-
Brazilian Journal of Microbiology :... Jul 2011Antihistaminics are widely used for various indications during microbial infection. Hence, this paper investigates the antimicrobial activities of 10 antihistaminics...
Antihistaminics are widely used for various indications during microbial infection. Hence, this paper investigates the antimicrobial activities of 10 antihistaminics belonging to both old and new generations using multiresistant Gram-positive and Gram-negative clinical isolates. The bacteriostatic activity of antihistaminics was investigated by determining their MIC both by broth and agar dilution techniques against 29 bacterial strains. Azelastine, cyproheptadine, mequitazine and promethazine were the most active among the tested drugs. Diphenhydramine and cetirizine possessed weaker activity whereas doxylamine, fexofenadine and loratadine were inactive even at the highest tested concentration (1 mg/ml). The MIC of meclozine could not be determined as it precipitated with the used culture media. The MBC values of antihistaminics were almost identical to the corresponding MIC values. The bactericidal activity of antihistaminics was also studied by the viable count technique in sterile saline solution. Evident killing effects were exerted by mequitazine, meclozine, azelastine and cyproheptadine. Moreover, the dynamics of bactericidal activity of azelastine were studied by the viable count technique in nutrient broth. This activity was found to be concentration-dependant. This effect was reduced on increasing the inoculum size while it was increased on raising the pH. The post-antimicrobial effect of 100 μg/ml azelastine was also determined and reached up to 3.36 h.
PubMed: 24031715
DOI: 10.1590/S1517-838220110003000018 -
Structure (London, England : 1993) Jan 2011The constitutive androstane receptor (CAR) transactivation can occur in the absence of exogenous ligand and this activity is enhanced by agonists TCPOBOP and meclizine.... (Comparative Study)
Comparative Study
The constitutive androstane receptor (CAR) transactivation can occur in the absence of exogenous ligand and this activity is enhanced by agonists TCPOBOP and meclizine. We use biophysical and cell-based assays to show that increased activity of CAR(TCPOBOP) relative to CAR(meclizine) corresponds to a higher affinity of CAR(TCPOBOP) for the steroid receptor coactivator-1. Additionally, steady-state fluorescence spectra suggest conformational differences between CAR(TCPOBOP):RXR and CAR(meclizine):RXR. Hydrogen/deuterium exchange (HDX) data indicate that the CAR activation function 2 (AF-2) is more stable in CAR(TCPOBOP):RXR and CAR(meclizine):RXR than in CAR:RXR. HDX kinetics also show significant differences between CAR(TCPOBOP):RXR and CAR(meclizine):RXR. Unlike CAR(meclizine):RXR, CAR(TCPOBOP):RXR shows a higher overall stabilization that extends into RXR. We identify residues 339-345 in CAR as an allosteric regulatory site with a greater magnitude reduction in exchange kinetics in CAR(TCPOBOP):RXR than CAR(meclizine):RXR. Accordingly, assays with mutations on CAR at leucine-340 and leucine-343 confirm this region as an important determinant of CAR activity.
Topics: Allosteric Site; Animals; Binding Sites; Constitutive Androstane Receptor; Humans; Meclizine; Mice; Models, Molecular; Nuclear Receptor Coactivator 1; Protein Binding; Protein Multimerization; Protein Stability; Protein Structure, Secondary; Protein Structure, Tertiary; Pyridines; Receptors, Cytoplasmic and Nuclear; Recombinant Fusion Proteins; Retinoid X Receptors; Thermodynamics; Transcriptional Activation
PubMed: 21220114
DOI: 10.1016/j.str.2010.11.008 -
Human Molecular Genetics Jan 2011Defects in cellular energy metabolism represent an early feature in a variety of human neurodegenerative diseases. Recent studies have shown that targeting energy...
Defects in cellular energy metabolism represent an early feature in a variety of human neurodegenerative diseases. Recent studies have shown that targeting energy metabolism can protect against neuronal cell death in such diseases. Here, we show that meclizine, a clinically used drug that we have recently shown to silence oxidative metabolism, suppresses apoptotic cell death in a murine cellular model of polyglutamine (polyQ) toxicity. We further show that this protective effect extends to neuronal dystrophy and cell death in Caenorhabditis elegans and Drosophila melanogaster models of polyQ toxicity. Meclizine's mechanism of action is not attributable to its anti-histaminergic or anti-muscarinic activity, but rather, strongly correlates with its ability to suppress mitochondrial respiration. Since meclizine is an approved drug that crosses the blood-brain barrier, it may hold therapeutic potential in the treatment of polyQ toxicity disorders, such as Huntington's disease.
