RESUMO
This month's Spotlight on... focuses on targeting aminoacyl-tRNA synthetases for the treatment of fungal infections. The emergence of drug-resistant strains of bacterial and fungal pathogens has led to the development of new antibiotic strategies. Aminoacyl-tRNA synthetases, crucial for protein synthesis, represent a new target for the treatment of different infectious diseases.
Assuntos
Aminoacil-tRNA Sintetases/antagonistas & inibidores , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Micoses/tratamento farmacológico , Aminoacilação de RNA de Transferência/efeitos dos fármacos , Aminoacil-tRNA Sintetases/metabolismo , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos de Boro/farmacologia , Compostos de Boro/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Ensaios Clínicos como Assunto , Cicloleucina/análogos & derivados , Cicloleucina/farmacologia , Cicloleucina/uso terapêutico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Isoleucina-tRNA Ligase/antagonistas & inibidores , Testes de Sensibilidade Microbiana , Mupirocina/farmacologia , Mupirocina/uso terapêutico , Micoses/metabolismo , Onicomicose/tratamento farmacológicoRESUMO
Icofungipen is a cyclic beta-amino acid being development by PLIVA, under license from Bayer, for the potential oral treatment of fungal infection. As of September 2002, the first phase II efficacy study was underway.
Assuntos
Antifúngicos/efeitos adversos , Antifúngicos/farmacologia , Cicloleucina/análogos & derivados , Micoses/tratamento farmacológico , Animais , Antifúngicos/síntese química , Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Antifúngicos/toxicidade , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Contraindicações , Cicloleucina/efeitos adversos , Cicloleucina/síntese química , Cicloleucina/farmacocinética , Cicloleucina/farmacologia , Cicloleucina/uso terapêutico , Cicloleucina/toxicidade , Humanos , Micoses/microbiologia , Relação Estrutura-AtividadeRESUMO
PLD-118, formerly BAY 10-8888, is a synthetic antifungal derivative of the naturally occurring beta-amino acid cispentacin. We studied the activity of PLD-118 in escalating dosages against experimental oropharyngeal and esophageal candidiasis (OPEC) caused by fluconazole (FLC)-resistant Candida albicans in immunocompromised rabbits. Infection was established by fluconazole-resistant (MIC > 64 microg/ml) clinical isolates from patients with refractory esophageal candidiasis. Antifungal therapy was administered for 7 days. Study groups consisted of untreated controls; animals receiving PLD-118 at 4, 10, 25, or 50 mg/kg of body weight/day via intravenous (i.v.) twice daily (BID) injections; animals receiving FLC at 2 mg/kg/day via i.v. BID injections; and animals receiving desoxycholate amphotericin B (DAMB) i.v. at 0.5 mg/kg/day. PLD-118- and DAMB-treated animals showed a significant dosage-dependent clearance of C. albicans from the tongue, oropharynx, and esophagus in comparison to untreated controls (P = 0.05, P = 0.01, P = 0.001, respectively), while FLC had no significant activity. PLD-118 demonstrated nonlinear plasma pharmacokinetics across the investigated dosage range, as was evident from a dose-dependent increase in plasma clearance and a dose-dependent decrease in the area under the plasma concentration-time curve. The biochemical safety profile was similar to that of FLC. In summary, PLD-118 demonstrated dosage-dependent antifungal activity and nonlinear plasma pharmacokinetics in treatment of experimental FLC-resistant oropharyngeal and esophageal candidiasis.
Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase/microbiologia , Cicloleucina/análogos & derivados , Cicloleucina/uso terapêutico , Inibidores Enzimáticos/farmacologia , Fluconazol/farmacologia , Isoleucina-tRNA Ligase/antagonistas & inibidores , Animais , Área Sob a Curva , Candida albicans/enzimologia , Candidíase Bucal/microbiologia , Cicloleucina/efeitos adversos , Cicloleucina/farmacocinética , Farmacorresistência Fúngica , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Doenças do Esôfago/microbiologia , Feminino , Meia-Vida , Terapia de Imunossupressão , CoelhosRESUMO
AIMS: To determine a possible role of metabotropic glutamate receptors in the spinobulbospinal micturition reflex pathway in the rat. MATERIALS AND METHODS: A selective metabotropic glutamate receptor agonist, trans-(+/-)-1-amino1,3-cyclopentanedicarboxylic acid (trans-ACPD) was administered to the lumbosacral spinal cord via an intrathecal catheter in urethane anesthetized rats. Amplitude of reflex bladder contractions evoked by bladder distension under isovolumetric condition as well as amplitude of bladder contractions elicited by electrical stimulation of the pontine micturition center (PMC) were examined before and after administration of trans-ACPD. The effect of trans-ACPD on the urethral activity during isovolumetric bladder contractions was also examined by monitoring urethral perfusion pressure and electromyography of the external urethral sphincter (EUS-EMG). RESULTS: Trans-ACPD (3-10 microg) completely inhibited reflex bladder contractions evoked by bladder distension and the duration of inhibition was dose dependent (3 microg: 11.4 +/- 2.8 min, 5 microg: 13.2 +/- 1.3 min, 10 microg: 36.2 +/- 2.4 min). The mean amplitude of bladder contractions evoked by electrical stimulation of the PMC was reduced to 12.6 +/- 2.3% of control by 10 microg of trans-ACPD. In addition, bursting activity of EUS-EMG and corresponding high frequency oscillations of urethral pressure during isovolumetric bladder contractions were completely abolished by 10 microg of trans-ACPD. CONCLUSIONS: These results indicate that intrathecal administration of a selective metabotropic glutamate receptor agonist to the lumbosacral spinal cord has an inhibitory effect on the spinobulbospinal micturition reflex pathway in urethane-anesthetized rats. This pharmacological action is attributed at least to the inhibitory effect on the descending pathway from the PMC to the lumbosacral spinal cord.
Assuntos
Cicloleucina/análogos & derivados , Cicloleucina/uso terapêutico , Receptores de Glutamato Metabotrópico/agonistas , Reflexo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Micção/efeitos dos fármacos , Anestesia Intravenosa , Anestésicos Intravenosos , Animais , Estimulação Elétrica , Eletromiografia , Injeções Intravenosas , Injeções Espinhais , Masculino , Contração Muscular/efeitos dos fármacos , Ratos , Ratos Wistar , Uretana , Bexiga Urinária/fisiopatologiaAssuntos
Antifúngicos/uso terapêutico , Cicloleucina/farmacologia , Cicloleucina/uso terapêutico , Farmacorresistência Fúngica , Micoses/tratamento farmacológico , Leveduras , Antifúngicos/farmacologia , Cicloleucina/análogos & derivados , Humanos , Micoses/microbiologia , Leveduras/efeitos dos fármacosRESUMO
1-Aminocyclopropanecarboxylic acid is a high affinity ligand with partial agonist properties at strychnine-insensitive glycine sites associated with the N-methyl-D-aspartate subtype of glutamate receptors. Since occupation of these sites appears required for operation of N-methyl-D-aspartate, receptor coupled cation channels, it was hypothesized that a glycine partial agonist could function as an N-methyl-D-aspartate antagonist. This hypothesis was examined by evaluating the in vivo and in vitro neuroprotective actions of 1-aminocyclopropanecarboxylic acid. 1-Aminocyclopropanecarboxlic acid (150-600 mg kg-1) administered to gerbils five minutes following twenty minutes of forebrain ischemia significantly improved seven day survival; the optimal dose (300 mg kg-1) increased 7 days survival > 4-fold, from 20% to 92%. Survival of hippocampal CA1 neurons (quantitated 7 days post-ischemia) was significantly (approximately 3-fold) increased by the 600 mg kg-1 dose. Seven day survival was not significantly increased when the interval between reperfusion and drug administration (300 mg kg-1) was increased from 5 to 30 min. In cerebellar granule cell cultures, NMDA combined with a saturating concentration of glycine (10 microM) resulted in a 500% increase in cGMP levels. cGMP levels were increased by 100% over basal when NMDA was combined with a saturating (10 microM) concentration of ACPC, indicating that in this measure, the efficacy of ACPC relative to glycine was approximately 0.2. Consistent with previous findings, 1-aminocyclopropanecarboxylic acid significantly reduced glutamate-induced neurotoxicity in cerebellar granule cell cultures. ACPC was most effective in blocking neurotoxicity at glutamate concentrations producing low to moderate levels of cell death.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Cicloleucina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Receptores de Glicina/agonistas , Estricnina/farmacologia , Animais , Isquemia Encefálica/prevenção & controle , Células Cultivadas , Feminino , Gerbillinae , Ratos , Ratos Sprague-DawleyRESUMO
