 7 days led to significant antinociceptive tolerance to oxycodone but not cross-tolerance to phenyzoline. Similarly, twice-daily treatment with 2 × ED50 dose of phenyzoline for 19 days led to significant antinociceptive tolerance to phenyzoline but not cross-tolerance to oxycodone. Twice-daily treatment with the combined oxycodone and phenyzoline using different ratios (1:3, 1:1 and 3: 1) at the doses that were functionally equivalent to the treatment doses of oxycodone and phenyzoline for 13-19 days generally led to delayed antinociceptive tolerance. CONCLUSIONS: Combination therapy with oxycodone and I2 receptor agonists maintains prolonged antinociceptive effectiveness with reduced propensity to develop tolerance.

Library of diversely substituted 2-(quinolin-4-yl)imidazolines delivers novel non-cytotoxic antitubercular leads.

A novel library based on quinolin-4-ylimidazoline core was designed to incorporate a general quinoline antimicrobial pharmacophore. A synthesis of the well-characterized library of 36 compounds was achieved using the Pd-catalyzed Buchwald-Hartwig-type imidazoline arylation chemistry developed earlier. Compounds were tested for biological activity and were found to possess no antimalarial activity. However, the library delivered two promising antitubercular leads, which are non-cytotoxic and can be further optimized with respect to antimycobacterial potency.

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas.

PURPOSE: p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM. EXPERIMENTAL DESIGN: We performed a preclinical evaluation of RG7112 MDM2 inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCL), each genetically characterized according to their P53 pathway status. We then performed a pharmacokinetic (PK) profiling of RG7112 distribution in mice and evaluated the therapeutic activity of RG7112 in orthotopic and subcutaneous GBM models. RESULTS: MDM2-amplified PDCLs were 44 times more sensitive than TP53-mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC50 of 0.52 µmol/L vs. 21.9 µmol/L). MDM4-amplified PDCLs were highly sensitive but showed intermediate response (avg. IC50 of 1.2 µmol/L), whereas response was heterogeneous in TP53 wild-type PDCLs with normal MDM2/4 levels (avg. IC50 of 7.7 µmol/L). In MDM2-amplified lines, RG7112 restored p53 activity inducing robust p21 expression and apoptosis. PK profiling of RG7112-treated PDCL intracranial xenografts demonstrated that the compound significantly crosses the blood-brain and the blood-tumor barriers. Most importantly, treatment of MDM2-amplified/TP53 wild-type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival. CONCLUSIONS: These data strongly support development of MDM2 inhibitors for clinical testing in MDM2-amplified GBM patients. Moreover, significant efficacy in a subset of non-MDM2-amplified models suggests that additional markers of response to MDM2 inhibitors must be identified.

Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors.

PURPOSE: RG7112, the first selective small-molecule MDM2 antagonist in clinical testing, is a non-genotoxic oral p53 activator. To optimize its dose and schedule, a number of clinical pharmacology characteristics were explored in this multicenter trial in patients with advanced solid tumors. METHOD: In part 1, the impact of high-energy/high-fat meal and formulations (crystalline and amorphous) on relative bioavailability was examined in single-dose crossover designs. In part 2, schedule optimization (4 schedules of drug administration under fasting condition and 2 cohorts with liquid supplementation) was investigated in parallel, dose escalation designs. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) including MIC-1 elevation and platelet reduction, and safety/tolerability. RESULTS: With a single-dose treatment, a high-fat/high-energy meal and a new formulation under fasting condition, respectively, enhanced overall bioavailability of RG7112 slightly over twofold. Following multiple-dose administrations, all four schedules yielded the comparable per-cycle (28-d) exposure (AUC), as designed; liquid supplements also enhanced bioavailability. High-dose treatments of consecutive daily dosing for 5 and 3 days resulted in higher on-treatment-day exposure to RG7112 than both weekly and low-dose/long-duration (20-day) daily schedules. Serum MIC-1 and blood platelet profiles showed similar patterns to those of PK when the clinical pharmacology conditions were varied, suggesting the relative importance of treatment-day exposure than overall per-cycle AUC. CONCLUSION: Food (both high-fat and low-fat meals) and new formulation enhanced bioavailability. High-dose consecutive daily treatment for 3-5 days is superior to weekly and low-dose/long-duration (20-day) daily schedules in yielding the sufficiently high drug exposure and PD effects potentially required for cancer treatment efficacy.

Antiproliferative effect induced by novel imidazoline S43126 in PC12 cells is mediated by ROS, stress activated MAPKs and caspases.

BACKGROUND: Some imidazoline compounds have pleiotropic effects including cell death in vitro. We examined the antiproliferative action of a novel imidazoline compound S43126, and the role of the I1-imidazoline receptor, ROS, MAPKs and caspases in S43126-induced cell death. METHODS: PC 12 cells were treated with various concentrations of S43126 in the presence or absence of several ligands, and the effects on cell proliferation, ROS levels, and apoptosis were evaluated using Trypan Blue, Alamar Blue, Western blot and microscopy. RESULTS: We showed that S43126 reduced PC12 cell proliferation by greater than 50%, increased cell death by greater than 40% and increased apoptotic body formation. These effects were reversed by I1R-antagonist, efaroxan. S43126 also increased intracellular ROS levels by greater than 2.5-fold relative to vehicle-treated control. These effects were significantly inhibited by N-acetyl-cysteine. In addition, pharmacologic inhibitors of ERK, JNK and p38 MAPK, significantly reduced S43126-induced antiproliferative activity. Caspases 3, 8 and 9 were all activated in a time-dependent manner by S43126. Pan caspase inhibitor z-VAD-fmk, ameliorated the effects of S43126 on cell death and cell proliferation. CONCLUSION: Our data showed that the effects of S43126 on PC12 cell death were partly mediated by ROS production, MAPK and caspase activation. These results further indicate an emerging role for I1R in apoptotic processes.

