The bradykinin antagonist Hoe 140 inhibits carrageenan- and thermically induced paw oedema in rats.

The new and highly potent B2 bradykinin (BK) antagonist Hoe 140 was tested for its ability to inhibit oedema of rat paws induced by scalding and carrageenan. The data show that Hoe 140 inhibits scalding and carrageenan oedema for more than four and six hours, respectively. Based on its potency against actions of endogenously generated kinins Hoe 140 is appropriate to investigate the role of kinins in human inflammatory diseases.

Hoe 140 a new potent and long acting bradykinin-antagonist: in vivo studies.

1. The potency, duration of action and tolerability of Hoe 140, a novel and highly potent bradykinin (BK) antagonist in vitro, has been tested in different in vivo models and compared with the well-known BK antagonist D-Arg-[Hyp2, Thi5,8, D-Phe7]BK. 2. Hoe 140 is highly potent and long acting in inhibiting BK-induced hypotensive responses in the rat. Four hours after s.c. administration of 20 nmol kg-1, inhibition still amounted to 60% whereas the effect of 200 nmol kg-1 of D-Arg-[Hyp2, Thi5,8, D-Phe7]BK was not significant. 3. BK-induced bronchoconstriction in guinea-pigs was strongly inhibited by Hoe 140. The magnitude and duration of inhibition confirmed the findings obtained in the blood pressure experiments in the rat. 4. Carrageenin-induced inflammatory oedema of the rat paw was considerably inhibited at i.v. doses between 0.1 and 1 mg kg-1. 5. In conscious dogs, intravenous doses of 0.01 and 0.1 mg kg-1 of Hoe 140 and D-Arg-[Hyp2, Thi5,8, D-Phe7]BK were well tolerated. At doses of 1 mg kg-1 adverse effects occurred that were attributed to the residual BK agonistic activity of both compounds. 6. Hoe 140 has been shown to be a highly potent and long acting BK antagonist in vivo in different animal species and models. This makes it appropriate to investigate further the physiological and pathophysiological role of BK.

Influence of the new angiotensin converting enzyme inhibitor ramipril on several models of acute inflammation and the adjuvant arthritis in the rat.

Paw oedema in the rat by carrageenin and kaolin partially caused by Hageman factor activation was potentiated by the new angiotensin converting enzyme (ACE) inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl-L-alanyl]-(lS,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid] (ramipril, Hoe 498) due to its inhibition of kininase II which results in increased bradykinin levels. A dose of 1 microgram ramipril injected into the hind paw of Sprague-Dawley rats concomitantly with, or 1 mg/kg given orally 30 min before administration of the irritants, led to significantly increased inflammatory reactions. The same effects were observed when ramipril was administered 3 h after carrageenin. In the kallikrein-kinin-deficient Brown-Norway rat strain Mai Pfd/f, ramipril did not significantly alter the paw oedema induced as described above. In addition, pretreatment of Sprague-Dawley rats with 10 mg/kg i.v. bromelains completely prevented the potentiation of inflammation by ramipril. Paw oedema provoked by the Hageman factor non-activators serotonin, dextran, ovalbumin and anti-rat IgG was not potentiated by ramipril. The chronic adjuvant arthritis in Lewis rats was not influenced by daily oral treatment with 0.1-3 mg/kg ramipril. Thus, in the rat only those inflammatory reactions involving kinins, presumably generated by Hageman factor activators, are potentiated by ramipril and presumably by other ACE-inhibitors.

[Chemistry and pharmacology of prednicarbate (Hoe 777), a halogen-free topical anti-inflammatory active derivative of prednisolone-17-ethyl carbonic acid ester]. / Zur Chemie und Pharmakologie von Prednicarbat (Hoe 777), einem halogenfreien, topisch anti-inflammatorisch wirksamen Derivat des Prednisolon-17-ethylkohlensäureesters.

Prednicarbate (Hoe 777) is a corticoid without halogenic groups (see formula Fig. 1), showing a remarkably favorable split between topical and systemic anti-inflammatory or rather corticoid effects, which could be proved by means of various animal experiments after dermal and systemic application. The topical efficacy resembles that of current corticoid preparations containing fluorine, but its systemic influence is definitely less.

