Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding

Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT_2A receptors and D₂-type receptors. Predominant 5HT_2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D₂ antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D₃ and in particular D₄ receptors has been proposed.In vitro, all compounds, except the typical antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT_2A than for D₂ receptors. Subnanomolar affinity for human 5HT_2A receptors was observed for ORG-5222, sertindole, resperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D₂ receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D₂ affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D₄ than for D₂ receptors. For most other compounds, D₄ affinity was only slightly lower than their D₂ affinity. Seroquel was totally devoid of D₄ affinity. None of the compounds had nanomolar affinity for D₁ receptors; their affinity for D₃ receptors was usually slightly lower than for D₂ receptors.In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT_2A than D₂ receptors. Risperidone and ORG-5222 had 5HT_2A versus D₂ potency ratio of about 20. Highest potency for 5HT_2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT_2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D₂ receptors. No regional selectivity for D₂ receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D₂ receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic ₁ receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more ₁ than D₂ receptors. Clozapine showed predominant occupancy of H₁ receptors and occupied cholinergic receptors with equivalent potency to D₂ receptors. A stronger predominance of 5HT_2A versus D₂ receptor occupancy combined with a more gradual occupancy of D₂ receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT_2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D₂ receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT_2A and D₂ occupancy and the avoidance of D₂ receptor overblockade are believed to reduce the risk for extrapyramidal symptoms.     

Elucidation of anti-allergic activities of curcumin-related compounds with a special reference to their anti-oxidative activities

The anti-allergic and anti-oxidative activities of curcumin-related compounds (glycosides, reductants and bis-demethoxy analogs) were investigated to elucidate the underlying active mechanisms and structural features of curcumin in exerting these activities. The anti-allergic activities were assessed by measurement of histamine release from rat basophilic leukemia cells, RBL-2H3. Curcumin and tetrahydrocurcumin (THC) caused a marked decrease in histamine release. Glycosides of curcumin, bis-demethoxycurcumin and THC also inhibited the release of histamine, though less potently than curcumin did. The anti-oxidative activities were assessed by measurement of cell-free or cellular radical scavenging. All compounds but diglycosides or bis-demethoxycurcumin analogs distinctly exerted anti-oxidative effects. The relationship between both of these activities revealed that all compounds with potent radical scavenging activities caused a definite decrease in histamine release, but some compounds with non-potent radical scavenging activities also inhibited the histamine release. These results suggest that the hydroxy groups of curcumin play a significant role in exerting both the anti-oxidative and anti-allergic activities, and that most of the compounds develop the anti-allergic activities through mechanisms related to anti-oxidative activities, but some through mechanisms unrelated to anti-oxidation activity.     

5种抗菌药物对厌氧菌的体外抗菌活性研究

测定了罗红霉素、ａｚｉｔｈｒｏｍｙｃｉｎ、头孢西丁、托舒沙星对６０株厌氧菌的体外抗菌活性，并同甲硝唑比较，发现托舒沙星对厌氧菌的体外抗菌活性最好，ＭＩＣ_（５０）和ＭＩＣ_（９０）为０．１２５和２ｍｇ／Ｌ优于甲硝唑（０．２５和１６ｍｇ／Ｌ）；罗红霉素（０．５、１６ｍｇ／Ｌ）与甲硝唑相似，ａｚｉｔｈｒｏｍｙｃｉｎ、头孢西丁的体外抗菌活性比甲硝唑略差，ＭＩＣ_（５０）和ＭＩＣ_（９０）分别为４和３２、２和３２ｍｇ／Ｌ，它们对脆弱拟杆菌的体外抗菌活性优于对其它拟杆菌的体外抗菌活性，对短真杆菌、变形链球菌、普氏消化链球菌等也具有较好的体外抗菌活性。     

Synthesis and antimicrobial activities of some new benzimidazole derivatives

Some benzimidazolylbenzamides were synthesized and their antimicrobial activities against Staphylococcus aureus, Streptococcus faecalis, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Candida albicans evaluated. It was shown that the compound 14 exhibited the best activity against B. subtilis, P. aeruginosa and C. albicans.     

