Attention has been paid to the thiocarbanilide derivative and the authors synthesized some new compounds of thiocarbanilides for experimental studies on tuberculosis and leprosy. The series of newly synthesized chemical compounds of thiocarbanilides were studied for comparision with the already known antimycobacterial agents; INH, PAS, Streptomycin and D. D. S. The strains of Mycobacterium tubercubsis (H37 Rv, Ravenel, and B. C. G.) and Mycobacterium phlei were used for the in vitro experiments. In the in vivo experiments, the strain of Mycobacterium tuberculosis var. bovis (Ravenel) was employed. The strain of Mycobacterium leprae murium (Hawaiian strain) was used for the murine leprosy experiments. The experimental animals for the in vivo tests were white mice (CFW strain) and these were extensively employed in tuberculosis and leprosy as well. Sixteen cases of Various types of human leprosy, were treated with one of the newly synthesized thiocarbanilides (L-4). Among the newly synthesized chemical compounds of thiocarbanilides studied for their antituberculous and antimurine leprosy activity in vitro and in vivo experiments, two compounds were shown to be suppressive agents for those infections without significant toxicity. These two compounds were named tentatively as L-1 and L-4. 1) LD50 of L-1 was 1,054 mg/kg and that of L-4 was 1,028 mg/kg, while the LD50 of INH was 650 mg/kg and PAS was 4,000mg/kg orally in the experimental animals. 2) L-1 and L-4 showed remarkable suppressive activity in vitro using solid media with 100r/ml. concentration. These data were parallel to 1r/ml. of INH and 50r/ml. of PAS. The inferiority of L-1 and L-4 to INH and PAS in vitro studies might have been due to the water insolubility of these compounds while INH and PAS were readily soluble in water. 3) In vivo experiments with L-1 showed a much-more superior antituberculous effect than was found with INH and PAS. 4) A method of grading the bacterial count in a homogenized tissue suspension of visceral organs (lungs, liver, spleen and kidneys) using the simple technique of the Gaffky scale was accurate and time saving technique in screening the results of the chemotherapeutic agents in tuberculosis. 5) Among the newly synthesized compounds L-4 showed the most remarkable suppressive effect on murine leprosy. The suppressive results were similar to those of INH. 6) The method of measuring the size and the weight of leproma at the inoculated site was simple and is an adequate screening test for chemotherapeutic effect in murine leprosy. 7) In the trials with human leprosy 16 cases of various types, using L-4, the effectiveness in clinical as well as in bacteriological improvement was remarkable. a) After L-4 treatment decrease in bactriologica1 indices and remarkable clinical improvement after a relative1y short period of treatment were observed. b) L-4, up to the maximum daily dose of 500 mg, can be safely administered orally to the patients without any significant side reactions. c) L-4 could be used with remarkable clinical improvement for the patients in lepra reactions.
Adult ; Animals ; Comparative Study ; Erythema Nodosum/drug therapy ; Female ; Human ; Leprosy/*drug therapy ; Male ; Mice ; Thiourea/*therapeutic use

Hepatic ischemia/reperfusion (I/R) injury leads to oxidative stress and acute inflammatory responses that cause liver damage and have a considerable impact on the postoperative outcome. Much research has been performed to develop possible protective techniques. We aimed to investigate the efficacy of SPA0355, a synthetic thiourea analog, in an animal model of hepatic I/R injury. Male C57BL/6 mice underwent normothermic partial liver ischemia for 45 min followed by varying periods of reperfusion. The animals were divided into three groups: sham operated, I/R and SPA0355 pretreated. Pretreatment with SPA0355 protected against hepatic I/R injury, as indicated by the decreased levels of serum aminotransferase and reduced parenchymal necrosis and apoptosis. Liver synthetic function was also restored by SPA0355 as reflected by the prolonged prothrombin time. To gain insight into the mechanism involved in this protection, we measured the activity of nuclear factor-kappaB (NF-kappaB), which revealed that SPA0355 suppressed the nuclear translocation and DNA binding of NF-kappaB subunits. Concomitantly, the expression of NF-kappaB target genes such as IL-1beta, IL-6, TNF-alpha and iNOS was significantly downregulated. Lastly, the liver antioxidant enzymes superoxide dismutase, catalase and glutathione were upregulated by SPA0355 treatment, which correlated with the reduction in serum malondialdehyde. Our results suggest that SPA0355 pretreatment prior to I/R injury could be an effective method to reduce liver damage.
Animals ; Anti-Inflammatory Agents/*therapeutic use ; Benzoxazines/*therapeutic use ; Liver/*drug effects/immunology/*injuries/pathology ; Male ; Mice, Inbred C57BL ; NF-kappa B/immunology ; Reperfusion Injury/*drug therapy/immunology/pathology ; Signal Transduction/drug effects ; Thiourea/*analogs & derivatives/therapeutic use

OBJECTIVE: To discuss the treatment of H3R agonist, IMETIT, on the allergic rhinitis(AR) ,and the influence to mRNA of Substance P(SP) and Substance P Receptor (SP-R) in AR model of guinea pigs. METHOD: The severity of AR was assessed by allergic symptoms (sneezing, nasal rubbing and nose blocking). The changes in the nasal mucosa were studied by pathological methods. The expression of SP positive cell was detected by immunohistochemistry, and the expression of SP-R mRNA was detected by reverse transcriptive polymerase chain reaction (RT-PCR). RESULT: Histamine H3R agonists, IMETIT can effectively improve the AR symptoms, sneezing, nasal itching, nasal congestion, reduce the pathological changes in the nasal mucosa, cut down the SP secretion and SP-R mRNA expression. CONCLUSION Histamine H3R agonist, IMETIT can effectively relieve the symptoms of AR in guinea pigs, which is related to reducing SP secretion and SP-R mRNA expression.
Animals ; Female ; Guinea Pigs ; Imidazoles ; therapeutic use ; Male ; Receptors, Histamine H3 ; drug effects ; Receptors, Neurokinin-1 ; genetics ; metabolism ; Rhinitis, Allergic, Perennial ; drug therapy ; metabolism ; Substance P ; metabolism ; Thiourea ; analogs & derivatives ; therapeutic use

