RESUMO
With the concept of precision medicine, combining multiple molecular-targeting therapies has brought new approaches to current cancer treatments. Malfunction of the tumor suppressor protein, p53 is a universal hallmark in human cancers. Under normal conditions, p53 is degraded through an ubiquitin-proteosome pathway regulated by its negative regulator, MDM2. In contrast, cellular stress such as DNA damage will activate p53 to carry out DNA repair, cell cycle arrest, and apoptosis. In this study, we focused on ovarian carcinoma with high EGFR and MDM2 overexpression rate. We assessed the effects of combined inhibition by MDM2 (JNJ-26854165) and EGFR (gefitinib) inhibitors on various ovarian cell lines to determine the importance of these two molecular targets on cell proliferation. We then used a proteomic strategy to investigate the relationship between MDM2 and EGFR inhibition to explore the underlying mechanisms of how their combined signaling blockades work together to exert cooperative inhibition. Our results demonstrated that all four cell lines were sensitive to both individual and combined, MDM2 and EGFR inhibition. The proteomic analysis also showed that gefitinib/JNJ-treated CAOV3 cells exhibited downregulation of proteins involved in nucleotide biosynthesis such as nucleoside diphosphate kinase B (NME2). In conclusion, our study showed that the combined treatment with JNJ and gefitinib exerted synergistic inhibition on cell proliferation, thereby suggesting the potential application of combining MDM2 inhibitors with EGFR inhibitors for enhancing efficacy in ovarian cancer treatment.
Assuntos
Antineoplásicos/farmacologia , Gefitinibe/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Triptaminas/farmacologia , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Gefitinibe/administração & dosagem , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proteoma/metabolismo , Proteômica , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Triptaminas/administração & dosagemRESUMO
Although interactions between drugs and acrylate pressure sensitive adhesives (PSAs) containing amide groups were reported in the previous studies, detailed studies elucidating their mechanism of action are still lacking. In the present study, an amide PSA (AACONH2) and a hydroxyl PSA (AAOH, as the control) were synthesized, and their molecular mechanism of controlled drug release was described. Using zolmitriptan (ZOL) and etodolac (ETO) as model drugs, in vitro drug release and skin permeation experiments were performed. Intermolecular interactions between drugs and PSAs were determined by Flory-Huggins model, FT-IR spectroscopic analysis and molecular modeling. In addition, PSA mobility was evaluated using differential scanning calorimetry and rheology study. Release percent of ZOL and ETO from AACONH2 were 43.9⯱â¯0.3% and 50.0⯱â¯2.0% respectively, while from AAOH, the release percent of ZOL and ETO were 61.4⯱â¯1.2% and 81.0⯱â¯1.2% separately. As a consequence of controlled drug release, skin permeation of both drugs was significantly controlled by AACONH2. It was demonstrated that AACONH2 markedly interacted with drugs, especially with ETO, through hydrogen bonding and weak intermolecular forces (e.g. dipole-dipole and van der waals). PSA mobility of AACONH2 was significantly increased due to drug-PSA interactions. In conclusion, AACONH2 had stronger controlled release properties compared with AAOH, which was mainly caused by the stronger interactions between amide groups and drugs. The amide PSA synthesized in the present study was a potential sustained-release excipient for transdermal drug delivery system.
Assuntos
Adesivos/administração & dosagem , Amidas/administração & dosagem , Radical Hidroxila/administração & dosagem , Adesivo Transdérmico , Adesivos/química , Amidas/química , Animais , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/química , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Liberação Controlada de Fármacos , Etodolac/administração & dosagem , Etodolac/química , Radical Hidroxila/química , Masculino , Modelos Moleculares , Oxazolidinonas/administração & dosagem , Oxazolidinonas/química , Ratos Wistar , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/química , Pele/metabolismo , Absorção Cutânea , Triptaminas/administração & dosagem , Triptaminas/químicaRESUMO
The present investigation deals with preparation and characterization of anti-migraine zolmitriptan (ZMT) nanostructured polymeric carriers for nose to brain drug targeting. The drug-loaded colloidal nanocarriers of ZMT were prepared by modified ionic gelation of cationic chitosan with anionic sodium tripolyphosphate and characterized for particle size, zeta potential, and entrapment efficiency. Further, in order to investigate nose to brain drug targeting, biodistribution, and brain kinetics studies were performed using 99mtechnetium radiolabeled nanocarriers (99mTc-ZMTNP) in Swiss albino mice. The results were compared with intranasal pure drug solution (99mTc-ZMT) and intravenous nanocarriers (99mTc-ZMTNP). A single photon emission computerized tomography (SPECT) radioimaging studies were also carried out to visualize and confirm brain uptake of nanocarriers. The optimized nanocarriers showed particle size of 161 nm, entrapment efficiency of 80.6%, and zeta potential of + 23.7 mV. The pharmacokinetic parameters, Cmax, and AUC0-∞ values for ZMT concentration in the brain expressed as percent radioactivity per gram of brain in intranasal and intravenous route of administration were calculated. The brain Cmax and AUC0-∞ values found in three groups, intranasal 99mTc-ZMTNP, intranasal 99mTc-ZMT, and intravenous 99mTc-ZMTNP were (0.427 and 1.889), (0.272 and 0.7157), and (0.204 and 0.9333), respectively. The higher Cmax values of intranasal 99mTc-ZMTNP suggests better brain uptake as compared to other routes of administration. The significant higher values of nose to brain targeting parameters namely, drug targeting index (5.57), drug targeting efficiency (557.08%), and nose to brain drug direct transport (82.05%) confirmed drug targeting to brain via nasal route. The coupled bimodal SPECT-CT scintigrams confirm the brain uptake of intranasal 99mTc-ZMTNP demonstrating major radioactivity accumulation in brain. This study conclusively demonstrated the greater uptake of ZMT-loaded nanocarriers by nose to brain drug targeting, which proves promising drug delivery system.
