RESUMO
Minodronic acid is an aminobisphosphonate that is an antagonist of purinergic P2X2/3 receptors involved in pain. The aim of this study was to investigate the action and distribution of minodronic acid and the potential for P2X2/3 receptor antagonism based on the estimated concentration of minodronic acid. Microlocalization of radiolabeled minodronic acid was examined in the femur of neonatal rats. The bone-binding characteristics of minodronic acid and morphological changes in osteoclasts were analyzed in vitro. The minodronic acid concentration around bone resorption lacunae was predicted based on bone binding and the shape of lacunae. In microautoradiography, radioactive silver grains were abundant in bone-attached osteoclasts and were detected in calcified and ossification zones and in the cytoplasm of osteoclasts but not in the hypertrophic cartilage zone. In an osteoclast culture with 1 µM minodronic acid, 65% of minodronic acid was bound to bone, and C-terminal cross-linking telopeptide release was inhibited by 96%. Cultured osteoclasts without minodronic acid treatment formed ruffled borders and bone resorption lacunae and had rich cytoplasm, whereas those treated with 1 µM minodronic acid were not multinucleated, stained densely with toluidine blue, and were detached from the bone surface. In the 1 µM culture, the estimated minodronic acid concentration in resorption lacunae was 880 µM, which is higher than the IC50 for minodronic acid antagonism of P2X2/3 receptors. Thus, inhibition of P2X2/3 receptors around osteoclasts may contribute to the analgesic effect of minodronic acid.
Assuntos
Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/patologia , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Osteoclastos/patologia , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Receptores Purinérgicos P2X2/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Animais , Autorradiografia , Conservadores da Densidade Óssea/farmacologia , Células Cultivadas , Osso Cortical/efeitos dos fármacos , Osso Cortical/patologia , Osso Cortical/ultraestrutura , Difosfonatos/farmacologia , Feminino , Fêmur/efeitos dos fármacos , Imidazóis/farmacologia , Modelos Biológicos , Osteoclastos/efeitos dos fármacos , Osteoclastos/ultraestrutura , Antagonistas do Receptor Purinérgico P2X/farmacologia , Coelhos , RatosRESUMO
An increase of serum creatine kinase (CK) has been observed in clinical studies of nitrogen-containing aminobisphosphonates (N-BPs). Osteoclasts are thought to be the source of the CK, but there is no clear evidence for the hypothesis. In this study, CK release from rabbit osteoclasts induced by N-BPs was examined in an in vitro culture system. Rabbit bone-derived cells were cultured for 3 days on the N-BPs pretreated cortical bone slices. CK activity in the culture medium was measured at 3 days of culture. The CK activity was increased with all N-BPs at concentrations at which showed antiresorptive activity over 60% inhibition of C-terminal cross-linking telopeptide of type I collagen (CTX-1) release. The maximum induction of CK activity was 2.6 times the control level. The lowest N-BP concentration inducing CK release was 3 times lower than that required to decrease the osteoclast number. Bafilomycin A1, an inhibitor of vacuolar H(+)-ATPase, abrogated all N-BP actions, including CK release. Bone-derived cells except osteoclasts were insensitive to bafilomycin A1, suggesting that osteoclasts were the source of CK. Regarding the time course, CK release occurred after a 1 day lag time and increased steadily until day 3 of culture. These results show that CK release is induced by N-BPs from osteoclasts at concentrations at which N-BPs show antiresorptive activity over 60% inhibition of CTX-1 release in vitro. These findings explain the mechanism of the CK increase induced by clinical use of N-BPs.
