Anti-inflammatory activity of 2-acyl-5(3)-hydroxytetrahydro-1H-pyrazole derivatives.

The anti-inflammatory effects of five pyrazolidine derivatives on white mice and laboratory rats were studied using models of thermal aseptic inflammation and inflammation induced by injection of carragenin and histamine, as well as models of "cotton-ball granuloma" and epinephrine (adrenaline)-induced pulmonary edema. These effects were compared with those of the most commonly used non-steroid anti-inflammatory drugs, such as phenylbutazone (CAS 50-33-9) and diclofenac (CAS 15307-79-6). It was found that the pyrazolidine compounds studied induced a pronounced anti-inflammatory effect by inhibiting both the proliferative and exudative phases of inflammation. At the same time, as compared to natural non-steroid anti-inflammatory drugs, these compounds had a lower toxicity and induced neither gastric ulcers nor suppression of hemopoiesis.     

Antibacterial properties of 5-substituted derivatives of rhodanine-3-carboxyalkyl acids. Part II

Two series of rhodanine-3-acetic and rhodanine-3-propionic acids derivatives having benzylidene and cinnamylidene substituents with additional electron donating and withdrawing groups at the C-5 position, were synthesised. The structures of the obtained derivatives were confirmed by spectroscopic methods and their lipophilicity was screened. The crystal structures were determined for selected compounds. The antibacterial activity of the derivatives was depended on the type of carboxyalkyl group in the N-3 position and on the type of the substituent in the C-5 position. The derivatives of rhodanine-3-propionic acid demonstrated the highest activity against Gram-positive bacteria. However, none of tested derivatives showed activity against Gram-negative bacteria and yeast. We believe that the presence of the N,N-diethylamine group in the aromatic system and the number of carbon atoms in the carboxyalkyl group is more significant for the biological activity than the fact that the benzylidene or cinnamylidene substituent was present at the C-5 position.     

Synthesis, antibacterial activity and structure-activity relationships of N-substituted 3-methyl-4-diazo-5-pyrazolecarboxamides

A number of N-substituted 3-methyl-4-diazo-5-pyrazolecarboxamides (IVa-p) have been synthesized and tested for their in vitro antibacterial activity. All the compounds have been assayed against several representative Gram-negative and Gram-positive bacteria, as well as against some intestinal bacterial species. Some of the 4-diazopyrazoles IVa-c have shown a quite interesting broad-spectrum activity, while they are ineffective against the "protective" intestinal flora. The structure-activity relationships of the series have been studied quantitatively, via both univariate and multivariate methods: the results are consistent and permit some rationalization of the behaviour of the compounds investigated.     

Pharmacological studies of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (M73101). (2). Anti-inflammatory activity (author's transl)]

The anti-inflammatory activity and the mode of action of M73101, a new non-steroid analgesic anti-inflammatory agent, were investigated in experimental animals and compared with those of reference drugs. M73101 inhibited the increase in vascular permeability induced by acetic acid and its activity was more potent than that of phenylbutazone. M73101 showed a marked inhibitory effect against rat paw edema induced by various phlogistic agents (carrageenin, dextran, histamine, serotonin and bradykinin) and the activities were equal to or more potent than those of aminopyrine, mepirizole and tiaramide HCl. M73101 also inhibited the edema induced by mustard, scalding and anti-rat rabbit serum in rats. In addition, the anti-edematous effect of M73101 on carrageenin-induced rat paw edema was not influenced by spinalectomy or adrenalectomy, indicating that the anti-inflammatory action of M73101 was not mediated by the central nervous system and the adrenals. Local and oral administration of M73101 inhibited significantly the leucocyte migration into the fluid of CMC pouch in rats and the activity was more potent than phenylbutazone, suggesting that the anti-inflammatory effect of M73101 was due to the direct action at the inflamed site. On the other hand, M73101 did not show any marked activities on the experimental chronic inflammatory models. From these results, it is suggested that M73101 may be useful for clinical application as a basic analgesic, anti-inflammatory drug with remarkable anti-inflammatory activity in acute and subacute cases. The mechanism of the anti-inflammatory action of M73101 probably involves inhibition of an increase in vascular permeability and leucocyte migration.     

Chemotherapeutically active nitro compounds. 4. 5-Nitroimidazoles (Part I).

