Parsalmide: a new anti-inflammatory agent. V. Pharmacokinetic and metabolic aspects in the rabbit

The bacterial mutation psuA1, known as (suA) a polarity suppressor, partially relieves all N defects in bacteriophage lambda growth. No evidence is found that psuA1 relieves Q defects in lambda growth. Specific mechanisms of action by the N and Q gene products are discussed. The psuA1 mutation was also found to suppress IS1 type but not IS2 type insertion mutations in lambda.     

Interaction between enoxacin, a new antimicrobial, and nimesulide, a new non-steroidal anti-inflammatory agent in mice

Convulsions induced by the combination of enoxacin, a new antimicrobial, and nonsteroidal anti-inflammatory drugs including nimesulide, ketoprofen, pranoprofen and loxoprofen sodium, were investigated in mice. The oral administration of nimesulide alone induced clonic convulsions at more than 300 mg/kg. The oral administration of ketoprofen, pranoprofen or loxoprofen sodium induced no convulsion up to 1000 mg/kg, 500 mg/kg and 600 mg/kg, respectively, and that of enoxacin induced no convulsion at more than 5000 mg/kg. The combination of nimesulide at 200 mg/kg and enoxacin at 400 mg/kg induced no convulsion. In contrast, the combination of enoxacin at 100 mg/kg and either ketoprofen at 125 mg/kg or pranoprofen at 500 mg/kg induced clonic convulsions, while that of enoxacin at 400 mg/kg and loxoprofen sodium at 600 mg/kg induced no convulsion. These results suggest that the combination of nimesulide and enoxacin may possibly induce few or less convulsions in the clinical setting.     

Chiral synthesis and pharmacological evaluation of the enantiomers of SM32, a new analgesic and cognition-enhancing agent

The enantiomers of 3-alpha-tropyl 2-(phenylthio)butyrate (SM32, 1) were prepared by chiral synthesis and tested for analgesic, cognition-enhancing, and ACh-releasing properties. They show enantioselectivity in some of the tests, the eutomer being related in configuration to R-(+)-hyoscyamine.     

GLC and NMR analysis of isomeric impurities in the new anti-inflammatory agent benoxaprofen

GLC and NMR methods are described for the determination of four possible isomeric impurities in the novel anti-inflammatory agent benoxaprofen. The 2- and 3-chlorophenyl isomers were determined by GLC after alkaline hydrolysis and subsequent methylation. A rapid NMR procedure, using the lanthanide shift reagent tris- (1, 1, 1, 2, 2, 3, 3-heptafluoro- 7, 7-dimethyl- 4, 6-octanedionato)-europium, was developed for the 6- and 7- (alpha-methylacetic acid) isomers. Similar methodolology, with tris-(3-heptafluorobutyryl-d-camphorato)europium, enabled the determination of the enantiomer ratio for benoxaprofen. For the positional isomers, the limits of detection were 0.05% by GLC and 0.2% by NMR.     

Nociceptin/orphanin FQ. A new opioid, a new analgesic?

Opioids form the major class of strong analgesics. Endogenous opioids and their receptors play important roles in central nervous system function. Thus, the discovery of a new opioid peptide, nociceptin or orphanin FQ, and its receptor, opioid receptor-like 1 (ORL-1) has caused considerable interest since this transmitter system appears to exhibit a number of key differences to the other opioids. Analgesia can be produced at spinal sites but there is compelling evidence that the peptide may also have 'anti-opioid' actions in the brain. Effects on auditory processing, pains from nerve injury coupled with an apparent lack of motivational effects have important implications for novel therapy. This review surveys the recent functional studies on this novel peptide.     

Structure-activity studies related to ABT-594, a potent nonopioid analgesic agent: effect of pyridine and azetidine ring substitutions on nicotinic acetylcholine receptor binding affinity and analgesic activity in mice

Analogs of A-98593 (1) and its enantiomer ABT-594 (2) with diverse substituents on the pyridine ring were prepared and tested for affinity to nicotinic acetylcholine receptor binding sites in rat brain and for analgesic activity in the mouse hot plate assay. Numerous types of modifications were consistent with high affinity for [3H]cytisine binding sites. By contrast, only selected modifications resulted in retention of analgesic potency in the same range as 1 and 2. Analogs of 2 with one or two methyl substituents at the 3-position of the azetidine ring also were prepared and found to be substantially less active in both assays.     

Nepetalactone: a new opioid analgesic from Nepeta caesarea Boiss

The essential oils of Nepeta species including Nepeta phyllochlamys P. H. Davis, N. nuda L. ssp. nuda, and N. caesarea Boiss. have been screened by use of the tail-flick and tail immersion (52.5 degrees C) methods. Of the species studied, only N. caesarea showed significant analgesic activity, besides marked sedation, which was also blocked by naloxone, indicating involvement of opioid receptors. Moreover, it was only active on mechanical, not thermal, algesic response which suggests specificity for specific opioid receptor subtypes, excluding mu-opioid receptors. Because 4a alpha,7alpha,7a alpha-nepetalactone is the main component of the essential oil of N. caesarea, and is present at very high levels (92-95%), it is concluded that 4a alpha,7alpha,7a alpha-nepetalactone is the active principle and has a specific opioid receptor subtype agonistic activity.     