RESUMO
The goal of the study was to compare the effects of minodronic acid on bone mineral density (BMD) and bone turnover in a rat ovariectomized (OVX) osteoporosis model, using two intermittent treatment regimens (weekly and 4 continuous days every 4 weeks) and a daily regimen. Female F344 rats (age 14 weeks) underwent ovariectomy or a sham operation. Minodronic acid was orally administered at 0.042, 0.21, and 1.05 mg/kg in the intermittent regimens, and at 0.03 and 0.15 mg/kg in the daily regimen for 12 weeks from the day after surgery. Minodronic acid dose-dependently ameliorated the decreases in areal BMD of the lumbar vertebrae and femur, and volumetric BMD of total and trabecular bone in the distal femur. Minodronic acid also suppressed the increase in urinary deoxypyridinoline levels and reduced serum osteocalcin levels. In bone histomorphometry, all three minodronic acid regimens suppressed OVX-induced increases in bone turnover at the tissue level and ameliorated all structural indices, except that an effect on trabecular thickness only occurred with daily treatment. In conclusion, minodronic acid administered weekly or for 4 continuous days every 4 weeks suppressed increased bone resorption and BMD to a similar extent to that of a similar total dose given daily in a rat OVX model.
Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Difosfonatos/administração & dosagem , Imidazóis/administração & dosagem , Osteoporose/metabolismo , Absorciometria de Fóton , Animais , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/metabolismo , Modelos Animais de Doenças , Feminino , Ovariectomia , Ratos , Microtomografia por Raio-XRESUMO
This study examined the effect of ONO-5334, a cathepsin K inhibitor, on bone turnover, mineral density (BMD), mechanical strength and microstructure in ovariectomized (OVX) cynomolgus monkeys. Vehicle, ONO-5334 (3, 10 or 30 mg/kg) or alendronate (0.5 mg/kg) was orally administered for eight months to sham- and OVX-operated monkeys. ONO-5334 dose-dependently suppressed OVX-induced increase in bone turnover markers (urinary C-terminal cross-linking telopeptide of type I collagen (CTX) and serum osteocalcin). At the dose of 30 mg/kg, ONO-5334 maintained urinary CTX at nearly zero level and kept serum osteocalcin around the level of the sham animals. Marker levels in the alendronate-treated animals were similar to those in the sham animals throughout the study. ONO-5334 dose-dependently reversed the effect of OVX on vertebral BMD as measured by dual-energy X-ray absorptiometry (DXA) with improvement of bone mechanical strength. Both ONO-5334 and alendronate suppressed OVX-induced changes in vertebral microstructure and turnover state. In the femoral neck, peripheral quantitative computed tomography (pQCT) analysis showed that ONO-5334 increased total and cortical BMD. In particular, ONO-5334 significantly increased cortical BMD with improvement of bone mechanical strength. In microstructural analysis, alendronate suppressed OVX-induced increase in femoral mid-shaft osteonal bone formation rate (BFR) to a level below that recorded in the sham group, whereas ONO-5334 at 30 mg/kg did not suppress periosteal, osteonal and endocortical BFR. This finding supports the significant effect of ONO-5334 on cortical BMD and mechanical strength in the femoral neck. The results of this study suggest that ONO-5334 has good therapeutic potential for the treatment of osteoporosis.
Assuntos
Osso e Ossos/efeitos dos fármacos , Catepsina K/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacologia , Ovariectomia , Tiazolidinas/farmacologia , Absorciometria de Fóton , Animais , Osso e Ossos/metabolismo , Osso e Ossos/fisiologia , Osso e Ossos/ultraestrutura , Feminino , Macaca fascicularisRESUMO
This study compared the effects of ONO-5334, a cathepsin K inhibitor, with those of alendronate on bone mass and strength in ovariectomized rats. Ovariectomy resulted in significant elevation in urinary deoxypyridinoline and plasma C-terminal cross-linking telopeptide of type I collagen (CTX) 8 weeks after surgery. Peripheral quantitative computed tomography analysis showed that total, trabecular, and cortical bone mineral content (BMC) decreased in the proximal tibia, which was paralleled with a significant decline in bone strength. Treatment with ONO-5334 (0.12, 0.6, 3 or 15 mg/kg) once daily for 8 weeks dose-dependently restored the decrease in total BMC and bone mineral density (BMD) in the proximal tibia and suppressed urinary deoxypyridinoline and plasma CTX levels. Alendronate (1 mg/kg, once daily) also fully restored these bone mass parameters. Separate analysis of trabecular and cortical bones, however, showed that ONO-5334 only partially restored trabecular BMD and BMC at 15 mg/kg, whereas alendronate fully restored these parameters. On the other hand, ONO-5334 increased both cortical BMD and BMC with an effect more potent than that of alendronate. Bone geometric analysis indicated that ONO-5334 at 15 mg/kg decreased endosteal circumference without affecting periosteal circumference, resulting in marked increase in cortical thickness. Interestingly, the effects of ONO-5334 on bone strength parameters were more prominent than those of alendronate, although the two test compounds had a similar effect on total BMC. Taken together, our results indicate that ONO-5334 has pharmacological characteristics different from those of alendronate and may offer a unique therapy for patients with osteoporosis.
