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An expert Working Group was set up in December 2000 to develop recommendations for users and industry on the evaluation of proper function and operation of individually ventilated cage (IVC) systems. The full report of their recommendations is in two parts—'Part 1: Test Instructions' and 'Part 2: Evaluation Criteria'—both of which have been published in full on the Laboratory Animals Ltd website. They can be found at http://www.lal.org.uk/IVC/index.html. Evaluation of and feedback on the recommendations to further refine their use and scientific basis is encouraged. This Summary Report provides a brief overview of the background to the development of the full report and the issues it addresses.

The synthesis is described of new 15,15-ethylene ketals of natural prostaglandins and prostaglandin analogues. Especially the crystalline trisamine salt of the 15,15-ethylene ketal of 15-dehydro-16-phenoxy-17,18,19,20-tetranorprostaglandin F2alpha is a very active inducer of luteolysis in laboratory animals and cattle.

Auser Adenosin-3′,5′-monophosphat (3′,5′-AMP) wurde Guanosin-3′,5′-monophosphat (3′,5′-GMP) als zweites cyclisches Nucleotid-3′,5′-monophosphat im Organismus verschiedener Tierarten nachgewiesen. An Ratten wurde untersucht, ob diese Substanz ebenso wie 3′,5′-AMP an der Steuerung der Insulinsekretion beteiligt sein konnte. Die vorliegenden Resultate sprechen nicht fur diese Moglichkeit. Wahrend bei adrenalektomierten, mit einem Glucocorticoid substituierten Ratten nach i.v. Injektion von 20 mg/kg Dibutyryl-3′,5′-AMP oder Monobutyryl-3′,5′-AMP eine deutliche Steigerung der Insulinkonzentration im Serum des Pfortaderblutes nachweisbar war, wurde ein derartiger Effekt weder unter dem Einflus von 20 mg/kg Dibutyryl-3′,5′-GMP noch gleicher Dosen der Monobutyrylderivate von bisher in der Natur nicht nachgewiesenen Cyclophosphaten (Inosin-3′,5′-monophosphat, Uridin-3′,5′-monophosphat) beobachtet.

Bei spontandiabetischen chinesischen Streifenhamstern besteht ein auf einerβ-Zelldegeneration beruhender Insulinmangel mit den sich daraus fur den Kohlenhydrat- und Fettstoffwechsel ergebenden Konsequenzen (Hyperglykamie, pathologische Glucosetoleranz, Erhohung der Gluconeogenese — u. a. erkennbar an einem Anstieg der Glucose-6-phosphatase-Aktivitat in der Leber —, Anstieg der Konzentration freier Fettsauren im Serum).

Die Zuchtleistungen stoffwechselgesunder und erblich diabetischer Chinesischer Streifen-hamster wurden verglichen. Wurfgrose und Wurffolge hatten keinen Einflus auf das Geburtsgewicht und das Wachstum bis zum Absetzen. Zwischen Nachkommen stoffwechselgesunder und diabetischer Muttertiere bestand kein Unterschied hinsichtlich der Korpergewichte, die Mortalitatsrate war jedoch hoher bei Nachkommen diabetischer Mutter. Mit steigender Generationsfolge zeigte sich eine Tendenz zu fruherer Diabetes-Manifestation.

N-methanesulfonyl 16-phenoxy-omega-tetranor PGE2 is a prostaglandin analog which is markedly more tissue selective than PGE2. This compound is 10-30 times more potent than PGE2 in animal models which are considered relevant to antifertility effects in humans. In pharmacological tests which are believed to be predictive for side effects in humans, the compound has potency either equal to or less than that of PGE2.

The naturally occurring prostacyclin (PGI2) is a highly potent vasodilator and effectively lowers blood pressure in experimental animals when applied intravenously. Prostacyclin has, however, the disadvantage that it rapidly deteriorates at physiological pH and at normal room temperature. When PGI2 is applied orally, it has no systemic effect as it is very rapidly disintegrated in the gastric juices.

In in vitro binding studies ZK 33.839 (4-(3-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propoxy]-4-methoxyphenyl)- 2-pyrrolidone) showed highly specific binding affinity for 5-hydroxytryptamine (5-HT2) and alpha 1-receptors. With 2.0 nmol/l and 5.2 nmol/l both Ki-values occur in the same concentration range. The pharmacodynamic profile of ZK 33.839 has been investigated under in vitro and in vivo conditions. In human platelets, in rat vascular smooth muscle and in guinea pig tracheal smooth muscle 5-HT-induced proaggregatory and contractile effects were inhibited dose-dependently with IC50-values ranging from 1.85 x 10(-8) mol/l to 9 x 10(-9) mol/l. 5-HT-induced amplification of the response of rabbit femoral artery to different vasoconstrictors (angiotensin II, histamine, norepinephrine, and prostaglandin F2 alpha) and 5-HT-mediated increase of microvascular permeability in hamster cheek pouch preparation were also inhibited by ZK 33.839. ZK 33.839 was found to be a potent alpha 1-receptor antagonist, the pA2-value in rat aortic strips determined against phenylephrine was 9.16. In blood-perfused hindquarters of anaesthetized rats, pretreated with reserpine, pressor dose-response curves to norepinephrine and 5-HT were shifted to a higher dose range. ZK 33.839 lowered blood pressure in conscious Dahl-S-rats and in anaesthetized rabbits. Decrease of blood pressure was due to a decrease of peripheral vascular resistance. Cardiac output and heart rate were not significantly altered. ZK 33.839 is a potential antihypertensive compound which combines vasodilatatory effects due to selective alpha 1-receptor antagonistic action and platelet antiaggregatory, antivasospastic, and vasoprotective properties due to selective 5-HT2-receptor blockade.