[Animal experiment studies on the topical and systemic effectiveness of prednisolone-17-ethylcarbonate-21-propionate]. / Tierexperimentell Untersuchungen zur topischen und systemischen Wirksamkeit von Prednisolon-17-ethylcarbonat-21-propionat.

Prednisolone-17-ethyl carbonate-21-propionate (PrEP, Hoe 777) was tested for antiinflammatory activity in various animal models by topical and systemic administration. In those models being indicative of topical efficacy, the potency of PrEP was the same as that of desoximetasone. However, systemic effects after topical administration of PrEP in shaved skin of the dorsum of rats were relatively weak compared with the reference compound. Moreover, there were less systemic corticoid effects after s.c. administration of PrEP than after desoximetasone. Thus, PrEP is obviously a compound with a considerable split of topical and systemic activity, suggesting its testing in man for systemic effects after topical administration.

Biochemical and pharmacological effects of dipyrone and its metabolites in model systems related to arachidonic acid cascade.

The metabolites of dipyrone (metamizol, Novalgin) were compared with appropriate standard drugs for their influences on the pathways of the arachidonic acid metabolism. The drugs in this study had no significant effects on the lipoxygenase pathway in human neutrophils in vitro. The dipyrone metabolites 4-methylaminoantipyrine (MAAP) and 4-aminoantipyrine (AAP) inhibited prostaglandin synthesis in the 10(-3) to 10(-4) mol/l range thus being comparable to acetylsalicylic acid (ASA), whereas the two additional metabolites 4-acetylaminoantipyrine (AAAP) and 4-formylaminoantipyrine (FAAP) were practically inactive. This result is in accordance with the effects of the metabolites on the formation of oedema in the arthritis rat model, and supports published data showing that MAAP and AAP are the metabolites responsible for the clinical effects of dipyrone. Further systems in our study depending at least partially on the prostaglandin pathway were the release of antiaggregatory activity from rat aortae in vitro and the aggregation of human platelets induced by arachidonic acid in vitro. MAAP exhibits antiaggregatory activity (IC50 5 x 10(-6) mol/l), whereas the inhibitory effect on the vascular antiaggregatory release is much weaker. Compared to normals platelet aggregability ex vivo is enhanced in arthritic rats, but could significantly be lowered again by treatment of the rats with MAAP. A further system studied was the release of 6-keto-PGF1 alpha from rat mucosa in vitro and ex vivo. In vitro there is inhibition to be found with MAAP as well as with ASA. Ex vivo, however, dipyrone or MAAP slightly stimulates mucosal 6-keto-PGF1 alpha rather than inhibiting it, whereas ASA exerts inhibition, as expected.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacology of a gut motility stimulating enkephalin analogue.

The enkephalin analogue pentapeptide Hoe 825 (Tyr-D-Lys-Gly-Phe-L-homocysteine-thiolactone) is a mixed mu/delta opiate agonist. The peptide stimulated interdigestive gut motility at all parts of the intestine in conscious and anaesthetized animals. In dogs digestive motility, measuring mechanical activity, was stimulated with respect to segmental and propulsive properties. The canine uterus was sensitive to the enkephalin. Hoe 825 acts by i.v. or s.c. application, whereas the latter increases the duration of action significantly. The compound's effect can be blocked by naloxone indicating a receptor mediated action, which is localised peripherally. The compound is devoid of a dependence risk, because it does not penetrate into the CNS. At therapeutic doses (in the dog 0.5-2 micrograms/kg i.v.) the compound does not affect cardiovascular, renal or endocrine functions and was without effect on serum blood glucose levels in rats and rabbits.

Central and peripheral action of enkephalin analogues.

Chemical modifications of enkephalins led to analogues with strongly increased biological potency. Compounds such as H-Tyr-DLys(CHO)-Gly-Phe-L-homocysteinethiolactone (Hoe 825) additionally show a remarkable split between central and peripheral action, favouring the stimulation of gastrointestinal contractions. Hoe 825 could, therefore, be useful in the treatment of conditions where gut motility is lacking in humans, especially in adynamic ileus.

Vascular effects of piretanide. Studies on extrarenal action in several animal models.