Assuntos
Densidade Óssea/efeitos dos fármacos , Catepsina K/antagonistas & inibidores , Osteoporose/tratamento farmacológico , Tiazolidinas/farmacologia , Tíbia/metabolismo , Alendronato/farmacologia , Animais , Conservadores da Densidade Óssea/farmacologia , Feminino , Osteoporose/metabolismo , Osteoporose/patologia , Ovariectomia , Ratos , Tíbia/patologiaRESUMO
In the present study, we examined the in vitro and in vivo pharmacological effects of ONO-5334, a novel inhibitor of cathepsin K, on bone metabolism. In vitro experiments indicated that ONO-5334 is a potent inhibitor of cathepsin K with Ki value of 0.1 nM. Although this compound inhibited other cysteine proteases, such as cathepsin S, L and B, its inhibitory activity for these enzymes was 8 to 320 fold lower than that for cathepsin K. ONO-5334 also inhibited human osteoclasts bone resorption in vitro at a concentration more than 100 fold lower than that of alendronate, a bisphosphonate. While alendronate disrupted actin ring and induced pyknotic nuclei in osteoclasts, ONO-5334 did not have such effects, suggesting that this compound does not affect osteoclasts viability. In in vivo experiments, oral administration of ONO-5334 dose-dependently reduced plasma calcium level increased by parathyroid hormone related peptide in thyroparathyroidectomized rats. Furthermore, in vivo experiment using normal monkeys demonstrated that ONO-5334 decreases serum and urine C-telopeptide of type I collagen level, a bone resorption marker, soon after oral dosing. These levels were consistently decreased below pre-dose levels by repeated oral dosing with ONO-5334 for 7 days. ONO-5334 on the other hand did not affect bone formation markers, serum osteocalcin and bone specific alkaline phosphatase. These findings indicate that ONO-5334 is a specific inhibitor for cathepsin K and thus may be a novel therapeutic agent for metabolic bone diseases.
Assuntos
Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Catepsina K/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Tiazolidinas/farmacologia , Actinas/metabolismo , Administração Oral , Animais , Biomarcadores/metabolismo , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/sangue , Reabsorção Óssea/enzimologia , Reabsorção Óssea/patologia , Reabsorção Óssea/fisiopatologia , Cálcio/sangue , Catepsina K/metabolismo , Colágeno Tipo I/sangue , Feminino , Haplorrinos , Humanos , Masculino , Osteogênese/efeitos dos fármacos , Paratireoidectomia , Peptídeos/sangue , Inibidores de Proteases/administração & dosagem , Ratos , Tiazolidinas/administração & dosagemRESUMO
The present study examined the effect of the highly potent nitrogen-containing bisphosphonate, minodronic acid (ONO-5920/YM529), on bone mineral density (BMD), bone turnover, bone histomorphometry and bone strength in ovariectomized (OVX) rats. Female F344/DuCrj rats, aged 14 weeks, were OVX or sham operated. After 3 months, the OVX rats showed an increase in bone turnover, and a decrease in bone mass and bone strength. Minodronic acid was administered orally once a day for 12 months at doses of 0, 0.006, 0.03 and 0.15 mg/kg from 3 months after OVX. Minodronic acid dose-dependently inhibited the decrease in BMD of lumbar vertebrae and femur. In the femur, treatment with 0.15 mg/kg minodronic acid increased the BMD of distal and mid sites to sham levels. Minodronic acid dose-dependently suppressed OVX-induced increase in urinary deoxypyridinoline, a bone resorption marker, after a month of treatment and these effects were maintained for 12 months of treatment. Minodronic acid also decreased serum osteocalcin, a bone formation marker. In bone histomorphometric analysis after 12 months of treatment, OVX rats showed an increase in bone resorption (Oc.S/BS and N.Oc/BS) and bone formation (MS/BS and BFR/BV) at lumbar vertebral