Topics: Animals; Apoptosis; Caenorhabditis elegans; Cell Respiration; Disease Models, Animal; Drosophila melanogaster; Humans; Huntingtin Protein; Huntington Disease; Meclizine; Mice; Nerve Tissue Proteins; Neurons; Neuroprotective Agents; Nuclear Proteins; Peptides
PubMed: 20977989
DOI: 10.1093/hmg/ddq464 -
AAPS PharmSciTech Jun 2010The recent challenge in orally disintegrating tablets (ODT) manufacturing encompasses the compromise between instantaneous disintegration, sufficient hardness, and...
The recent challenge in orally disintegrating tablets (ODT) manufacturing encompasses the compromise between instantaneous disintegration, sufficient hardness, and standard processing equipment. The current investigation constitutes one attempt to fulfill this challenge. Maltodextrin, in the present work, was utilized as a novel excipient to prepare ODT of meclizine. Tablets were prepared by both direct compression and wet granulation techniques. The effect of maltodextrin concentrations on ODT characteristics--manifested as hardness and disintegration time--was studied. The effect of conditioning (40 degrees C and 75% relative humidity) as a post-compression treatment on ODT characteristics was also assessed. Furthermore, maltodextrin-pronounced hardening effect was investigated using differential scanning calorimetry (DSC) and X-ray analysis. Results revealed that in both techniques, rapid disintegration (30-40 s) would be achieved on the cost of tablet hardness (about 1 kg). Post-compression conditioning of tablets resulted in an increase in hardness (3 kg), while keeping rapid disintegration (30-40 s) according to guidance of the FDA for ODT. However, direct compression-conditioning technique exhibited drawbacks of long conditioning time and appearance of the so-called patch effect. These problems were, yet, absent in wet granulation-conditioning technique. DSC and X-ray analysis suggested involvement of glass-elastic deformation in maltodextrin hardening effect. High-performance liquid chromatography analysis of meclizine ODT suggested no degradation of the drug by the applied conditions of temperature and humidity. Overall results proposed that maltodextrin is a promising saccharide for production of ODT with accepted hardness-disintegration time compromise, utilizing standard processing equipment and phenomena of phase transition.
Topics: Administration, Oral; Carbohydrates; Compressive Strength; Delayed-Action Preparations; Drug Compounding; Drug Stability; Excipients; Hardness; Phase Transition; Polysaccharides; Tablets
PubMed: 20405257
DOI: 10.1208/s12249-010-9423-y -
Nature Biotechnology Mar 2010Most cells have the inherent capacity to shift their reliance on glycolysis relative to oxidative metabolism, and studies in model systems have shown that targeting such...
Most cells have the inherent capacity to shift their reliance on glycolysis relative to oxidative metabolism, and studies in model systems have shown that targeting such shifts may be useful in treating or preventing a variety of diseases ranging from cancer to ischemic injury. However, we currently have a limited number of mechanistically distinct classes of drugs that alter the relative activities of these two pathways. We screen for such compounds by scoring the ability of >3,500 small molecules to selectively impair growth and viability of human fibroblasts in media containing either galactose or glucose as the sole sugar source. We identify several clinically used drugs never linked to energy metabolism, including the antiemetic meclizine, which attenuates mitochondrial respiration through a mechanism distinct from that of canonical inhibitors. We further show that meclizine pretreatment confers cardioprotection and neuroprotection against ischemia-reperfusion injury in murine models. Nutrient-sensitized screening may provide a useful framework for understanding gene function and drug action within the context of energy metabolism.
Topics: Animals; Cell Line; Cell Survival; Drug Discovery; Fibroblasts; Galactose; Glucose; Glycolysis; Humans; Male; Meclizine; Mice; Mice, Inbred C57BL; Mitochondria; Models, Biological; Oxidative Phosphorylation
PubMed: 20160716
DOI: 10.1038/nbt.1606 -
Case Reports in Medicine 2009Vertigo, was provoked and right torsional up-beat nystagmus was observed in a 47-year-old patient when she was placed into the right Hallpike-Dix test position using...
Vertigo, was provoked and right torsional up-beat nystagmus was observed in a 47-year-old patient when she was placed into the right Hallpike-Dix test position using infrared goggle technology. The clinical diagnosis was benign paroxysmal positional vertigo (BPPV), specifically right posterior canalithiasis, resulting from a mild traumatic brain injury (TBI) suffered approximately six-months earlier. Previous medical consultations did not include vestibular system examination, and Meclizine was prescribed to suppress her chief complaint of vertigo. Ultimately, the patient was successfully managed by performing two canalith repositioning maneuvers during a single clinical session. The patient reported 100% resolution of symptoms upon reexamination the following day, and the Hallpike-Dix test was negative. Continued symptom resolution was subjectively reported 10 days postintervention via telephone consultation. This case report supports previous publications concerning the presence of BPPV following TBI and the need for inclusion of vestibular system examination during medical consultation.