Evaluation of the novel anti-inflammatory agent tetrandrine as a pulpotomy medicament in a canine model

Tetrandrine, a bisbenzylisoquinoline alkaloid with unique broad-spectrum anti-inflammatory properties, was evaluated as a pulpotomy medicament in a canine model. Histological sections were evaluated after three days (acute inflammation) and six weeks (chronic inflammation) by two criteria: 1) intensity and degree of inflammation, and 2) extent of pulp involvement. The results of the three-day dressings revealed significant neutrophil infiltration in only 30% of teeth treated with tetrandrine, compared with 81%, 84%, and 100% of teeth treated with Ledermix, (Lederle Pharmaceuticals, Wolfrathausen, Germany), formocresol (Creighton Pharmaceuticals, Sydney, Australia) and saline (controls) respectively (P < 0.01). After six weeks, there was significant lymphocyte infiltration in only 30% of teeth treated with tetrandrine, compared with 66%, 90%, and 100% on teeth treated with Ledermix, formocresol, and saline controls respectively. (P < 0.01). In both three-day and six-week specimens in tetrandrine-treated teeth the extent of inflammation was limited to less than one-third of the coronal section of the pulp, whereas teeth treated with Ledermix or formocresol showed cellular infiltration extending to greater than two-thirds of the pulp (P < 0.01). Comparative studies with berbamine, a natural analog of tetrandrine, showed that it was less potent than tetrandrine, but significantly better than Ledermix and formocresol on both acute and chronic pulp inflammation (P < 0.05 and P < 0.01 respectively). These results suggest that tetrandrine may have value as a pulpotomy medicament.     

4-nitro-2-phenoxymethanesulfonanilide (R-805): a chemically novel anti-inflammatory agent

The anti-inflammatory activity of the sulfonanilide, 4-nitro-2-phenoxymethanesulfonanilide (R-805) has been demonstrated in conventional models (carrageenan-induced edema of the rat's paw, UV-induced erythema of guinea-pig skin, adjuvant-induced arthritis of the rat). R-805 differs from most currently available acidic anti-inflammatory drugs in that its functional acidic group is not carboxyl. The relative anti-inflammatory potency of R-805 is comparable to indomethacin. Calculation of acute therapeutic indices (LD50/ED50) for 8 acidic anti-inflammatory drugs show R-805 to possess a more favourable index than the other drugs examined.     

Gemcitabine: a new chemotherapy agent for solid cancers

Gemcitabine, a new nucleotide analogue, is a promising chemotherapeutic agent for pancreatic, lung, ovarian and breast carcinomas. Its low toxicity (mainly hematologic) makes it a good choice for palliative treatment in patients who would otherwise be unable to tolerate aggressive therapy. The combination of gemcitabine with other anticancer agents such as cisplatin and anthracyclines appears to be associated with high response rates. Finally, gemcitabine is a potent radiosensitizing agent and should definitely be tested in combination with radiotherapy mainly in locally advanced disease.     

Synthesis and anti-inflammatory activity of some indazole derivatives. 36. Azoles

The synthesis of water soluble hydrochlorides of indazole derivatives 1b, 8 and 9 is described. By treating of 2,5-dinitroindazole with thiomorpholine 3-thiomorpholino-5-nitroindazole (10) and 3,5-dinitroindazole (11) in the form of the molecular compound 11a are obtained. The known indazole derivatives 1 and 7 as well as the newly synthesized hydrochlorides of 1b, 8 and 9 are, except of 8.HCl, less toxic than benzydamine hydrochloric (BZD). The same compounds show with some excepts a comparable or greater antiinflammatory effect than BZD in the carrageenin induced oedema test.     

Topotecan: a new topoisomerase I inhibiting antineoplastic agent

OBJECTIVE: To review the pharmacologic, pharmacokinetic, therapeutic, and safety aspects of irinotecan, a new antineoplastic agent, and to assess its role in the treatment of colorectal and lung cancer. DATA SOURCES: English-language articles from the MEDLINE database, January 1990-March 1998; Pharmacia & Upjohn Company; published articles and meeting abstracts. STUDY SELECTION: Studies in humans with cancer, clinical case reports, and open clinical studies were reviewed. Efficacy studies were limited to trials with at least 20 evaluable patients. DATA EXTRACTION: Relevant data were extracted from published reports and abstracts. DATA SYNTHESIS: Irinotecan is an effective agent for the treatment of advanced colorectal cancer. It demonstrates significant activity as a first-line agent and in patients with disease that is refractory to fluorouracil-containing regimens. Activity against lung cancer has also been demonstrated. Limited data indicate activity against cancers of the ovary, cervix, stomach, and in non-Hodgkin's lymphomas. Major toxicity consists of myelosuppression and diarrhea. CONCLUSIONS: Irinotecan is a useful addition to the antineoplastic drug family and offers significant efficacy for treatment of patients with fluorouracil-refractory colorectal cancer.     

Behavioural effects of a new non-phenylethylamine anorexigenic agent: mazindol

Mazindol, a new anorexigenic agent which possesses a different chemical structure from phenylethylamine derivatives such as amphetamine, causes anorexia along with increases in locomotor activity and body temperature. Mazindol also induces stereotyped behaviour and, if injected into rats with unilateral nigro-striatal lesions, causes turning towards the lesioned side. Mazindol-induced anorexia is antagonized by pretreatment with alpha-methyl-p-tyrosine or pimozide. Pimozide pretreatment prevents the rotation induced by Mazindol in rats with unilateral nigro-striatal lesions. The involvement of dopamine in the mechanism whereby Mazindol elicits anorexia and turning behaviour is discussed.     

The exotoxin of Bacillus thuringiensis: a new C-mitotic agent

Thuringiensin A, an exotoxin from Bacillus thuringiensis, a constituent of the microbial insectide thuricide has been found to inhibit mitotic spindle, condense and scatter chromosomes. It may therefore be a promizing tool in future cell biological studies.