Intracerebroventricular (i.c.v.) infusion in mice of the selective metabotropic excitatory amino acid receptor agonist 1S,3R-1- aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) (0.6-575 nmol/min) dose dependently induced face washing and scratching. In contrast, the subtype-specific ionotropic excitatory amino acid receptor agonists N-methyl-D-aspartate (NMDA), kainate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) (0.3-3.0 nmol/min) dose dependently induced clonic convulsions. I.c.v. infusion of the non-selective metabotropic receptor agonists ibotenate (6 nmol/min) or quisqualate (30 nmol/min) induced clonic convulsions. However, when ionotropic receptors were blocked with (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)cyclohepten-5,10-imine maleate (MK-801, dizoclipine) (3 nmol/min) or 2,3-dihydroxy-6-nitro-7- sulfamoyl-benzo(f)-quinoxaline (NBQX) (9 nmol/min), respectively, face washing and scratching behavior emerged. Neither MK-801 or NBQX (ED50 value > 100 nmol/min), nor the putative metabotropic receptor antagonist L-amino-3-phosphoro-propionic acid (L-AP3) (> 176 nmol/min); nor the dopamine receptor antagonists SCH 23390 (> 74 nmol/min), metoclopramide (> 89 nmol/min) and haloperidol (> 27 nmol/min) antagonized 1S,3R-ACPD-induced scratching (144 nmol/min). These results suggest that the behavioral consequences of i.c.v. infusion of 1S,3R-ACPD in mice reflect a selective activation of metabotropic receptors that differs from the behavioral changes observed with i.c.v. infusion of ionotropic receptor agonists.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cicloleucina/análogos & derivados , Ácido Caínico/farmacologia , N-Metilaspartato/farmacologia , Receptores de Glutamato/efeitos dos fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia , Animais , Cicloleucina/administração & dosagem , Cicloleucina/farmacologia , Cicloleucina/uso terapêutico , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Ácido Ibotênico/farmacologia , Ácido Caínico/administração & dosagem , Ácido Caínico/uso terapêutico , Masculino , Camundongos , N-Metilaspartato/administração & dosagem , N-Metilaspartato/uso terapêutico , Quinoxalinas/farmacologia , Ácido Quisquálico/farmacologia , Receptores de Glutamato/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/administração & dosagem , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/uso terapêuticoRESUMO
The role of the glutamate 'metabotropic' receptor was investigated in an experimental model of focal ischaemia-induced neurodegeneration. The metabotropic agonist, trans-1-amino cyclopentane-1,3-dicarboxylic acid (t-ACPD, 20 mg/kg i.p.), was administered to mice immediately after middle cerebral artery occlusion (MCAO), which causes cerebral infarct. Seven days after MCAO, the mean infarct volume value of the t-ACPD-treated group (mean +/- S.E. = 4.57 +/- 0.73 mm3) was significantly reduced, by 34.3%, compared to the vehicle-treated group (mean +/- S.E. = 6.95 +/- 0.59 mm3, P less than 0.01). This suggests that metabotropic receptor activation in the adult brain reduces excitotoxicity.
Assuntos
Cicloleucina/análogos & derivados , Ataque Isquêmico Transitório/tratamento farmacológico , Receptores de Glutamato/metabolismo , Animais , Artérias Cerebrais , Cicloleucina/farmacologia , Cicloleucina/uso terapêutico , Modelos Animais de Doenças , Ataque Isquêmico Transitório/metabolismo , Masculino , Camundongos , Receptores de Glutamato/efeitos dos fármacosRESUMO
Cispentacin [-)-(1R,2S)-2-aminocyclopentane-1-carboxylic acid) is a new antifungal antibiotic possessing potent anti-Candida activity. The 50% inhibitory concentration (IC50) and IC100 values of cispentacin against clinical isolates of Candida albicans were in the ranges 6.3 approximately 12.5 and 6.3 approximately 50 micrograms/ml, respectively, by turbidimetric measurement in yeast nitrogen base glucose medium. No significant activity was seen against any yeasts and molds when tested by the agar dilution method using three different agar media: KNOPP's agar, yeast extract-glucose-peptone agar and Sabouraud dextrose agar. This antibiotic demonstrated good therapeutic efficacy against a systemic Candida infection in mice by both parenteral and po administrations. The 50% protection dose (PD50) values after single iv and po administrations were 10 and 30 mg/kg, respectively. It was also effective in a systemic infection with Cryptococcus neoformans and in both lung and vaginal infections with C. albicans in mice. Cispentacin did not induce acute lethal toxicity at 1,000 mg/kg by iv injection and 1,500 mg/kg by ip and po administrations in mice.