Assuntos
Encéfalo/metabolismo , Portadores de Fármacos/administração & dosagem , Nanoestruturas/administração & dosagem , Oxazolidinonas/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Triptaminas/administração & dosagem , Administração Intranasal , Administração Intravenosa , Animais , Encéfalo/diagnóstico por imagem , Quitosana/administração & dosagem , Quitosana/química , Quitosana/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Cinética , Masculino , Camundongos , Nanoestruturas/química , Oxazolidinonas/química , Oxazolidinonas/farmacocinética , Polifosfatos/administração & dosagem , Polifosfatos/química , Polifosfatos/farmacocinética , Agonistas do Receptor 5-HT1 de Serotonina/química , Agonistas do Receptor 5-HT1 de Serotonina/farmacocinética , Tecnécio , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Triptaminas/química , Triptaminas/farmacocinéticaRESUMO
OBJECTIVES: To describe prophylactic and acute medication treatment patterns, including timing, medication type, and duration of use in migraine patients initiating prophylaxis. BACKGROUND: Patients with migraine can be treated with acute and prophylactic therapies. Current treatment options for migraine prophylaxis are associated with poor tolerability and low adherence and persistence. METHODS: This retrospective cohort study used the Truven Health Analytics MarketScan® Research Databases to identify adults in the United States with a migraine diagnosis who initiated migraine prophylactic medication (index event) between January 1, 2008, and December 31, 2011. Prescribed prophylactic medications evaluated included topiramate, beta-blockers, and tricyclic antidepressants. Patients were required to have 12 months of pre- and post-index continuous enrollment. Patient characteristics, migraine-specific prescribed prophylactic treatment patterns (including gaps in therapy, treatment switches, and additions of index medications), and prescribed acute medication utilization were assessed. RESULTS: The study population comprised 107,122 patients, with 52,275 (49%) initiating topiramate, 22,658 (21%) initiating beta-blockers, and 32,189 (30%) initiating tricyclic antidepressants. Mean (SD) age was 41 (12) years and 83% were female. Persistence with migraine prophylactic medication was low; 81% of patients had gaps of >90 days in their migraine prophylaxis in the first year. The gap in therapy occurred early in treatment (mean, 95 days), and only 10% of patients restarted prophylactic therapy within that year. Switching from index medication to another prophylactic medication or adding prophylaxis was uncommon (13% and 5%, respectively). One year after initiating prophylaxis, 65% of patients were not receiving any prophylactic therapies. Most patients initiating migraine prophylaxis also utilized acute treatments (81%); opioid use was more frequent than triptan use (53% vs 48%) and was common (40%) among patients without other chronic pain conditions (eg, arthritis, fibromyalgia, and lower back pain). CONCLUSION: Patients with migraine who initiated prophylactic therapy had poor persistence with early gaps in therapy, were unlikely to switch prophylactic treatments, and most discontinued prophylaxis by the end of the first year.