Synthesis and antimicrobial activities of some new nitroimidazole derivatives

In this study, some new nitroimidazole derivatives were obtained from 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethylamine dihydrochloride (4) and 1-(2-bromoethyl)-2-methyl-5-nitroimidazole (5), which were prepared using metronidazole. Compound 4 was reacted with arylisothiocyanates (6) to obtain 1-[2-(2-methyl-5-nitroimidazol-1-yl)ethyl]-3-arylthioureas (7) and the latter with alpha-bromoacetophenones (8) to give 3-[2-(2-methyl-5-nitroimidazol-1-yl)ethyl]-2-arylimino-4-aryl-4-thiazolines (9). Also 1-[2-(2-methyl-5-nitroimidazol-1-yl)ethyl]-2-phenyl-4-arylideneimidazolin-5-ones (11) were prepared by reaction of 4 with 2-phenyl-4-arylidene-5-oxazolones (10). The reaction of the other starting material 5 with 5-arylidenethiazolidin-2,4-dione (12) gave 3-[2-(2-methyl-5-nitroimidazol-1-yl)ethyl]-5-arylidenethiazolidin-2,4-dione (13) derivatives. Structural elucidation of the compounds was performed by IR, 1H-NMR and MASS spectroscopic data and elemental analysis results. Antimicrobial activities of the compounds were examined and moderate activity was obtained.     

关注抗结核药物的研究开发

目前世界结核病发病率呈上升趋势,其中1/3要归咎于艾滋病的病例增加。事实上结核病是当今影响发展中国家人口数最大的疾病,危害很大。尽管通过世界卫生组织属下全球大宗药品贸易机构(GlobalDrugFacilityforBulkPurchase)可以很低的价格(每个病人每年9美元)获得有效的药物,直接督导下的短程化疗(DirectlyObservedTreatmentShort-courseschemes,DOTS)治愈率95%,但高发病率的国家未必能负担得起这笔费用。着眼于商业利益,这一领域确实没有投资价值,因此抗结核新药开发长久以来未受重视。30多年以前,在欧洲、美国和日本,结核病已经不是一…     

Comparative in vitro activities of several antimicrobial agents against Helicobacter pylori

Comparative in vitro activities of several antimicrobial agents against Helicobacter pylori were evaluated. Minimum inhibitory concentrations against 41 strains of H. pylori were determined by using E test. All 41 strains were isolated from gastric mucosa of patients suspected to have gastric ulcer. The ranges of MIC of amoxicillin was from 0.016 microgram/ml and less to 0.064 microgram/ml. The ranges of MIC of clarithromycin, erythromycin, and azithromycin were from 0.016 microgram/ml and less to 64 micrograms/ml, from 0.016 microgram/ml and less to more than 256 micrograms/ml, from 0.064 to more than 256 micrograms/ml, respectively. The ranges of MIC of ciprofloxacin, sparfloxacin, levofloxacin, norfloxacin were from 0.016 microgram/ml and less to 32 micrograms/ml, from 0.002 microgram/ml and less to more than 32 micrograms/ml, from 0.002 microgram/ml and less to more than 32 micrograms/ml, from 0.064 to more than 32 micrograms/ml, respectively.     