bodies. Minodronic acid suppressed the OVX-induced increase in bone turnover at tissue level. Trabecular bone volume, trabecular thickness and trabecular number of lumbar vertebral bodies were decreased after OVX. Minodronic acid increased these structural indices, indicating that it prevented the deterioration in trabecular architecture. In a mechanical test at 12 months of treatment, ultimate load of lumbar vertebral bodies and mid femur in the OVX-control group was decreased compared to the sham group. Minodronic acid prevented the reduction in bone strength at both sites. In particular, in the mid femur, treatment with 0.03 and 0.15 mg/kg minodronic acid increased bone strength to sham levels or greater. In conclusion, minodronic acid suppressed increased bone turnover, plus prevented the decrease in BMD, deterioration of bone microarchitecture and reduction in bone strength in OVX rats with established osteopenia. These results suggest that minodronic acid may be clinically useful for treatment of osteoporosis.
Assuntos
Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/patologia , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiologia , Difosfonatos/farmacologia , Imidazóis/farmacologia , Animais , Osso e Ossos/anatomia & histologia , Difosfonatos/uso terapêutico , Feminino , Imidazóis/uso terapêutico , Osteoporose/tratamento farmacológico , Ovariectomia , Ratos , Ratos Endogâmicos F344 , Estresse MecânicoRESUMO
This study examined the effect of the highly potent nitrogen-containing bisphosphonate, minodronic acid (ONO-5920/YM529), on bone mineral density (BMD), bone turnover, bone microarchitecture and bone strength in ovariectomized (OVX) cynomolgus monkeys. Skeletally mature female cynomolgus monkeys, aged 9-17 years, were ovariectomized or sham-operated. Minodronic acid was administered orally once a day in doses of 0, 0.015, and 0.15 mg/kg from the day after surgery for 17 months. Bone resorption markers (urinary N-terminal cross-linking telopeptide of type I collagen and deoxypyridinoline), bone formation markers (serum osteocalcin and bone alkaline phosphatase) and lumbar vertebral BMD were measured at baseline and at 4, 8, 12 and 16 months after surgery. Treatment with minodronic acid dose-dependently inhibited OVX-induced increase in bone turnover markers and decrease in lumbar vertebral BMD, and minodronic acid at 0.15 mg/kg completely prevented these changes. At 17 months after surgery, minodronic acid also suppressed bone resorption (Oc.S/BS and N.Oc/BS) and bone formation (OS/BS, MS/BS, MAR, BFR/BS, and BFR/BV) in the lumbar vertebral bodies and tibia. In the mechanical tests, ultimate load on lumbar vertebral bodies and femoral neck of the OVX-control animals were significantly reduced compared to the sham animals. Minodronic acid prevented these reductions in bone strength at 0.15 mg/kg. There was significant correlation between BMD and bone strength, suggesting that the increase in bone strength was associated with the increase in BMD produced by minodronic acid. In micro-CT analysis of the lumbar vertebral bodies, minodronic acid improved trabecular architecture, converting rod structures into plate structures, and preventing the increase in trabecular disconnectivity at 0.15 mg/kg. In conclusion, similar to patients with postmenopausal osteoporosis, reduction in bone strength of lumbar vertebral bodies and femoral neck was clearly demonstrated in OVX cynomolgus monkeys. Minodronic acid prevented these reductions at a once-daily oral administration. Also, minodronic acid prevented OVX-induced changes in bone turnover, bone mass and bone microarchitecture. Long-term minodronic acid treatment was well tolerated and no adverse effects could be detected. These results suggest that minodronic acid may be a clinically useful drug for osteoporosis.