Assuntos
Antifúngicos/uso terapêutico , Candidíase/tratamento farmacológico , Anfotericina B/farmacologia , Animais , Candida/efeitos dos fármacos , Cicloleucina/farmacologia , Cicloleucina/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Flucitosina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade MicrobianaRESUMO
Cycloleucine (CL), a non-metabolizable amino acid analogue, was found to reduce thymus and spleen weights in Semliki Forest virus (SFV) strain A7(74) infected and control mice. The maximum effects were seen when three daily doses of CL were given to mice 24 h after an SFV A7(74) infection. In these mice thymus atrophy led to abolition of thymus dependent immune responses and changes in the pathological features of the viral infection--the most striking feature being prevention of demyelination. In addition virus titres in the brains of CL treated infected mice were increased and prolonged. These results show that demyelination following an SFV A7(74) infection is not a result of direct virus action, but of a T-cell mediated mechanism.
Assuntos
Aminoácidos/uso terapêutico , Cicloleucina/uso terapêutico , Infecções por Togaviridae/tratamento farmacológico , Animais , Anticorpos Antivirais/análise , Encéfalo/patologia , Doenças Desmielinizantes/prevenção & controle , Relação Dose-Resposta a Droga , Imunoglobulina M/análise , Imunossupressores/uso terapêutico , Camundongos , Camundongos Endogâmicos , Tamanho do Órgão/efeitos dos fármacos , Vírus da Floresta de Semliki/isolamento & purificação , Baço/patologia , Timo/patologia , Infecções por Togaviridae/imunologiaRESUMO
Nitrous oxide (N2O) inactivates the vitamin B12-dependent enzyme methionine synthetase with subsequent impairment of folate metabolism and a reduction of cellular proliferation. Indications exist that this effect is antagonized by S-adenosylmethionine (SAM), and it was investigated whether combination with an inhibitor of SAM synthesis, cycloleucine, would result in increased inhibition of growth in rat leukaemia model (BNML). Leukaemic growth was compared in untreated rats, in rats treated with either nitrous oxide/oxygen (1:1) or cycloleucine (50 mg kg-1 i.p.), and in rats receiving both agents. Combined treatment resulted in the strongest reduction of leukaemic infiltration in spleen and liver, and this reduction often was more than the added effects of single treatments. Peripheral leukocyte counts were also lowest after combined treatment. The deoxyuridine suppression test, measuring folate-dependent de novo synthesis of thymidine, was more severely disturbed with combined treatment. Levels of vitamin B12 in plasma were reduced in rats receiving N2O, but an increase in plasma folate occurred in all treated rats. These results indicate that a reduction of SAM synthesis by cycloleucine can increase the disturbance of folate metabolism that is caused by nitrous oxide, with a potentiation of the effects on leukaemic growth.
Assuntos
Aminoácidos/uso terapêutico , Cicloleucina/uso terapêutico , Leucemia Experimental/tratamento farmacológico , Óxido Nitroso/uso terapêutico , Animais , Desoxiuridina , Sinergismo Farmacológico , Ácido Fólico/sangue , Leucemia Experimental/sangue , Leucemia Experimental/patologia , Contagem de Leucócitos , Fígado/patologia , Masculino , Tamanho do Órgão , Ratos , Ratos Endogâmicos BN , S-Adenosilmetionina/antagonistas & inibidores , Baço/patologia , Vitamina B 12/antagonistas & inibidores , Vitamina B 12/sangueAssuntos
Aminoácidos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Cicloleucina/administração & dosagem , Neoplasias Retais/tratamento farmacológico , Adulto , Idoso , Cicloleucina/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In this patient series, doxorubicin and cycloleucine at a dose of 300 mg/kg both show response rates in the treatment of advanced soft tissue sarcomas of about 15%. Lower doses of cycloleucine (200 mg/kg) yielded less toxicity but were less effective against the sarcomas (6% response rate, three of 51 patients). There were no complete responses with cycloleucine and there were three with doxorubicin. Survival times for patients receiving doxorubicin were significantly longer than those of patients receiving cycloleucine at doses of 300 mg/kg (P less than 0.001) or 200 mg/kg (P = 0.02). The estimated survival times were 29 weeks for doxorubicin and 21 (300 mg/kg) and 18 (200 mg/kg) weeks for cycloleucine. Toxic effects due to cycloleucine were excessive, with severe thrombocytopenia and central nervous system depression being the most prominent.