Assuntos
Seguro Saúde/tendências , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/epidemiologia , Profilaxia Pré-Exposição/métodos , Adolescente , Antagonistas Adrenérgicos beta/administração & dosagem , Adulto , Idoso , Analgésicos/administração & dosagem , Antidepressivos Tricíclicos/administração & dosagem , Estudos de Coortes , Esquema de Medicação , Prescrições de Medicamentos , Substituição de Medicamentos/métodos , Substituição de Medicamentos/tendências , Feminino , Seguimentos , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Transtornos de Enxaqueca/diagnóstico , Profilaxia Pré-Exposição/tendências , Estudos Retrospectivos , Triptaminas/administração & dosagem , Estados Unidos/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: To characterize demographics, clinical characteristics, and treatment patterns of patients with cluster headache (CH). BACKGROUND: CH is an uncommon trigeminal autonomic cephalalgia with limited evidence-based treatment options. Patients suffer from extremely painful unilateral headache attacks and autonomic symptoms with episodic and chronic cycles. DESIGN/METHODS: This retrospective analysis used insurance claims from Truven Health Analytics MarketScan® research databases from 2009 to 2014. Two cohorts were compared: CH patients (with ≥2 CH claims) were propensity score matched with 4 non-headache controls, all with continuous enrollment for 12 months before and after the date of first CH claim or matched period among controls. RESULTS: CH patients (N = 7589) were mainly male (57.4%) and 35-64 years old (73.2%), with significantly more claims for comorbid conditions vs controls (N = 30,341), including depressive disorders (19.8% vs 10.0%), sleep disturbances (19.7% vs 9.1%), anxiety disorders (19.2% vs 8.7%), and tobacco use disorders (12.8% vs 5.3%), with 2.5 times greater odds of suicidal ideation (all P < .0001). Odds of drug dependence were 3-fold greater among CH patients (OR = 2.8 [95% CI 2.3-3.4, P < .0001]). CH patients reported significantly greater use of prescription medications compared with controls; 25% of CH patients had >12 unique prescription drug claims. Most commonly prescribed drug classes for CH patients included: opiate agonists (41%), corticosteroids (34%), 5HT-1 agonists (32%), antidepressants (31%), NSAIDs (29%), anticonvulsants (28%), calcium antagonists (27%), and benzodiazepines (22%). Only 30.4% of CH patients received recognized CH treatments without opioids during the 12-month post-index period. These patients were less likely to visit emergency departments or need hospitalizations (26.8%) as compared to CH patients with no pharmacy claims for recognized CH treatments or opioids (33.6%; P < .0001). CONCLUSIONS: The burden of CH is associated with significant co-morbidity, including substance use disorders and suicidal ideation, and treatment patterns indicating low use of recognized CH treatments.
Assuntos
Demandas Administrativas em Assistência à Saúde , Cefaleia Histamínica/epidemiologia , Cefaleia Histamínica/terapia , Bases de Dados Factuais/tendências , Revisão da Utilização de Seguros/tendências , Adolescente , Adulto , Idoso , Analgésicos Opioides/administração & dosagem , Cefaleia Histamínica/psicologia , Estudos de Coortes , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Transtornos Relacionados ao Uso de Substâncias/terapia , Ideação Suicida , Resultado do Tratamento , Triptaminas/administração & dosagem , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Despite several studies suggesting the therapeutic use of 5-hydroxytryptamine receptors type 2A (5-HT2A ) agonists in the treatment of substance use disorders, the neurobiological basis accounting for such effects are still unknown. It has been observed that chronic exposure to drugs of abuse produces molecular and cellular adaptations in ventral tegmental area (VTA) neurons, mediated by brain-derived neurotrophic factor (BDNF). These BDNF-induced adaptations in the VTA are associated with the establishment of aversive withdrawal motivation that leads to a drug-dependent state. Growing evidence suggests that 5-HT2A receptor signaling can regulate the expression of BDNF in the brain. In this study, we observed that a single systemic or intra-VTA administration of a 5-HT2A agonist in rats and mice blocks both the aversive conditioned response to drug withdrawal and the mechanism responsible for switching from a drug-naive to a drug-dependent motivational system. Our results suggest that 5-HT2A agonists could be used as therapeutic agents to reverse a drug dependent state, as well as inhibiting the aversive effects produced by drug withdrawal.
Assuntos
Alucinógenos/uso terapêutico , Dependência de Heroína/tratamento farmacológico , N,N-Dimetiltriptamina/análogos & derivados , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Triptaminas/uso terapêutico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Alucinógenos/administração & dosagem , Dependência de Heroína/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , N,N-Dimetiltriptamina/administração & dosagem , N,N-Dimetiltriptamina/uso terapêutico , Ratos , Ratos Wistar , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Síndrome de Abstinência a Substâncias/prevenção & controle , Triptaminas/administração & dosagem , Área Tegmentar Ventral/metabolismoRESUMO
Polysialic acid (PSA) is a large negatively charged glycan mainly attached to the neural cell adhesion molecule (NCAM). Several studies have shown that it is important for correct formation of brain circuitries during development and for synaptic plasticity, learning and memory in the adult. PSA also plays a major role in nervous system regeneration following injury. As a next step for clinical translation of PSA based therapeutics, we have previously identified the small organic compounds 5-nonyloxytryptamine and vinorelbine as PSA mimetics. Activity of 5-nonyloxytryptamine and vinorelbine had been confirmed in assays with neural cells from the central and peripheral nervous system in vitro and shown to be independent of their function as serotonin receptor 5-HT1B/1D agonist or cytostatic drug, respectively. As we show here in an in vivo paradigm for spinal cord injury in mice, 5-nonyloxytryptamine and vinorelbine enhance regain of motor functions, axonal regrowth, motor neuron survival and remyelination. These data indicate that 5-nonyloxytryptamine and vinorelbine may be re-tasked from their current usage as a 5-HT1B/1D agonist or cytostatic drug to act as mimetics for PSA to stimulate regeneration after injury in the mammalian nervous system.
