Search

Several polyphloretin phosphate (PPP) fractions (low mol. wt LC1259; high mol. wt LC1261; crude mixture, LC101) were confirmed in their established property as antagonists of the pharmacological actions of prostaglandins in a preparation of guinea-pig isolated ileum stimulated by prostaglandin (PG)E2. Further samples of the same material were then compared in-vitro with indomethacin in their ability to inhibit prostaglandin biosynthesis from arachidonic acid by a microsomal enzyme preparation. All three PPP fractions potently inhibited prostaglandin generation, with the rank order of potency LC1259 = LC101 = indomethacin > LC1261. The oral LD50 in mice was 25 mg kg−1 for indomethacin and > 1 g kg−1 for LC101. PPP fractions (especially LC101) may therefore have therapeutic potential as anti-inflammatory agents.

There is an increasing trend towards computerization in medicine, including cognition. Nine systems of assessment are reviewed in this article. A number of initiatives involving these systems are in their infancy, and the development of computerized testing is having an influence on their definition.

Several β-adrenoceptor blocking agents have been evaluated for spermicidal activity using a transmembrane migration method. The rank order of potency of the active compounds was: penbutolol > (+) - propranolol > bufuralol > (—) - alprenolol > oxprenolol > metoprolol. Atenolol, pindolol, practolol, tolamolol were without activity. The observed potencies of spermicidal activity are believed to be unrelated to β-blocking activities, and we have shown that whilst they are not predictable from lipid solubility or nonspecific membrane properties of the compound alone, both these aspects appear to play a role in this pharmacological activity.

Using the modified transmembrane migration method to measure sperm motility, it was shown that the surfactant nonoxynol-9 alone, was twice as potent as (+)-propranolol alone as a spermicidal agent. Addition of (+)-propranolol to nonoxynol-9 shifted the dose-response curve to the left of the curves for either component alone, and a surprising synergistic action was evident. These observations may form the basis for the development of a new advantageous topical contraceptive combination product.Researchers from the Cambridge Research Institute in England conducted i vitro research on the effects of (+)-propranolol and nonoxynol-9, alone and in combination, on human sperm motility. They used modified transmembrane migration method of Hong et al since it allowed dose- response curves to be done on each semen sample from 7 donors. They also applied the PCONLIN computer program to more detailed data to define the shape of the curve more accurately. Nonoxynol-9 exhibited twice the potency of (+)-propranolol. Their drug concentrations at which 50% maximal inhibition occurred (IC50) were .156 mg mL-1 and .373 mg mL-1 respectively. Moreover, with the addition of 1-2.5 mM (+)- propranolol to nonoxynol-9, the dose-response curve moved to the left of the curves for either (+)-propranolol and nonoxynol-9 alone. Therefore the 2 agents exhibited a synergistic effect. Later they applied data from other experiments to a simple effect model and found a 3-10 fold increase in potency of nonoxynol-9 and 1 mM (+)-propranolol together compared to nonoxynol-9 alone. These results gave further credence to a synergistic action of the 2 drugs. The combination which resulted in the greatest inhibition of sperm motility (99.9%) included 1.6 mM nonoxynol-9 and 2.5 mM (+)-propranolol. Nevertheless they did not see a need to use 1 mM (+)-propranolol because the concentration of nonoxynol-9 causing total inhibition of sperm motility was similar. Therefore effective concentrations of each in a topical contraceptive agent can be .5 mg mL-1 nonoxynol-9 and .3 mg mL-1 (+)-propranolol (about 1 mM). This results in using about 1/10th of the nonoxynol-9 used in current contraceptive formulations which reduces the potential problems of sensitivity.

The effects were investigated of cyclical rhythm and hormonal contraception on serum fat-mobilizing activity, glycerol, cholesterol and whole blood glucose during 2 menstrual cycles in a group of normally menstruating young women and a second group of young women using hormonal contraception. A control group of normal young men was also investigated. There was no evidence of any change in mean level of any of the parameters measured, among the follicular, ovulatory and luteal phases. No cyclical pattern was discernable in the male subjects. The mean value for serum cholesterol concentration in women using hormonal contraception was higher than the value for the untreated human female group. The overall mean value for serum glycerol concentration in the women was significantly (0.01 > P > 0.001) higher than the mean value obtaining in the men.