4-Phenoxy-3-(1-pyrrolidinyl)-5-sulfamoyl benzoic acid (piretanide, Arelix) was studied for its vasoactive effects in several experimental models. In rat and rabbit thoracic aorta strips, piretanide dose-dependently attenuated contractions induced by norepinephrine (noradrenaline). When contractions were induced by KCl no concentration response curve could be established. Piretanide inhibited the vasoconstrictor response to norepinephrine and to KCl in the rat mesenteric vascular bed. IC50's of 0.5 mmol/l and 4.9 mmol/l, resp., were calculated. In bovine coronary artery strips piretanide caused a marked relaxation. The vasoconstrictor response to PGE2 in piretanide superfused preparations was attenuated in a concentration related manner. Infusion of piretanide (1 mg X ml-1 X min-1) in the isolated guinea pig heart produced a reversible increase of coronary flow. In both normotensive and spontaneously hypertensive bilaterally nephrectomized pithed rats piretanide caused a significant reduction of diastolic blood pressure. The results contribute to the understanding of the antihypertensive effect of piretanide.

[Experimental animal studies on the topical and systemic activity of prednisolone-17-ethylcarbonate-21-propionate]. / Tierexperimentelle Untersuchungen zur topischen und systemischen Wirksamkeit von Prednisolon-17-ethylcarbonat-21-propionat.

Prednisolone-17-ethylcarbonate-21-propionate (PrEP, Hoe 777) was tested for antiinflammatory activity in various animal models by topical and systemic administration. In those models being indicative of topical efficacy, the potency of PrEP was the same as that of desoximetasone. However, systemic effects after topical administration of PrEP in shaved skin of the dorsum of rats were relatively weak compared with the reference compound. Moreover, there were less systemic glucocorticoid effects after s.c. administration of PrEP than after desoximetasone. Thus, PrEP is obviously a compound with a considerable split of topical and systemic activity, suggesting its testing in man for systemic effects after topical administration.

Prevention of changes after UV-irradiation by sunscreen products in skin of hairless mice.

Female hairless mice (strain mutant hr/hr) have been irradiated with increasing doses of UV-B over a period of 4 weeks. They were compared with untreated controls Additional groups of 30 mice were treated with milk base or cream base or milk SPF6 or cream SPF6 or cream SPF8 daily before irradiation. No changes of body weight indicating systemic effects were found. Skin thickness was increased significantly after irradiation. These changes were partially antagonized by cream or milk bases and completely prevented by the corresponding formulations containing sunscreen agents. Under the chosen conditions ultimate load of excised skin samples was increased by irradiation. This effect was not reversed by the bases but by the sunscreen products. Ultimate strain of excised skin samples proved to be the most sensitive indicator. The decrease of ultimate strain after irradiation was partially antagonized by the bases. The sunscreen products had more powerful effect. Due to the effects on skin thickness and ultimate load tensile strength and modulus of elasticity did not show significant changes under the chosen conditions. Likewise, collagen and elastin content per gram wet weight did not show significant changes. Considering the increase of thickness of skin which is prevented by sunscreen products one may conclude also a prevention of formation of additional intercellular material. The results prove the value of sunscreen products. Furthermore, they demonstrate a new method for evaluation of chemicals and sun protection preparations.

[Studies on the pharmacology and toxicology of ciclopiroxolamine (author's transl)]. / Zur Pharmakologie und Toxikologie von Ciclopiroxolamin.

Pharmacological studies with 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, 2-aminoethanol salt (ciclopiroxolamine, Cic, Hoe 296, Batrafen) have been carried out in various test animal species and in isolated organs. The studies did not reveal any indication of effects on the central nervous system or an metabolic functions such as body temperature, urinary and biliary excretion, blood coagulation and acute inflammatory processes. Blood pressure and heart rate were slightly decreased. In the isolated ileum of the guinea pig, slight antagonism towards Ba2+, histamine, carbachol and nicotine was observed. With the doses of ciclopiroxolamine used in local therapy, no systemic pharmacological effects can be expected. Short-term toxicity studies carried out in the usual species of test animals produced oral LD50 values in the range of g/kg of body weight. A 4-week oral administration of 30 mg/kg body weight was virtually symptom-free and the corresponding dose in a 3-month administration was 10 mg/kg. The compound revealed a favourable therapeutic index. As anticipated, the cutaneous tolerance was dependent on animal species, pharmaceutical preparation, concentration of pure drug and duration of the application. The same applies to the tolerance in the vaginal mucosa of the dog. Studies on reproduction toxicology, mutagenicity, carcinogenicity and phototoxicity of ciclopiroxolamine produced no prohibitive findings.