Assuntos
Neurônios Motores/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Citostáticos/administração & dosagem , Camundongos , Neurônios Motores/patologia , Neurônios Motores/fisiologia , Moléculas de Adesão de Célula Nervosa/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Ácidos Siálicos/administração & dosagem , Ácidos Siálicos/química , Traumatismos da Medula Espinal/patologia , Triptaminas/administração & dosagem , Triptaminas/química , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , VinorelbinaRESUMO
Daily exposure to light synchronizes the circadian clock, located in the suprachiasmatic nucleus (SCN), to external day/night cycles. These responses to light can be modified by serotonergic drugs, such as serotonin 5HT1B receptor agonists. Triptans are specific 5HT1B agonists prescribed to treat migraines. Here, we examined the effects of two triptans (zolmitriptan and sumatriptan) on photic phase resetting in Syrian hamsters. Pre-treatment with intra-SCN sumatriptan significantly attenuates, and at higher doses completely blocks, phase advances to light during the late night. Pre-treatment with systemic zolmitriptan significantly attenuates both light-induced phase advances and phase delays. Neither of these drugs, nor their vehicles, causes phase shifts on their own. Pre-treatment with zolmitriptan also significantly reduces the expression of light-induced c-fos in the SCN. Neither zolmitriptan nor vehicle alone induces significant c-fos expression in the SCN. Finally, pre-treatment with zolmitriptan does not attenuate phase shifts to intra-SCN N-methyl-d-aspartate injections, indicating that the mechanism of action for zolmitriptan is likely to be through activation of presynaptic 5HT1B receptors on retinal terminals, thereby decreasing light-induced neurotransmitter release. As triptans are commercially available medications, there is potential for their use in blocking unwanted photic phase shifting during shift-work or jet-lag. Additionally, triptans may also affect the circadian clock in patients receiving them regularly for migraines. Finally, our results may hint at the mechanism by which triptans can alleviate the photophobia that frequently accompanies migraines, namely by activating 5HT1B receptors on retinal terminals elsewhere in the brain, and thereby diminishing visually-evoked neurotransmitter signalling in those areas.
Assuntos
Ritmo Circadiano/efeitos dos fármacos , Oxazolidinonas/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Sumatriptana/farmacologia , Núcleo Supraquiasmático/efeitos dos fármacos , Triptaminas/farmacologia , Animais , Cricetinae , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Agonistas de Aminoácidos Excitatórios/farmacologia , Genes fos/efeitos dos fármacos , Masculino , Mesocricetus , N-Metilaspartato/administração & dosagem , N-Metilaspartato/farmacologia , Oxazolidinonas/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Sumatriptana/administração & dosagem , Triptaminas/administração & dosagemRESUMO
Previous data showed that neuropathic pain induced by mechanical lesion of peripheral nerves responds differently to alleviating drugs at cephalic versus extracephalic level. Because neuropathic pain evoked by anti-cancer drugs differs from that triggered by mechanical nerve lesion, we investigated whether differences between cephalic and extracephalic levels could also be characterized in rodents rendered neuropathic by treatment with the anti-cancer platinum derivative oxaliplatin. C57BL/6J mice received two injections and Sprague-Dawley rats three injections of oxaliplatin (10 mg/kg, i.p.) or its vehicle, with three days intervals. Supersensitivity to mechanical (von Frey filaments), cold (acetone drop) and chemical/inflammatory (formalin) stimulations was assessed in vibrissae and hindpaw territories. Transcripts of neuroinflammatory markers were quantified by real-time RT-qPCR in rat ganglia and central tissues. Oxaliplatin induced mechanical allodynia, cold hyperalgesia and chemical/inflammatory supersensitivity at both hindpaw and vibrissal levels in mice and rats. Acute treatment with gabapentin (30 mg/kg i.p.), morphine (3 mg/kg s.c.) or the 5-HT1A receptor agonist 8-OH-DPAT (0.16 mg/kg s.c.) significantly reduced oxaliplatin-induced supersensitivity in hindpaw but not vibrissal territory. In contrast, the antimigraine drugs naratriptan (0.1 mg/kg s.c.) and olcegepant (0.6 mg/kg i.v.) decreased oxaliplatin-induced supersensitivity in vibrissal territory only. Among the various markers investigated, only TRPA1 transcript was upregulated in ganglia of oxaliplatin-treated rats. These data showed that oxaliplatin induced supersensitivity to various stimuli in both cephalic and extra-cephalic territories in rodents. Regional differences in the efficacy of drugs to alleviate oxaliplatin-induced allodynia/hyperalgesia further support the idea that mechanisms underlying neuropathic pain have peculiarities at cephalic versus extra-cephalic level.