Methylation of imidazoline related compounds leads to loss of α2-adrenoceptor affinity. Synthesis and biological evaluation of selective I1 imidazoline receptor ligands.

Methylated analogues of imidazoline related compounds (IRC) were prepared; their abilities to bind I(1) imidazoline receptors (I(1)Rs), I(2) imidazoline binding sites (I(2)BS) and α(2)-adrenoceptor subtypes (α(2)ARs) were assessed. Methylation of the heterocyclic moiety of IRC resulted in a significant loss of α(2)AR affinity. Amongst the selective ligands obtained, LNP 630 (4) constitutes the first highly selective I(1)R agent showing hypotensive activity after intravenous administration.

Attenuation of collagen-induced arthritis by orally available imidazoline-based NF-κB inhibitors.

The pathogenesis of rheumatoid arthritis is mainly driven by NF-κB-mediated production of cytokines, such as TNF-α. We report herein that the orally available imidazoline-based NF-κB inhibitor, TCH-013, was found to significantly reduce TNF-α signaling and attenuate collagen antibody induced arthritis in BALB/c mice.

Novel I1-imidazoline S43126 enhance insulin action in PC12 cells.

The I(1)-imidazoline receptor is a novel target for drug development for hypertension and insulin resistance, major disorders associated with type 2 diabetes. In the present study, we examined the effects of a novel imidazoline agonist S43126, on phosphorylation of protein kinase B (PKB/Akt) and extracellular signal-regulated kinase (ERK1/2) in PC12 cells. We further examined the effects of S43126 on insulin stimulated PKB and ERK phosphorylation. PC12 cells were treated with varying doses of S43126 (10(-10) to 10(-6) M) or insulin (10(-10) to 10(-6) M) or combination treatment with insulin (10(-6) M) and varying doses of S43126 (10(-6) - 10(-11) M) for 10 min. Western blot analysis of treated samples showed that S43126 increased both ERK1/2 and PKB phosphorylation by 5 fold. Combination treatment with insulin (10(-6) M) and varying doses of S43126 (10(-6) - 10(-11) M) enhanced phosphorylation of PKB and ERK1/2 above the level of insulin alone, in a dose and time dependent manner. Treatment with siRNA against Nischarin (mouse homologue of I(1)-imidazoline receptor) reduced the phosphorylation of both ERK and PKB following combination treatments. These results indicate that S43126 has the potential to augment insulin action and should be further studied as a possible candidate drug for the treatment of insulin resistance states.

Identification of 2-oxo-N-(phenylmethyl)-4-imidazolidinecarboxamide antagonists of the P2X(7) receptor.

A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented.

Evidence that some imidazoline derivatives inhibit peripherally the vasopressor sympathetic outflow in pithed rats.

Imidazoline derivatives (e.g. clonidine and moxonidine) and alpha(2)-adrenoceptor agonists (e.g. B-HT 933) have been shown to inhibit sympathetically-induced [(3)H]noradrenaline release in several isolated blood vessels. The present study has compared the potential capability of agonists at imidazoline I(1/2) receptors and/or alpha(1/2)-adrenoceptors to inhibit the sympathetically-induced vasopressor responses in pithed rats. For this purpose, male Wistar rats were pithed and prepared for measurement of diastolic blood pressure and heart rate. Then, the vasopressor responses induced by either selective electrical stimulation (2 ms, 60 V; 0.03, 0.1, 0.3, 1 and 3 Hz) of the vascular sympathetic outflow (T(7)-T(9)) or i.v. bolus injections of exogenous noradrenaline (0.03, 0.1, 0.3, 1 and 3 microg/kg) were determined before and during i.v. continuous infusions of the agonists B-HT 933 (alpha(2)), clonidine (alpha(2), I(1)), moxonidine (alpha(2), I(1)), cirazoline (alpha(1), I(2)), agmatine (putative endogenous ligand of imidazoline receptors) and methoxamine (alpha(1)), or equivalent volumes of physiological saline. Electrical sympathetic stimulation elicited frequency-dependent vasopressor responses which were significantly inhibited during the continuous infusions of B-HT 933, clonidine, moxonidine, cirazoline and agmatine, but not of physiological saline. Interestingly, the vasopressor responses to exogenous noradrenaline, which remained unaffected during the infusions of physiological saline, B-HT 933, moxonidine, cirazoline and agmatine, were significantly blocked during the infusions of clonidine or methoxamine. These results suggest that B-HT 933, moxonidine, cirazoline and agmatine induced a prejunctional inhibition of the vasopressor sympathetic outflow in pithed rats, whilst clonidine inhibited the vasopressor sympathetic outflow by both prejunctional and postjunctional mechanisms.

Drug facilitated sexual assault using an over-the-counter ocular solution containing tetrahydrozoline (Visine).

Drug facilitated sexual assault (DFSA) has been defined as sexual activity occurring where consent is invalid or absent due to the effects of drugs and or alcohol. We report the use of a commonly available over-the-counter drug to induce an obtunded compliant victim with no memory of the period during the sexual assault. An adult male repeatedly used tetrahydrozoline to induce a comatose state in an adult female and four female children for the purposes of sexual assault. It may be warranted to include imidazoline derivatives in the testing for cases of DFSA.