The total nitrogen and L-hydroxyproline concentrations of two intra-abdominal and two subcutaneous sites of adipose tissue were measured in male and female Wistar rats. At 100 g body weight the nitrogen concentration of intra-abdominal adipose tissue was slightly lower than that of subcutaneous adipose tissue. As age advanced beyond sexual maturity, the nitrogen content of intra-abdominal adipose tissue was steadily reduced, whereas that of subcutaneous tissue did not change. The L-hydroxyproline concentration of intra-abdominal adipose tissue was also lower than in subcutaneous adipose tissue. In male rats it rose in most adipose tissue sites when sexual maturity was reached, then fell with advancing age. In female rats the pattern of change was less consistent, but the l-hydroxyproline content of intra-abdominal adipose tissue was reduced as age increased.

After intravenous injection of glucose, 750 mg/kg, together with a tracer dose of [U-14C] glucose, into fasted, adult white rats, the following percentages of the administered dose were found in whole organs and tissues: 1. after five minutes: skeletal muscle 30.3, skin 28.1, blood 13.1, adipose tissue 10.7, liver 8.9. 2. Forty minutes after injection the corresponding values were: 35.0, 11.1, 5.0, 4.6 and 9.4%. Expired 14CO2 was negligible after five minutes: after 40 min it comprised 8% of the total dose administered. — After intragastric administration of 1500 mg/kg of glucose given with a tracer dose of [U-14C] glucose under the same experimental conditions, the alimentary tract contained, after 15, 90 and 180 min, 60.5, 14.8 and 8.4% respectively of the total 14C dose given. At these times the liver contained 2.9, 10.7 and 15.0%; skin contained 7.5, 7.1 and 5.4%; adipose tissue 2.0, 3.8 and 3.5%, and expired 14CO2 0.4, 11.8 and 31.3% respectively. Details of the uptake of 14C glucose by other organs and tissues are given, and a balance sheet for the injected material is attempted.

Serum and plasma obtained from fasted rats were examined for their capacity to promote glycerol release from isolated fat cells of the rat,in vitro. Dose-response curves indicated that the lipolytic potencies of serum and plasma were very similar. Plasma comparison experiments suggested that lipolysis promoted by this circulating agonist had a requirement for calcium ions. Since adrenaline can enhance lipolysis in a calcium-free medium, the lipolytic capacity of serum and plasma could not be simply explained in terms of circulating catecholamines. The concentrations of glycerol or free fatty acids did not increase when serum or plasma were incubated in the absence of fat cells.

The effects were examined of the universal solvent dimethyl sulphoxide (DMSO) on human platelet aggregatory activity, in-vitro, of the endogenous mediators ADP, adrenaline, arachidonic acid, collagen and PAF-acether which are believed to play important roles in cardiovascular diseases in man. DMSO inhibited aggregation induced by all of the mediators in the order ADP > adrenaline = arachidonic acid = PAF-acether > collagen. Since DMSO is widely used as a solvent for drug substances, an awareness of its intrinsic activity in any such evaluations is essential.

The effects of two alpha-1-adrenergic agonists (phenylephrine, cirazoline) and two alpha-2-adrenergic agonists (clonidine, guanabenz) were investigated on lipolysis stimulated by noradrenaline, isoprenaline, dibutyryl cyclic AMP (dbc AMP) or methylisobutylxanthine (MIX) in hamster adipose cells, in vitro. Phenylephrine enhanced basal lipolysis and that stimulated by dbc AMP and MIX, whereas cirazoline showed no measurable effects. Clonidine produced a slight but significant decrease of basal lipolysis. Both clonidine and guanabenz (from 10(-7) M) provoked a similar and clear inhibition (50-60 per cent) of MIX-stimulated lipolysis, compatible with the view that the alpha-adrenergic receptor of the hamster white fat cell is of the alpha-2 type. Noradrenaline-stimulated lipolysis was unaffect and isoprenaline-stimulated lipolysis moderately inhibited, by clonidine and guanabenz. Since the beta-adrenergic lipolytic effects of noradrenaline are known to be associated with a simultaneous alpha-adrenergic inhibitory stimulus, and one possible explanation of the but moderate inhibition of isoprenaline-induced lipolysis could be simultaneous beta-adrenergic stimulation (resulting in lipolysis), and alpha-adrenergic stimulation (inhibition of lipolysis), as with noradrenaline, the nature of isoprenaline as a pure beta-adrenergic agonist requires clarification.