Assuntos
Analgésicos/administração & dosagem , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Aminas/administração & dosagem , Animais , Temperatura Baixa , Ácidos Cicloexanocarboxílicos/administração & dosagem , Dipeptídeos/farmacologia , Formaldeído , Gabapentina , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfina/administração & dosagem , Compostos Organoplatínicos , Oxaliplatina , Piperazinas , Piperidinas/administração & dosagem , Quinazolinas/farmacologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Canal de Cátion TRPA1 , Canais de Cátion TRPC/metabolismo , Tato , Triptaminas/administração & dosagem , Ácido gama-Aminobutírico/administração & dosagemRESUMO
OBJECTIVE: Only a limited proportion of patients needing pharmacological control of portal hypertension are hemodynamic responders to propranolol. Here we analyzed the effects of zolmitriptan on portal pressure and its potential interaction with propranolol. METHODS: ZOLMITRIPTAN, PROPRANOLOL OR BOTH WERE TESTED IN TWO RAT MODELS OF PORTAL HYPERTENSION: common bile duct ligation (CBDL) and CCl4-induced cirrhosis. In these animals we measured different hemodynamic parameters including portal venous pressure, arterial renal flow, portal blood flow and cardiac output. We also studied the changes in superior mesenteric artery perfusion pressure and in arterial wall cAMP levels induced by zolmitriptan, propranolol or both. Moreover, we determined the effect of splanchnic sympathectomy on the response of PVP to zolmitriptan. RESULTS: In both models of portal hypertension zolmitriptan induced a dose-dependent transient descent of portal pressure accompanied by reduction of portal flow with only slight decrease in renal flow. In cirrhotic rats, splanchnic sympathectomy intensified and prolonged zolmitriptan-induced portal pressure descent. Also, propranolol caused more intense and durable portal pressure fall when combined with zolmitriptan. Mesenteric artery perfusion pressure peaked for about 1 min upon zolmitriptan administration but showed no change with propranolol. However propranolol enhanced and prolonged the elevation in mesenteric artery perfusion pressure induced by zolmitriptan. In vitro studies showed that propranolol prevented the inhibitory effects of ß2-agonists on zolmitriptan-induced vasoconstriction and the combination of propranolol and zolmitriptan significantly reduced the elevation of cAMP caused by ß2-agonists. CONCLUSION: Zolmitriptan reduces portal hypertension and non-selective beta-blockers can improve this effect. Combination therapy deserves consideration for patients with portal hypertension failing to respond to non-selective beta-blockers.
Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão Portal/tratamento farmacológico , Hipertensão Portal/fisiopatologia , Oxazolidinonas/farmacologia , Pressão na Veia Porta/efeitos dos fármacos , Propranolol/farmacologia , Triptaminas/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Animais , Anti-Hipertensivos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Tetracloreto de Carbono , Catecolaminas/farmacologia , Ducto Colédoco/efeitos dos fármacos , Ducto Colédoco/patologia , Ducto Colédoco/fisiopatologia , AMP Cíclico/metabolismo , Sinergismo Farmacológico , Quimioterapia Combinada , Infusões Intravenosas , Ligadura , Cirrose Hepática Experimental/tratamento farmacológico , Cirrose Hepática Experimental/fisiopatologia , Lipressina/análogos & derivados , Lipressina/farmacologia , Lipressina/uso terapêutico , Artéria Mesentérica Superior/efeitos dos fármacos , Artéria Mesentérica Superior/patologia , Artéria Mesentérica Superior/fisiopatologia , Oxazolidinonas/administração & dosagem , Oxazolidinonas/uso terapêutico , Perfusão , Propranolol/uso terapêutico , Ratos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Artéria Renal/efeitos dos fármacos , Artéria Renal/fisiopatologia , Circulação Esplâncnica/efeitos dos fármacos , Simpatectomia , Terlipressina , Triptaminas/administração & dosagem , Triptaminas/uso terapêutico , Vasodilatação/efeitos dos fármacosRESUMO
Triptans are an established treatment for acute migraine attacks. By activating 5HT1B/1D receptors they lead to vasoconstriction of the cerebral blood vessels which are dilated during migraine attacks. Moreover, they reduce secretion of vasoactive peptides and conduction of pain stimuli over the cerebral cortex. In up to 7% of cases of treatment with triptans, thoracic pain occurs, although this is mostly transient, mild and without lasting ischemia. We present the case of a 45 year-old woman with a history of migraine with visual aura since the age of 20. She had no history of diabetes mellitus, hypertension, smoking or any other risk factors for cardiovascular events before she was admitted to our emergency room with typical chest pain. An electrocardiogram revealed anterior myocardial infarction following her monthly dose of oral zolmitriptan. Catherization revealed a normal coronary arterial system. The laboratory indices for cardiac risk were within normal ranges. The patient was advised to avoid triptans permanently on being discharged.