The human myometrium contains two different forms of phosphodiesterase (PDE). One form is characterized by its lack of substrate specificity and its calcium-calmodulin dependence. The other one is selective for cyclic adenosine monophosphate (cAMP). Rolipram (4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidinone, ZK 62711) is a specific cAMP-PDE inhibitor. The physiological significance of the two forms of PDE is still unknown, particularly the role of the cAMP-specific form in the control of uterine motility. The latter form largely occurs in myometrium of pregnant women near term and is also present during the third trimester of pregnancy. Using isolated guinea-pig uteri it has been shown that rolipram in the concentration of 9 x 10(-4) mol/l caused the organ to remain insensitive to the stimulatory action of oxytocin. 9 x 10(-6) mol/l rolipram led to immediate relaxation of the uterus when it was added to the organ bath after the maximum concentration was reached following oxytocin stimulation. A new drug like rolipram effecting uterine motility in a not receptor-mediated manner might have advantages in comparison to beta-mimetics for the treatment of premature labor.

Chronic oral treatment of male diabetic Chinese hamsters with 100 mg/kg/day 5-methoxyindole-2-carboxylic acid (MICA) causes a depression of blood glucose in fasted animals and an improvement in the glucose profile in fed animals. Glycogen levels in the liver and body weight are decreased. Treated animals die at a higher rate than do controls. It is concluded that treatment with a potent inhibitor of gluconeogenesis like MICA will not provide a useful tool in managing diabetes.

Gliflumide is an optically active sulfonylaminopyrimidine. In rats, the drug exhibited a long-lasting hypoglycemic effect following oral as well as intravenous administration. This effect resembled the action of glibenclamide, but was brought about by doses 5-10 times lower. In healthy volunteers, oral administration (0.0125 mg/kg) or intravenous injection (0.01mg/kg) of gliflumide resulted in a 30-40 per cent decrease of blood glucose characterized by slow onset and long duration. The stimulation of insulin secretion was studied after intravenous injection of gliflumide (0.01 mg/kg) and compared to the action of glibenclamide (0.01 mg/kg) and tolbutamide (10 mg/kg). Although the effect of these doses, measured by the area above the initial level, was similar, a different time course of action was found. Gliflumide and glibenclamide, compared with tolbutamide, produced a delayed and prolonged response. These characteristics were more pronounced with gliflumide. Maximal serum insulin levels were found after 3, 23, and 90 minutes for tolbutamide, glibenclamide, and gliflumide, respectively. In maturity-onset diabetics requiring glibenclamide or glibenclamide + biguanide, gliflumide was shown to have about the same efficacy as glibenclamide, the corresponding doses being 1.5-5 (generally 3) times lower.

The reaction of insulin with potassium cyanate and methyl isothiocyanate at pH 7.5 has been studied. The products formed were separated by DEAE-Sephadex chromatography and were characterised by end-group analysis, isoelectric focussing and sulphitolysis. Derivatives were prepared in which the two α-amino groups of insulin were modified. A tricarbamylinsulin derivative was also prepared using a large excess of reagent. Modification of the amino groups of insulin with these reagents produced no statistically significant decrease in the biological activity of the hormone. However, modification of the phenylalanine B1 amino group by these reagents resulted in a large decrease in the affinity of such insulin derivatives towards insulin antibodies raised in mongrel guinea pigs.

An Ratten wurde untersucht, ob die im Tierexperiment nach Gabe von Biguaniden auftretende Hypoglykamie durch einen direkten Eingriff in den Stoffwechsel verursacht wird oder auf eine Verstarkung der blutzuckersenkenden Wirkung von Insulin (I) [1] zuruckzufuhren ist. Die Versuche wurden mit Buformin durchgefuhrt. Unsere Ergebnisse lassen den Schlus zu, das die Wirkung der Biguanide auf einer insulinunabhangigen Hemmung der Gluconeogenese in den dazu befahigten Organen und gleichzeitiger Steigerung der Glucoseutilisation in der Skeletmuskulatur beruht. Hierfur sprechen folgende Beobachtungen: 90 min nach i.p. Injektion von 100 mg/kg Buformin ist die Glucosekonzentration im Blut (BZK) nicht nur bei normalen Ratten (NR), sondern auch bei alloxan-diabetischen Tieren (AR) erniedrigt, der BZK-senkende Effekt von exogenem Insulin wird bei diesen Ratten nicht verstarkt (Tabelle).