More than 135 new 2-methyl-5-nitroimidazoles substituted in 1-position and 1-methyl-5-nitroimidazoles substituted in 2-position were investigated for their activity against various protozoan species, in particular Entamoeba histolytica in the golden hamster, Trichomonas fetus, Trypanosoma brucei and T. cruzi in the NMRI mouse. Among the nitroimidazoles substituted in the 1-position only two preparations exhibited a similar effect as metronidazole preparations exhibited a similar effect as metronidazole against T. fetus. In the class of the nitroimidazoles substituted in the 2-position 16 compounds were as effective as metronidazole, 19 showed an effect superior to metronidazole, 1 was as good as tinidazole and 2 exhibited an activity superior to tinidazole against T. fetus. Only few compounds displayed any amoebicidal activity. Of the mono and bis-hydrazones of 1-methyl-5-nitroimidazole-2-aldehyde substituted in the 2-position 3 compounds had an amoebicidal effect 2 to 8 times stronger than that of metronidazole. Only few representatives of the 1-methyl-5-nitroimidazoles substituted in the 2-position produced a useful trypanocidal effect when given in relatively high doses. The structure-activity relationship of 5-nitroimidazole derivatives has been discussed.     

Chemotherapeutically acitve nitro compounds. 4. 5-Nitroimidazoles (Part III).

More than 100 1-methyl-5-nitroimidazoles substituted in the 2-position via an oxymethyl group were synthesized and their structure-activity relationship toward various protozoa was investigated. Among the derivatives substituted with an aromatic radical there are most of the compounds which are highly effective against trichomonads; 9 preparations are superior to tinidazole and 29 are superior to metronidazole in mice infected with Trichomonas fetus, and 9 compounds exhibit a better effect than metronidazole in golden hamsters intrahepatically infected with Entamoeba histolytica. In the same series one dialkylamino-acetamide derivative shows excellent trypanocidal activity in the NMRI mouse, but this effect is limited to Trypanosoma brucei; 12 preparations developed a trypanocidal effect only after relatively high doses; their range of efficacy included Trypanosoma cruzi, among others, after repeated treatment. Of the carboxyl acid, carbamic acid and sulphonic acid esters synthesized only the already known group of carbamic acid esters possesses a pronounced antiprotozoal effect. Among the preparations substituted with a heterocyclic radical some of the pyridine derivatives proved to have distinct trichomonacidal activity. The influence of the type of substitution and the stability of the C-X bond in 2-substituted 5-nitroimidazoles of all compounds synthesized so far (I--III, 4th report) are discussed in 2 tables.     

Adrenocorticotropin. 49.1 Synthesis and biological activity of [2-delta-aminovaleric acid, 5-arginine-a1adrenocorticotropin-(2-19).

An adrenocorticotropin analogue, [2-delta-aminovaleric acid, 5-arginine]adrenocorticotropin-(2-19), has been synthesized by the solid-phase method and its biological activity has been determined. It was found that substitution of arginine for glutamic acid at position 5 of [2-delta-aminovaleric acid]adrenocorticotropin-(2-19) increased the steroidogenic potency in idolated rat adrenal cells and the lipolytic potency in isolated rat fat cells but decreased the lipolytic potency in isolated rabbit fat cells. The synthetic analogue had only 2% of the melanotropic potency of the parent molecule.     

5-Hydroxytryptamine (5-HT3) receptor antagonists. 2. 1-Indolinecarboxamides

Indazole 1 has previously been shown to be a potent and selective 5-HT3 receptor antagonist. A novel series of potent 5-HT3 receptor antagonists, 1-indolinecarboxamides 2a-q and 1-indolecarboxamides 3b,i,j,k, is described. The activity of the indolines suggests that aromaticity of the 5-membered ring is not an essential requirement for potency provided that an "in plane" orientation of the carbonyl group is favored. Upon the basis of this hypothesis indene 9 was prepared in which the "in plane" orientation of the carbonyl group is maintained by conjugation with the aromatic ring through the sp2 hybridized carbon. It was also found to be a potent 5-HT3 receptor antagonist.     

Antimicrobial activity of 5-arylidene aromatic derivatives of hydantoin. Part 2

Various 5-chloroarylidene-2-amino substituted derivatives of imidazoline-4-one were synthesized and evaluated for their activity in vitro against Mycobacterium tuberculosis and other type strains of bacteria and fungi. 2-Chloro- and 2,4-dichlorobenzylidene substituted hydantoins exhibited antimycobacterial effect. The most potent compounds 3i, 3j, 3o, 3q and 3s were classified for further tests. The antimitotic effect of the investigated hydantoins was also examined.     