Correlation of in vitro activities of the fluoroquinolones to their in vivo efficacies

The new fluoroquinolones have activity against Gram-positive and Gram-negative bacteria. In order to differentiate between the compounds, the authors have compared their in vitro activities and correlated these results with their in vivo efficacies. Norfloxacin (N), pefloxacin (P), enoxacin (E), ofloxacin (O), difloxacin (D), ciprofloxacin (C), fleroxacin (F), A-61827 (A), temafloxacin (T) and lomefloxacin (L) were used in these studies. In vitro, C was the most active compound against Gram-negative aerobic bacteria and A was the most active compound against Gram-positive cocci and anaerobic bacteria. In mouse protection tests, C, D, A, O, T and F had similar activities against Escherichia coli and Pseudomonas aeruginosa. D, T and A were the most active quinolones against Staphylococcus aureus and Streptococcus pyogenes and Strep. pneumoniae in mouse protection tests. D was the most active agent against intracellular infection with Salmonella typhimurium, followed by O, T, A and F. The other compounds were ineffective in this test. All the quinolones were effective in treating E. coli pyelonephritis in mice. The doses required to treat P. aeruginosa pyelonephritis in mice were four times greater than those required to treat E. coli. Resistant P. aeruginosa mutants could be isolated from the kidneys after quinolone treatment. Systemic infections with E. coli, Staph. aureus and P. aeruginosa in neutropenic mice required high doses of the fluoroquinolones and F, T and A were ineffective at doses of 100 mg/kg against P. aeruginosa in this model. Differences in in vitro potencies were not reflected in in vivo efficacies.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vitro and in vivo antimicrobial activities of cefmetazole against Bacteroides fragilis

Cefmetazole was investigated on stability to beta-lactamases produced by Bacteroides fragilis and on therapeutic effects in mice infected with B. fragilis. 1. Cefmetazole, like other cephamycins, was found extremely stable to beta-lactamases obtained from B. fragilis. 2. Cefmetazole showed good antimicrobial activities to 50 strains of B. fragilis and extremely high stability to their beta-lactamases. 3. Cefmetazole showed an excellent protecting effect to infections due to beta-lactamase producing B. fragilis. 4. Cefmetazole exhibited an excellent chemotherapeutic effect against polymicrobial infections in mice due to E. coli (beta-lactamase -)and B. fragilis (beta-lactamase +).     

18种抗菌药物体外抗解脲枝原体活性的比较

采用微量稀释法，比较了１８种抗菌药物对６２株解脲枝原体的体外抑制作用。结果显示解脲枝原体对青霉素、氨苄西林、利福平、多粘菌素Ｂ、林可霉素、磺胺嘧啶钠、呋喃妥因不敏感，其ＭＩＣ_（９０）＞１０２４μｇ／ｍｌ；对红霉素、头孢唑林、大观霉素、庆大霉素、卡那霉素、链霉素、诺氟沙星有一定的耐药性，其ＭＩＣ_（９０）在１６～６４μｇ／ｍｌ之间，对盐酸四环素、氯霉素、氧氟沙星和多西环素有较高的敏感性，其ＭＩＣ_（９０）≤８μｇ／ｍｌ，尤以多西环素为著，其对四环素耐药的解脲枝原体株都有较强的抑制作用。     

A comparison of some atropine-like drugs in man, with particular reference to their end-organ specificity

Atropine, methanthelinium, propantheline, oxyphenonium, hyoscine, and hyoscine methylbromide have been compared in man. After graded subcutaneous doses of these drugs simultaneous observations were made on the heart rate, salivary secretion, pupil size, near point of accommodation, micturition, and palmar sweating. This permitted a quantitative assessment of any differential effects of the drugs on the different end-organs.

Small doses which depressed salivary secretion and palmar sweating did not necessarily accelerate the heart or slow micturition. Atropine and hyoscine, which are tertiary amines, had a greater effect than the other (quaternary) drugs on the iris and the ciliary muscle, compared with the effects on the other end-organs studied. This difference may be related to the fact that quaternary compounds penetrate cellular membranes with difficulty.

The time course of the drug effects differed for different end-organs. The changes in heart rate, salivary secretion, and sweating began and ended sooner than those affecting accommodation and the pupil. As the dose of a drug was increased, the peak effect on the heart rate and salivary secretion tended to occur sooner, but the peak effect on the iris and ciliary muscle always occurred later. It is suggested that the aqueous humour may be acting as a reservoir for the drugs. After methanthelinium, all the drug effects began sooner and reached their peak sooner than after the other drugs.