Assuntos
Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/ultraestrutura , Difosfonatos/farmacologia , Imidazóis/farmacologia , Animais , Biomarcadores/metabolismo , Peso Corporal , Osso e Ossos/química , Feminino , Humanos , Macaca fascicularis , Ovariectomia , Distribuição Aleatória , Resistência à TraçãoRESUMO
The participation of histamine H(3) receptors in the regulation of skin vascular permeability changes in mast cell-deficient mice was studied. Although intradermal injection of histamine H(3) antagonists, iodophenpropit and clobenpropit, at a dose of 100 nmol/site caused significant increases in skin vascular permeability in both mast cell-deficient (WBB6F1 W/W(v)) and wild-type (WBB6F1 +/+) mice, this response was significantly lower in mast cell-deficient mice than in the wild-type controls. Histamine also caused dose-related increases in skin vascular permeability in both wild-type and mast cell-deficient mice. Significant effects were observed at doses of 10 and 100 nmol/site, and no significant difference in skin vascular permeability was observed between mast cell-deficient and wild-type mice. However, histamine contents of dorsal skin in mast cell-deficient mice were significantly lower than in wild-type mice. In addition, the H(1) antagonists diphenhydramine and chlorpheniramine and the NK(1) antagonists, L-732,138 and L-733,060, were able to antagonize H(3) antagonist-induced skin vascular permeability. These results indicated that blockade of H(3) receptors by H(3) antagonists induce skin vascular permeability through mast cell-dependent mechanisms. In addition, histamine and, to a lesser extent substance P are involved in the reaction.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Isotiurônio/análogos & derivados , Receptores Histamínicos H3/fisiologia , Pele/efeitos dos fármacos , Tioureia/análogos & derivados , Triptofano/análogos & derivados , Animais , Clorfeniramina/farmacologia , Difenidramina/farmacologia , Azul Evans/farmacologia , Feminino , Histamina/análise , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Imidazóis/farmacologia , Injeções Intradérmicas , Injeções Intravenosas , Isotiurônio/farmacologia , Mastócitos/metabolismo , Mastócitos/patologia , Camundongos , Camundongos Mutantes , Piperidinas/farmacologia , Pele/irrigação sanguínea , Pele/patologia , Tioureia/farmacologia , Triptofano/farmacologiaRESUMO
The involvement of chemical mediators other than histamine in eosinophil infiltration in the nasal mucosa was studied using histamine H(1) receptor-deficient mice. Histamine H(1) receptor-deficient mice and wild-type controls were immunized with ovalbumin and consecutive topical antigen instillation was performed. Histological alterations and eosinophil infiltration into the nasal mucosa of mice were examined. Diffuse infiltration of inflammatory cells and edema after sensitization with antigen were observed in the nasal mucosa in both wild-type and histamine H(1) receptor-deficient mice. The number of eosinophils in the nasal mucosa in mice sensitized with antigen was significantly increased as compared with controls. The number of eosinophils in the nasal mucosa was significantly decreased by cetirizine and epinastine, ramatroban and zafirlukast in wild-type mice. Not only histamine but also thromboxane A(2) and leukotrienes play important roles in allergic rhinitis, especially in the late phase participating in nasal eosinophilia.
Assuntos
Adjuvantes Imunológicos/farmacologia , Eosinofilia/imunologia , Mucosa Nasal/efeitos dos fármacos , Rinite Alérgica Perene/imunologia , Animais , Modelos Animais de Doenças , Eosinofilia/etiologia , Eosinofilia/patologia , Eosinófilos/citologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Contagem de Leucócitos , Antagonistas de Leucotrienos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucosa Nasal/imunologia , Mucosa Nasal/patologia , Ovalbumina/imunologia , Receptores Histamínicos H1/genética , Receptores de Tromboxanos/antagonistas & inibidores , Rinite Alérgica Perene/complicações , Rinite Alérgica Perene/genéticaRESUMO
We examined the effect of propolis granular A. P. C on lung tumorigenesis in female A/J mice. Lung tumors were induced by the tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) administered in drinking water for 7 weeks in mice maintained on an AIN-76A semi-synthetic diet. Propolis granular A. P. C (100 mg/kg body wt.) was administered orally daily for 6 days/week from 1 week before NNK administration and throughout the experiment. Sixteen weeks after the NNK treatment, the mice were killed and the number of surface lung tumors was measured. The number of lung tumors in mice treated with NNK alone for 7 weeks (9.4 mg/mouse) was significantly more than in that observed in control mice. Propolis granular A. P. C significantly decreased the number of lung tumors induced by NNK. These results indicate that propolis granular A. P. C is effective in suppressing NNK-induced lung tumorigenesis in mice.