Assuntos
Aminoácidos/uso terapêutico , Cicloleucina/uso terapêutico , Doxorrubicina/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Adulto , Ensaios Clínicos como Assunto , Cicloleucina/administração & dosagem , Cicloleucina/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
The hypothesis that certain amino acid analogues possessing a five-membered ring structure or amino acid analogues that can be viewed as fragments derived from such a ring would have anticonvulsant activity was proposed and tested. The compounds 1-aminocyclopentane carboxylic acid, 1-amino-3-methylcyclopentane carboxylic acid, 3-aminotetrahydrothiophene carboxylic acid, and alpha-aminoisobutyric acid were found to protect rats against seizures in the maximal electroshock test but offered no protection against metrazol- (pentylenetetrazol) induced seizures in mice. The structural feature of this class of anticonvulsants that allows for hydrophobic interactions at the receptor site is considered to be a major physical factor necessary in promoting the activity of this class of anticonvulsants.
Assuntos
Aminoácidos/uso terapêutico , Anticonvulsivantes , Cicloleucina/uso terapêutico , Ácidos Aminoisobutíricos/uso terapêutico , Animais , Anticonvulsivantes/administração & dosagem , Cicloleucina/análogos & derivados , Relação Dose-Resposta a Droga , Eletrochoque , Masculino , Camundongos , Pentilenotetrazol , Ratos , Convulsões/induzido quimicamente , Relação Estrutura-AtividadeRESUMO
Cytostatic activity of 18 new phosphonic acid derivatives of cycloleucine, aspartic acid and glutamic acid was tested against human KB and mouse L1210s leukemia cell lines in vitro. The tests were performed according to international protocol 1.600 for screening of chemical agents against tissue culture system. Four of the tested compounds revealed their cytostatic activity at the dose 10 micrograms/ml.
Assuntos
Aminoácidos/uso terapêutico , Antineoplásicos/uso terapêutico , Ácido Aspártico/análogos & derivados , Cicloleucina/uso terapêutico , Glutamatos/uso terapêutico , Animais , Ácido Aspártico/uso terapêutico , Células Cultivadas , Fenômenos Químicos , Química , Cicloleucina/análogos & derivados , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Técnicas In Vitro , Leucemia L1210/patologia , Camundongos , Neoplasias Nasofaríngeas/patologia , Nasofaringe/patologiaAssuntos
Aminoácidos/uso terapêutico , Cicloleucina/uso terapêutico , Encefalomielite Autoimune Experimental/terapia , Fluorenos/uso terapêutico , Terapia de Imunossupressão , Tilorona/uso terapêutico , Animais , Soro Antilinfocitário/uso terapêutico , Ciclofosfamida/uso terapêutico , Sinergismo Farmacológico , Feminino , RatosAssuntos
Aminoácidos/farmacologia , Cicloleucina/farmacologia , Encefalomielite Autoimune Experimental/prevenção & controle , Macrófagos/efeitos dos fármacos , Adrenalectomia , Animais , Encéfalo/citologia , Encéfalo/imunologia , Cicloleucina/administração & dosagem , Cicloleucina/uso terapêutico , Ciclofosfamida/farmacologia , Esquema de Medicação , Encefalomielite Autoimune Experimental/imunologia , Adjuvante de Freund/farmacologia , Hidrocortisona/farmacologia , Imunização Passiva , Inflamação/tratamento farmacológico , Linfonodos/imunologia , Macrófagos/imunologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Baço/anatomia & histologia , Timo/anatomia & histologiaRESUMO
A tentative evaluation is proposed for the clinical status of 15 early and investigational drugs in human solid tumors.