     

Synthesis of some triazolophthalazine derivatives for their anti-inflammatory and antimicrobial activities

Several novel series of triazolophthalazine derivatives namely; pyrazolylethenyltriazolophthalazinones (4a-d), styryltriazolophthalazinones (5a,b), aryloxopropenyltriazolophthalazinones (7a,b), pyrazolinyl- (8a,b), (9a,b) and (10a-f), pyrazolyl- (11a-d), (1,2-oxazol-5-yl)-1,2,4-triazolo[3,4-a]phthalazin-6(5H)-ones (14a,b), triazolo[3,4-a]phthalazin-3-yl-pyridine-3-carbonitriles (12a,b), triazolo[3,4-a]phthalazin-3-yl)ethylthioacetic acids (13a,b) and 2-aryl-5-arylamino-1H,5H-pyrazolo[2″,3″-1',5']imidazo[3',4'-1,5]-1,2,4-triazolo[3,4-a]phthalazin-12(13H)-ones (15a-c) have been synthesized. The anti-inflammatory activity of representative compounds has been studied. Compounds 8b, 10c, 10f, 11b, 12a, 13b, and 15a showed anti-inflammatory activities comparable to that of the reference standard, indomethacin. They exhibit also minimal ulcerogenic effect relevant to the reference standard and were found to be non-toxic up to 120 mg/kg orally or up to 75 mg/kg through parenteral route. Concerning the antimicrobial activity; compounds 12b and 13b were found to be equipotent to ampicillin against Staphylococcus aureus, while compounds 10a and 10f were found to be as potent as ampicillin against E. coli, whereas compound 14b exhibited equipotency to clotrimazole against Candida albicans. Compounds 8b, 10f, 11b, 12a, and 13b exhibited, besides their antimicrobial activity, moderate to potent anti-inflammatory profiles. This represents a fruitful matrix for the development of a new class of dual non-acidic anti-inflammatory/antimicrobial agents.     

Current status of drugs in development for celiac disease

Introduction: Gluten is the main trigger for celiac disease, and the current treatment is based on its elimination from the diet. Although the symptoms usually disappear during the diet, it is restrictive and difficult to maintain. Further, despite a strict treatment the small-bowel mucosal damage does now always heal. Consequently, adherence is often poor and new treatment approaches are needed. With an increased understanding of the disease pathogenesis, several novel treatments have been suggested, and some of them have already entered Phase II clinical trials.

Areas covered: This article reviews the latest status of the drugs in development for celiac disease. The article focuses mainly on synthetic drugs currently entering in clinical trials.

Expert opinion: It is anticipated that some of the treatments under investigation will soon enter Phase III clinical trials, although challenges remain. For instance, histological studies are problematic in wide-scale clinical studies. On the other hand, the existing non-invasive serological methods and clinical outcome measures might be too insensitive for monitoring responses to the possible drug candidates. There is also no animal model which would accurately reflect celiac disease. Well-conducted basic and clinical research is required to develop better non-invasive surrogate markers and patient-related outcomes for future pharmacological studies.     

The future challenges facing the development of new antimicrobial drugs

The emergence of resistance to antibacterial agents is a pressing concern for human health. New drugs to combat this problem are therefore in great demand, but as past experience indicates, the time for resistance to new drugs to develop is often short. Conventionally, antibacterial drugs have been developed on the basis of their ability to inhibit bacterial multiplication, and this remains at the core of most approaches to discover new antibacterial drugs. Here, we focus primarily on an alternative novel strategy for antibacterial drug development that could potentially alleviate the current situation of drug resistance--targeting non-multiplying latent bacteria, which prolong the duration of antimicrobial chemotherapy and so might increase the rate of development of resistance.