PubMed: 19826635
DOI: 10.1155/2009/910596 -
Academic Emergency Medicine : Official... Oct 2009The most common vestibular disorders seen in the emergency department (ED) are benign paroxysmal positional vertigo (BPPV) and acute peripheral vestibulopathy (APV;...
OBJECTIVES
The most common vestibular disorders seen in the emergency department (ED) are benign paroxysmal positional vertigo (BPPV) and acute peripheral vestibulopathy (APV; i.e., vestibular neuritis or labyrinthitis). BPPV and APV are two very distinct disorders that have different clinical presentations that require different diagnostic and treatment strategies. BPPV can be diagnosed without imaging and is treated with canalith-repositioning maneuvers. APV sometimes requires neuroimaging by magnetic resonance imaging (MRI) to exclude posterior fossa stroke mimics and should be treated with vestibular sedatives and corticosteroids. We sought to determine if emergency physicians (EPs) apply best practices to diagnose and treat these common vestibular disorders.
METHODS
This was a cross-sectional study of ED visits from the National Hospital Ambulatory Medical Care Survey (NHAMCS). A weighted sample of U.S. ED visits (1993-2005) was used. Patients at least 16 years of age who were given a final ED diagnosis of BPPV (International Classification of Diseases, 9th Revision [ICD-9], 386.11) or APV (ICD-9 386.12 or 386.3x) comprised the study population. The frequency of imaging and drug therapy in those diagnosed as BPPV or APV versus controls was the main outcome measure.
RESULTS
A total of 9,472 dizzy patient visits were sampled over 13 years (weighted estimate 33.6 million U.S. ED visits over that period). A weighted estimate of 2.5 million patients (7.4%) were given a vestibular diagnosis, mostly BPPV (weighted 0.2 million) or APV (weighted 1.9 million). Patients given BPPV (19%) and APV (19%) diagnoses were more likely to undergo imaging (all by computed tomography [CT]) than controls (7%; p < 0.001). Patients given BPPV (58%) and APV (70%) diagnoses were more likely to receive meclizine than controls (0.1%; p < 0.001). Corticosteroid administration was rarely documented (2% BPPV, 1% APV).
CONCLUSIONS
Patients given a vestibular diagnosis in the ED may not be managed optimally. Patients given BPPV and APV diagnoses undergo imaging (predominantly CT) with equal frequency, suggesting overuse of CT (BPPV) and probably underuse of MRI (APV). Most patients diagnosed with BPPV are given meclizine, which is not indicated. Specific therapy for APV (corticosteroids) is probably underutilized. Educational initiatives and clinical guidelines merit consideration.
Topics: Adolescent; Adult; Aged; Cross-Sectional Studies; Decision Making; Diagnostic Imaging; Emergency Service, Hospital; Female; Health Care Surveys; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Practice Patterns, Physicians'; United States; Vertigo; Vestibular Neuronitis
PubMed: 19799573
DOI: 10.1111/j.1553-2712.2009.00523.x -
Australian Family Physician Jun 2008Vertigo is a common clinical problem managed by general practitioners. (Review)
Review
BACKGROUND
Vertigo is a common clinical problem managed by general practitioners.
OBJECTIVE
This article focuses on the acute management of a vertigo attack, specific management of conditions causing vertigo, and the long term management issues associated with chronic vertigo.
DISCUSSION
Supportive treatment, antiemetic and vestibular blocking agents help relieve an acute vertigo attack, however the prolonged use of such medications is not recommended. Specific treatments for various conditions causing vertigo are available, however, the majority of patients are managed symptomatically. The patient's ability to drive safely should be carefully assessed according to Austroads guidelines and advice from an ear, nose and throat surgeon should be sought when in doubt. There is evidence to support the efficacy of vestibular rehabilitation programs for unilateral peripheral vestibular disorder and these programs should be considered. A simple program including patient education and home based exercises can be sufficient.
Topics: Acute Disease; Antiemetics; Automobile Driving; Brain Stem; Chronic Disease; Family Practice; Humans; Meclizine; Methylprednisolone; Patient Education as Topic; Physical Therapy Modalities; Posture; Vertigo
PubMed: 18523693
DOI: No ID Found -
The Journal of Pain Feb 2006Formalin (0.25, 0.5, 3, and 5%) injected into the knee joint of rats induced a dose-dependent nociception that was featured by 2 phases of intense guarding behavior of...