OBJECTIVETo explore the influence of histamine H3 receptor agonist, IMETIT and simultaneous use of IMETIT and H1-receptor antagonist, Loratadine, on the symptoms of allergic rhinitis (AR) and substance P(SP) secretion and expression of SP receptor (SP-R) mRNA in AR model in guinea pigs.

METHODSGuinea pigs were divided randomly into 4 groups: AR group (group A), IMETIT group (group B), Loratadine group (group C) and IMETIT+Loratadine group (group D). The severity of AR was assessed by determining the extent of three markers of allergic symptoms (sneezing, nasal rubbing and nose blocking). The changes in the nasal mucosa were studied by pathological methods. The expression of positive cell of SP was detected by immunohistochemistry. SP-R mRNA expression in nasal mucosa was used to do reverse transcriptive-polymerase chain reaction (RT-PCR). Statistical analysis was performed using a SPSS 13.0 software.

RESULTSIn Group B, the mean (x ± s) number of sneeze [(15.0 ± 1.3) times], scratching nose [(16.5 ± 2.3) times] and respiratory frequency [(76.3 ± 4.1) times/min] were significantly improved than those in group A [(23.5 ± 2.6) times, (26.1 ± 4.1) times and (66.5 ± 5.8) times/min, respectively), P value were 0.000, 0.000 and 0.001, respectively]. The numbers of SP-positive cells [(11.6 ± 3.6)/HP] and SP-R mRNA expression (0.64 ± 0.04) in group B were reduced significantly compared to group A [(27.1 ± 9.7)/HP, (0.83 ± 0.03), P value were 0.000, 0.000, respectively]. Sneeze [(10.0 ± 2.3) times], scratching nose [(11.8 ± 1.7) times] and respiration [(90.0 ± 5.0) times/min] in Group D were improved significantly than those in group B (P value were 0.000, 0.002 and 0.000, respectively). SP-positive cells [(2.0 ± 1.7)/HP] and SP-R mRNA expression (0.52 ± 0.06) in Group D compared with group B were also significantly reduced (P value were 0.012 and 0.000, respectively). Pathological changes in guinea pig nasal mucosa in group B, group D were alleviated than those in group A. The combination of IMETIT and Loratadine had a synergistic effect on these effects (F value were 11.59, 8.28, 5.61, 5.48, 6.50, respectively, P value were 0.002, 0.008, 0.025, 0.027, 0.017).

CONCLUSIONSIMETIT and the combination of IMETIT with Loratadine can effectively relieve the symptoms of AR in guinea pigs, its mechanism may be relevant to reduce SP secretion and the expression of SP-R mRNA, and the two has a synergistic effect. It may be useful as a novel therapeutic approach in nasal allergy.

Animals ; Female ; Guinea Pigs ; Histamine Agonists ; pharmacology ; therapeutic use ; Imidazoles ; pharmacology ; therapeutic use ; Loratadine ; pharmacology ; therapeutic use ; Male ; Nasal Mucosa ; drug effects ; metabolism ; RNA, Messenger ; metabolism ; Receptors, Neurokinin-1 ; genetics ; metabolism ; Rhinitis, Allergic, Perennial ; metabolism ; Substance P ; genetics ; metabolism ; Thiourea ; analogs & derivatives ; pharmacology ; therapeutic use

Cytokines activate several inflammatory signals that mediate beta-cell destruction. We recently determined that SPA0355 is a strong anti-inflammatory compound, thus reporting its efficacy in protecting beta cells from various insults. The effects of SPA0355 on beta-cell survival were studied in RINm5F cells and primary islets. The protective effects of this compound on the development of type 1 diabetes were evaluated in non-obese diabetic (NOD) mice. SPA0355 completely prevented cytokine-induced nitric oxide synthase (iNOS) expression and cytotoxicity in RINm5F cells and isolated islets. The molecular mechanism of SPA0355 inhibition of iNOS expression involves the inhibition of nuclear factor kappaB and Janus kinase signal transducer and activator of transcription pathways. The protective effects of SPA0355 against cytokine toxicity were further demonstrated by normal insulin secretion and absence of apoptosis of cytokine-treated islets. In experiments with NOD mice, the occurrence of diabetes was efficiently reduced when the mice were treated with SPA0355. Therefore, SPA0355 might be a valuable treatment option that delays the destruction of pancreatic beta cells in type 1 diabetes.
Animals ; Apoptosis ; Benzoxazines/pharmacology/*therapeutic use ; Cell Line ; Cell Survival ; Cells, Cultured ; Diabetes Mellitus, Experimental/*prevention & control ; Insulin-Secreting Cells/*drug effects/metabolism ; Janus Kinases/genetics/metabolism ; Mice ; Mice, Inbred NOD ; NF-kappa B/genetics/metabolism ; Nitric Oxide Synthase Type II/genetics/metabolism ; Rats ; Thiourea/*analogs & derivatives/pharmacology/therapeutic use