Assuntos
Infarto Miocárdico de Parede Anterior/induzido quimicamente , Enxaqueca com Aura/tratamento farmacológico , Oxazolidinonas/efeitos adversos , Agonistas do Receptor 5-HT1 de Serotonina/efeitos adversos , Triptaminas/efeitos adversos , Administração Oral , Infarto Miocárdico de Parede Anterior/diagnóstico , Cateterismo Cardíaco , Angiografia Coronária , Eletrocardiografia , Feminino , Humanos , Pessoa de Meia-Idade , Oxazolidinonas/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Triptaminas/administração & dosagemRESUMO
The effects of different formulation variables including pressure sensitive adhesive (PSA), thickness of the matrix, solvent system, inclusion of crystallization inhibitor, loading amount of drug and enhancers on the transdermal absorption of zolmitriptan were investigated. Acrylic adhesive with hydroxyl functional group provided good adhesion force and high flux of zolmitriptan. Pseudopolymorphs of zolmitriptan were found to possess different solid-state properties that affected the permeation rate. Polyoxyethylene alkyl ethers significantly increased the permeation of zolmitriptan through hairless mouse skin. However, these enhancers induced crystallization of zolmitriptan. Kollidon(®) 30 delayed the crystallization without altering the permeation profile of zolmitriptan. Stability studies suggested that terpenes did not induce crystallization of zolmitriptan in the patch and stable formulations could be produced by using cineole and limonene, or their combination.
Assuntos
Excipientes/química , Oxazolidinonas/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Absorção Cutânea , Triptaminas/administração & dosagem , Adesivos/química , Administração Cutânea , Animais , Cristalização , Cicloexanóis/química , Cicloexenos/química , Sistemas de Liberação de Medicamentos , Eucaliptol , Limoneno , Camundongos , Camundongos Pelados , Monoterpenos/química , Oxazolidinonas/farmacocinética , Permeabilidade , Polietilenoglicóis/química , Povidona/química , Agonistas do Receptor 5-HT1 de Serotonina/farmacocinética , Solventes/química , Terpenos/química , Adesivo Transdérmico , Triptaminas/farmacocinéticaRESUMO
OBJECTIVE: This study aimed to assess the pharmacokinetics and tolerability of once- and twice-daily frovatriptan given for 6 days, a regimen that has previously been reported to reduce the incidence and severity of menstrual migraine when administered during the perimenstrual period. METHODS: This was a double-blind, placebo-controlled, two-period crossover study carried out in healthy premenopausal female volunteers aged >or=18 years (equal number taking or not taking estrogen-containing contraceptives [ECCs]) who were admitted to a clinical pharmacology unit. Women alternately received frovatriptan once daily (day 1: 5 mg; days 2-6: 2.5 mg) and twice daily (day 1: 5 mg [10 mg total]; days 2-6: 2.5 mg [5 mg total]) in a randomized treatment sequence. Dosing was also random with respect to the menstrual cycle. Whole blood samples were obtained on days 1 and 6 (predose and at 0.5, 1, 2, 4, 6, 8, 12 [before evening dose], 13, 14, 16 and 18 hours post-dose) and on days 2-5 (samples were taken before the morning dose). A final sample was drawn at 24 hours after the last treatment on day 6. A fully validated liquid chromatography assay coupled to a tandem mass spectroscopy assay measured drug concentrations (simultaneous measurement of frovatriptan and its metabolites). Pharmacokinetic parameters were determined using a noncompartmental approach. Safety and tolerability were measured by monitoring adverse events, haematology and biochemistry, vital signs, ECG results and physical examination findings. RESULTS: Twenty-six healthy women participated in the study and 24 (12 ECC users and 12 ECC nonusers) completed the study. One ECC user during period 1 and one nonuser during period 2 withdrew before completion; both were taking frovatriptan once daily. Most women were White (n = 21), three were Black, and one each was Hispanic or Asian; mean +/- SD age was 25.4 +/- 4.9 years; and mean +/- SD weight was 61.9 +/- 6.5 kg. For both once- and twice-daily dosing, time to reach maximum blood concentration (C(max)) [t(max)] was in the range of 2-4 hours. The loading dose enabled steady state (defined as constant trough blood concentration [C(min)]) to be reached by day 2 with both regimens. Geometric mean C(max) and area under the blood concentration-time curve from 0 to 12 hours (AUC(12)) were higher with twice- versus once-daily dosing (day 1: p < 0.02; day 6: p < 0.001 for both). C(min) was lower with once- (range 0.8-1.7 ng/mL) versus twice-daily frovatriptan (range 1.7-3.6 ng/mL). The ratio of C(max) : C(min) on days 1 and 6 was lower with twice- than with once-daily dosing, indicating less fluctuation in frovatriptan blood concentrations. ECC users had 26-68% higher C(max) and AUC from 0 to 24 hours values than nonusers on days 1 and 6 (p < 0.02); the clinical relevance of this is not known. Both dosing regimens were well tolerated; one incident of vomiting and one of headache were rated as moderate, with all other adverse events being rated as mild. CONCLUSION: Both frovatriptan regimens achieved steady-state therapeutic blood concentrations by day 2. Twice-daily dosing maintained more consistent drug concentrations than once-daily dosing and was well tolerated.