Assuntos
Anticarcinógenos/farmacologia , Antineoplásicos/farmacologia , Carcinógenos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/prevenção & controle , Nitrosaminas , Inibidores da Síntese de Ácido Nucleico/farmacologia , Fenilpropionatos/farmacologia , Própole/farmacologia , Administração Oral , Animais , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Fatores de TempoRESUMO
The purpose of this study was to investigate the involvement of chemical mediators other than histamine in nasal allergic signs using histamine H(1) receptor-deficient mice. In passively sensitized mice, antigen instillation into the nasal cavity induced significant increases in sneezing and nasal rubbing in wild-type mice, but no such increases were observed in histamine H(1) receptor-deficient mice. In actively sensitized mice, both sneezing and nasal rubbing were also significantly increased in a dose-dependent manner in both wild-type and histamine H(1) receptor-deficient mice. Histamine H(1) receptor antagonists such as cetirizine and epinastine significantly inhibited antigen-induced nasal allergic signs in wild-type mice, although the effects were incomplete. In addition, the thromboxane A(2) receptor antagonist ramatroban also inhibited these responses in wild-type mice. However, the leukotriene receptor antagonist zafirlukast showed no effects in wild-type mice. These results suggested that in the acute allergic model (passive sensitization), only histamine H(1) receptors are related to nasal signs induced by antigen, whereas in the chronic allergic model (active sensitization), both histamine H(1) receptors and thromboxane A(2) receptors were involved in the responses.
Assuntos
Receptores Histamínicos H1/fisiologia , Rinite Alérgica Sazonal/fisiopatologia , Animais , Antialérgicos/farmacologia , Antígenos/imunologia , Comportamento Animal/fisiologia , Carbazóis/farmacologia , Cetirizina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Antagonistas dos Receptores Histamínicos H1/farmacologia , Imunização , Imunoglobulina E/imunologia , Indicadores e Reagentes , Indóis , Antagonistas de Leucotrienos/farmacologia , Camundongos , Camundongos Knockout , Ovalbumina/imunologia , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Fenilcarbamatos , Receptores Histamínicos H1/genética , Rinite Alérgica Sazonal/genética , Rinite Alérgica Sazonal/psicologia , Espirro/fisiologia , Sulfonamidas/farmacologia , Tromboxano A2/antagonistas & inibidores , Compostos de Tosil/farmacologiaRESUMO
The role of histamine H1 receptors in nasal allergic symptoms (sneezing and nasal rubbing) were studied using histamine H1 receptor-deficient mice. Intranasal instillation of histamine solution resulted in significant increases in sneezing and nasal rubbing in wild-type mice, whereas no increases were observed in histamine H1 receptor-deficient mice. The histamine H1 receptor agonist 2-pyridylethylamine induced sneezing and nasal rubbing in a dose-dependent-manner in wild-type mice, but no such increase was found in histamine H1 receptor-deficient mice. On the other hand, the histamine H2 receptor agonist dimaprit did not increase sneezing and nasal rubbing in wild-type mice. Histamine H1 receptor antagonists such as chlorpheniramine and epinastine significantly inhibited nasal allergic symptoms caused by histamine, but the histamine H2 receptor antagonists cimetidine and famotidine showed no effect. No additional effects were observed by combined use of chlorpheniramine and cimetidine or famotidine compared with cimetidine or famotidine alone. These results suggested that histamine H1 receptors play an important role in nasal allergy symptoms induced by histamine.