Antiviral activity of some beta-diketones. 3. Aryl bis(beta-diketones). Antiherpetic activity.

A series of bis(beta-diketones) was synthesized and tested in vitro for antiviral actitity against herpes simplex type 2. Two parameters which were studied in an effort to optimize activity were the nature of the aryl group and the length of the alkyl bridge. One of the more active compounds, 4,4'-[(1,4-phenylenedioxy)bis(6,1-hexanediyl)]-bis[3,5-heptanedione] (6), was evaluated more extensively and found to inhibit the cytopathic effect in tissue culture of herpes simplex virus type 1 as well as type 2. Compound 6 was evaluated in vivo topically against herpes simplex type 1 in experimentally induced skin infections in guinea pigs. A topical treatment with 2% of 6 in a vanishing cream base, administered 24 h postinfection applied five times daily for 4 days, significantly reduced the number and size of herpetic vesicles.     

Toxicity of Australian essential oil Backhousia citriodora (Lemon myrtle). Part 1. Antimicrobial activity and in vitro cytotoxicity.

The antimicrobial and toxicological properties of the Australian essential oil, lemon myrtle, (Backhousia citriodora) were investigated. Lemon myrtle oil was shown to possess significant antimicrobial activity against the organisms Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, methicillin-resistant S. aureus (MRSA), Aspergillus niger, Klebsiella pneumoniae and Propionibacterium acnes comparable to its major component-citral. An in vitro toxicological study based on the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) cytotoxicity assay was performed. In vitro cytotoxicity testing indicated that both lemon myrtle oil and citral had a very toxic effect against human cell lines: HepG2 (a hepatocarcinoma-derived cell line); F1-73 (a fibroblast cell line derived from normal skin) and primary cell cultures of human skin fibroblasts. Cytotoxicity IC50 (50% inhibitory concentration) values ranged from 0.008 to 0.014% (w/v) at 4 h to 0.003-0.012% (w/v) at 24 h of exposure. The no-observed-adverse-effect level (NOAEL) for lemon myrtle oil was calculated as 0.5 mg/l at 24 h exposure and the RfD (reference dose) was determined as 0.01 mg/l. A product containing 1% lemon myrtle oil was found to be low in toxicity and could potentially be used in the formulation of topical antimicrobial products.     

The bioavailability of Tamoplex (tamoxifen). Part 1. A pilot study

Tamoxifen and N-desmethyltamoxifen plasma concentrations were found to be similar after a first single dose and during two months therapy with Tamoplex or Nolvadex in groups of 6 and 8 patients, respectively. Single dose absorption results in 10 healthy male volunteers demonstrated bioequivalence of Tamoplex and Nolvadex 10 mg tablets. A large interindividual variation in tamoxifen absorption data was observed, probably related to the dominating metabolic clearance of tamoxifen.     

Clinical studies of intravenous drip infusion of micronomicin. 1. Pharmacokinetics (Part 2). Intravenous Micronomicin Research Group

Following the previous report on pharmacokinetics of micronomicin (MCR) in healthy volunteers, pharmacokinetic studies were made again in patients with different degree of renal impairment, and a nomogram was obtained. MCR at a dose of 60 mg/time was given by 1-hour drip infusion to 14 inpatients who consented to receive MCR (age: 35 to 84 years, Ccr: 17.96 to 104.35 ml/min). The blood collection was performed in accordance with the schedule made upon the degree of renal impairment, and the serum concentration was determined by HPLC method. The results were analyzed by MULT program using two- or one-compartment open model. The serum concentration (Cmax) just after administration of MCR was 5.8 +/- 0.9 microgram/ml (mean +/- S.D.). The biological half-life was 1.81 to 12.35 hours. Taking the above results into consideration together with the previous ones of healthy males, the following correlation was obtained between the elimination constant (Kel or beta) and Ccr calculated from S-Cr.: Kel or beta = 0.0038 X Ccr - 0.0097. Further, no side effect was observed in these studies. Elimination of MCR from blood was dependent on renal function like other aminoglycosides, and so it was possible to estimate the elimination constant from Ccr. From these results, a nomogram for the optimum dosage regimen of MCR was obtained.