Assuntos
Carbazóis/farmacocinética , Menstruação , Transtornos de Enxaqueca/prevenção & controle , Agonistas do Receptor de Serotonina/farmacocinética , Triptaminas/farmacocinética , Adulto , Área Sob a Curva , Carbazóis/administração & dosagem , Carbazóis/efeitos adversos , Cromatografia Líquida/métodos , Anticoncepcionais/administração & dosagem , Estudos Cross-Over , Método Duplo-Cego , Esquema de Medicação , Estrogênios/administração & dosagem , Feminino , Humanos , Incidência , Transtornos de Enxaqueca/etiologia , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/efeitos adversos , Índice de Gravidade de Doença , Espectrometria de Massas em Tandem , Triptaminas/administração & dosagem , Triptaminas/efeitos adversos , Adulto JovemRESUMO
Acute treatment of menstrual migraine (MM) attacks is often incomplete and unsatisfactory, and perimenstrual prophylaxis with triptans, oestrogen supplementation or naproxen sodium may be needed for decreasing frequency and severity of the attack. In this pilot, open-label, non-randomised, parallel group study we evaluated, in 38 women with a history of MM, the efficacy of frovatriptan (n=14) 2.5 mg per os or transdermal oestrogens (n=10) 25 microg or naproxen sodium (n=14) 500 mg per os once-daily for the short-term prevention of MM. All treatments were administered in the morning for 6 days, beginning 2 days before the expected onset of menstrual headache. All women were asked to fill in a diary card, in the absence of (baseline) and under treatment, in order to score headache severity. All women reported at least one episode of MM at baseline. During treatment all patients taking transdermal oestrogens or naproxen sodium and 13 out of the 14 patients (93%) taking frovatriptan had at least one migraine attack (p=0.424). Daily incidence of migraine was significantly (p=0.045) lower under frovatriptan than under transdermal oestrogens or NS. At baseline, the overall median score of headache severity was 4.6, 4.2 and 4.3 in the group subsequently treated with frovatriptan, transdermal oestrogens and naproxen sodium, respectively (p=0.819). During treatment the median score was significantly lower under frovatriptan (2.5) than under transdermal oestrogens (3.0) and naproxen sodium (3.9, p=0.049). This was evident also for each single day of observation (p=0.016). Among treatments differences were particularly evident for the subgroup of patients with true MM (n=22) and for frovatriptan vs. naproxen sodium. This study suggests that short-term prophylaxis of MM with frovatriptan may be more effective than that based on transdermal oestrogens or naproxen sodium.
Assuntos
Carbazóis/administração & dosagem , Estrogênios/administração & dosagem , Distúrbios Menstruais/tratamento farmacológico , Transtornos de Enxaqueca/tratamento farmacológico , Naproxeno/administração & dosagem , Triptaminas/administração & dosagem , Administração Cutânea , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Feminino , Humanos , Distúrbios Menstruais/fisiopatologia , Distúrbios Menstruais/prevenção & controle , Transtornos de Enxaqueca/fisiopatologia , Transtornos de Enxaqueca/prevenção & controle , Medição da Dor/efeitos dos fármacos , Projetos Piloto , Prevenção Secundária , Agonistas do Receptor de Serotonina/administração & dosagem , Resultado do TratamentoRESUMO
Migraine is common in patients with Sturge-Weber syndrome, yet treatment options are poorly described. An Internet-based questionnaire was completed anonymously by 104 Sturge-Weber syndrome patients, 74 of whom reported experiencing migraines (median age, 25 years; range, 3-64 years). Sixteen (22%) subjects self-reported trying triptans. Five of 12 (42%) describing triptan response believed they were very efficacious (median time of onset of 26 minutes), compared to 13 of 65 (20%) using over-the-counter analgesics (P = .08). Eighty-eight percent (14/16) of triptan users self-reported that when they do not use medications, migraines had a moderate to severe impact on their quality of life; however, while taking triptans, only 50% (7/14) of users reported such an impact (P = .03). Two patients using triptans reported transient unilateral weakness. Of the 26 patients (35%) who received daily preventative medications, 80% experienced improved quality of life. In addition, only 10 of 24 (42%) reported a significant negative impact of migraines on quality of life with daily preventative use, compared to 22 of 26 (85%) without their use (P = .002). Sturge-Weber syndrome patients with migraines are using triptans and preventative agents and self-reporting good efficacy. The small sample size precludes any safety analysis, however, and future prospective trials of both treatment options are needed.