UNLABELLED
Formalin (0.25, 0.5, 3, and 5%) injected into the knee joint of rats induced a dose-dependent nociception that was featured by 2 phases of intense guarding behavior of the affected limb, interposed by a period of quasinormal gait (quiescent phase). The guarding behavior during a period of forced gait was measured by the total time the paw of the affected limb was not in contact with the surface of a revolving cylinder (paw elevation time [PET]). Pretreatment with morphine (4 mg/kg, subcutaneously) reduced PET in both nocifensive phases, and naloxone (1 mg/kg, subcutaneously) antagonized morphine's effect. The cyclooxygenase inhibitor diclofenac (5 mg/kg, intraperitoneal) reduced only the second phase of nocifensive responses. A low dose of the benzodiazepine midazolam (0.25 mg/kg, intraperitoneal) significantly reduced only the second phase of response, but a higher dose (1 mg/kg, intraperitoneal) had no effect. A subconvulsant, anxiogenic dose of pentylenetetrazol (30 mg/kg, intraperitoneal) also did not affect the PET increase induced by formalin. The antihistamine meclizine (2.5 mg/kg, intraperitoneal) caused an increase of the response in the second phase, but a higher dose (7.5 mg/kg, intraperitoneal) caused inhibition. The peripheral antihistamine loratadine (5 and 10 mg/kg, intraperitoneal) also caused an increase of the second phase. Neither antihistamine altered the first phase of PET. These results reproduced previous findings with classical analgesics in formalin-induced nociception. However, the pronociceptive effect of antihistamines, and the antinociceptive effect of midazolam observed here suggest that formalin-induced incapacitation introduces new characterists of nociceptive system that may complement the study of analgesics.
PERSPECTIVES
Anxiety is thought to influence pain experience in an opposing manner depending on nociception originates in cutaneous or deep somatic/visceral tissues. The present formalin-induced nociceptive test may help to predict more reliably the pain-killing effect of new pharmacologic strategies, with classical or nonclassical mechanisms, for the treatment of clinically relevant pains, which are generally originated in deep structures.
Topics: Analgesics; Animals; Behavior, Animal; Disease Models, Animal; Formaldehyde; GABA Agents; Histamine H1 Antagonists; Injections, Intra-Articular; Knee Joint; Male; Motor Activity; Pain; Rats; Rats, Wistar
PubMed: 16459275
DOI: 10.1016/j.jpain.2005.09.002 -
Mediators of Inflammation Jun 2002Rats are commonly used in anaphylaxis models, mainly in intestinal anaphylaxis. Hypersensitivity mechanisms are complex and they are not clearly defined. Ovalbumin (OVA)...
Rats are commonly used in anaphylaxis models, mainly in intestinal anaphylaxis. Hypersensitivity mechanisms are complex and they are not clearly defined. Ovalbumin (OVA) is commonly used for studies on the hypersensitivity mechanism. However, the potential pro-inflammatory mediators induced by this antigen in the model of paw oedema in immunized rats are still not completely understood. This work examines the pharmacological modulation of several mediators involved in rat hind paw immune oedema induced by OVA. Wistar rats were previously immunized (14-18 days) with OVA (30 microg, intraperitoneally) or sham-sensitized with aluminum hydroxide (control). The paw volumes were measured before the antigenic stimuli and 1, 2, 3 and 4 h after the intraplantar injection of OVA (10 microg/paw). Subcutaneous injection of dexamethasone, diphenhydramine, cyproheptadine, chlorpromazine or methysergide significantly inhibited (p < 0.05) the allergic paw oedema. The dual inhibitor of cyclooxygenase and lipoxygenase (NDGA), the cyclooxygenase inhibitor (indomethacin), the lipoxygenase inhibitor (MK-886), the PAF antagonist (WEB 2086), the mast cell stabilizer (ketotifen), and the anti-histamine (meclizine) did not inhibit the immune oedema. In addition, thalidomide and pentoxifylline (anti-tumour necrosis factor drugs) were ineffective against OVA-induced oedema. The fact that indomethacin, MK-886, NDGA and WEB 2086 are unable to inhibit this allergic oedema indicates that the dexamethasone action seems not to be via phospholipase A2, but possibly due to the synthesis and/or the inhibitory activity of cytokines. The paw oedema inhibition by diphenhydramine, but not by meclizine, may suggest a different mechanism, which is independent of the effect of histamine. These data indicate that allergic oedema is more sensitive to anti-serotonin drugs, mainly anti-5-HT2, suggesting that the principal mediator of this inflammatory response is serotonin.
Topics: Animals; Anti-Allergic Agents; Azepines; Chlorpromazine; Dopamine Antagonists; Dose-Response Relationship, Immunologic; Edema; Enzyme Inhibitors; Foot; Histamine H1 Antagonists; Hypersensitivity; Immunization; Immunosuppressive Agents; Ketotifen; Ovalbumin; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Triazoles
PubMed: 12137244
DOI: 10.1080/09622935020138000