Assuntos
Revisão de Uso de Medicamentos/estatística & dados numéricos , Comportamentos Relacionados com a Saúde , Transtornos de Enxaqueca/terapia , Automedicação/estatística & dados numéricos , Síndrome de Sturge-Weber/terapia , Adolescente , Adulto , Analgésicos/administração & dosagem , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/etiologia , Automedicação/métodos , Síndrome de Sturge-Weber/complicações , Síndrome de Sturge-Weber/epidemiologia , Inquéritos e Questionários , Triptaminas/administração & dosagem , Triptaminas/efeitos adversosRESUMO
The S9-mediated mutagenesis of IQ and MeIQ in Salmonella strain TA98 was modulated by introduction to the assay of tryptamine or tyramine. Both biogenic amines inhibited or enhanced the mutagenic response as a function of amine concentration, strain of rat used as the S9 source, and the IQ-type mutagen tested. Enhancement of IQ mutagenesis by tryptamine (10-80 microM) was observed in the presence of S9 preparations derived from Aroclor 1254-pretreated Fischer rats; the enhancing effect ceased at tryptamine concentrations > 160 microM. When Sprague-Dawley-S9 or Wistar-S9 were used for activation, the enhancement of IQ mutagenesis by tryptamine shifted to inhibition at tryptamine concentrations > 40 microM, with Sprague-Dawley-S9, and > 20 microM, with Wistar-S9. By contrast, MeIQ-mutagenesis was enhanced by tryptamine (10-160 microM), regardless of the rat strain used as S9 source. Tyramine was a weaker enhancer of MeIQ mutagenesis than was tryptamine and, unlike tryptamine, its inhibitory effects on IQ mutagenesis were observed only with Wistar-S9. Tryptamine (10-80 microM) inhibited cytochromes P450IA1 and P450IA2 activities, monitored by the O-deethylation of ethoxyresorufin and Glu-P-1 mutagenesis in TA98, respectively. These data suggest that the effects of biogenic amines on IQ and MeIQ bioactivation are complex. Furthermore, this study demonstrates that tryptamine and tyramine act both as enhancers (comutagens) and as inhibitors (antimutagens) of IQ and MeIQ mutagenesis, depending on the testing conditions.
Assuntos
Quinolinas/administração & dosagem , Triptaminas/administração & dosagem , Tiramina/administração & dosagem , Animais , Inibidores das Enzimas do Citocromo P-450 , Imidazóis/metabolismo , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Testes de Mutagenicidade , Oxazinas/metabolismo , Ratos , Ratos Endogâmicos F344/metabolismo , Ratos Sprague-Dawley/metabolismo , Ratos Wistar , Salmonella typhimurium/efeitos dos fármacos , Especificidade da EspécieRESUMO
The method of mathematical theory of experiment was used to find optimum variants of the radioprotective complex APAETP + mexamine. The character of their pharmacological interaction, depending on their dose ratio, was determined. It is suggested that it is conditioned by the specific role of different mechanisms involved in the radioprotective effect.
Assuntos
5-Metoxitriptamina/administração & dosagem , Amifostina/administração & dosagem , Compostos Organotiofosforados/administração & dosagem , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação , Triptaminas/administração & dosagem , Amifostina/metabolismo , Animais , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Masculino , Camundongos , Distribuição TecidualRESUMO
In experiments on (CBA X C57Bl)F1 mice irradiated with doses of 8-12 Gy a study was made of the effect of a mixture of polyI-polyC (2.5 mg/kg, 2 days before irradiation) and mexamine (30 mg/kg, 5 min before irradiation) on the survival rate of animals and the times of their death. It was shown that polyI-polyC potentiates the protective effect of mexamine not increasing its toxicity. The protective agents used in a combination decrease the "intestinal" death of irradiated animals while used separately fail to produce this effect.