The extent of cyclic AMP (cAMP) mediated lipolysis in adipose tissue cells of man and several other animal species is regulated by the interplay of alpha- and beta-adrenoceptors modulating adenyl cyclase activity. Although the naturally-occurring catecholamines, and isoprenaline, are thought to act at the same pro-lipolytic beta-adrenoceptor antilipolytic agents, working through the alpha 2-adrenoceptor moiety of adenyl cyclase, appear to act at separate sites for: true alpha 2-agonists such as clonidine, for adenosine and for prostaglandins. Further, such antilipolytic agents are conspicuously more potent against lipolysis stimulated by methyl-isobutylxanthine (MIX) than against that stimulated by catecholamines. The nature of the dual character of adenyl cyclase remains to be elucidated. alpha 2 Adrenoceptor antagonists which promote lipolysis, and may possibly serve a therapeutic role in the treatment of obesity, may also provoke inappropriate insulin release which is contraindicated. Thus a problem in chemotherapy exists which may be resolved by new agents with differential tissue specificities. An example of this chemotherapeutic dilemma is possibly provided by the body weight accruing actions of tricyclic antidepressant compounds whose mechanism of action involves also (central) alpha 2-adrenoceptors.

The plasma obtained from fed and starved lean, normal and obese women was estimated, by a radio-immunoassay method, for prostaglandins, owing to their implication in the regulation of adipose tissue lipolysis and the development of obesity. No significant differences were found due to nutritional status or body-build. However, a significantly higher plasma concentration of prostaglandins of the E-type than of the F-type, was found consistently. The very low levels of prostaglandins observed (a range of 0.10--0.15 ng ml-1 for E-type and a range of 0.05--0.07 ng ml-1 for the F-type) may be due, in part, to the activity of a plasmatic prostaglandin metabolizing system.

The dose-response curves of the beta-adrenergic agonists isoprenaline (mixed beta 1 and beta 2), prenalterol (beta 1-selective), noradrenaline (more beta 1 than beta 2) and salbutamol (beta 2-selective) were studied on adipose cells of the rat, in vitro. The observed lipolytic potencies were in the order: isoprenaline greater than noradrenaline greater than salbutamol greater than prenalterol. The effects of beta-adrenergic antagonists betaxolol (beta 1-selective) propranolol (non-selective) and ICI 118551 (beta 2-selective) on lipolysis stimulated by the various beta-adrenergic agonists showed that in each case propranolol was the most potent blocking agent. These observations are not compatible with the concept that regulation of lipolysis in adipose tissue is mediated exclusively either by adrenergic receptors of the classical beta 1 type, or of the classical beta 2 type. We propose therefore, that this beta-adrenergic receptor, because of its non-compliance with the current classification system, be termed a 'beta-3' or beta-hybrid' adrenoceptor. Thus cardio-selective beta-adrenergic blocking agents, like betaxolol, may offer a hitherto unrecognized clinical advantage in obese patients undergoing anti-hypertensive therapy by offering a reduced impediment to hormone-induced utilization of calorie stores in adipose tissue.

In rats allowed access to food, and in food-deprived rats, fenfluramine (20 and 100 mg kg-1) and amphetamine (10 and 20 mg kg-1) provoked a hypotriglyceridaemic effect. No changes in plasma cholesterol concentration were observed. The time course of the absorption of a lipid load differed according to the nutritional status of the animals; being bellshaped under fed, and curvilinear under fasted, conditions. However, absorption under both nutritional conditions was inhibited by amphetmine and fenfluramine. When rats which had received the test compounds were administered glycerol trioleate containing a tracer dose of glycerol [1-14C]-trioleate or [2-3H]-glycerol trioleate, there was an inhibition in the increase of plasma radioactivity only in the case when the fatty acid contained the radioactive label. The net effect of lipid absorption was a transfer of dietary lipid from the gut to adipose tissue stores. There was never more than 5 per cent of the administered load in the liver. These observations indicate that amphetamine and fenfluramine may have acute effects in reducing circulating triglycerides, separate from the effects on lipid absorption from the gut. In this latter, the palmitoyl-CoA monooleinacyltransferase enzyme probalby plays a key role and appears a major target of the overall anti-obesity of fenfluramine.

The total nitrogen and L-hydroxyproline concentrations of two intra-abdominal and two subcutaneous sites of adipose tissue were measured in male and female Wistar rats. At 100 g body weight the nitrogen concentration of intra-abdominal adipose tissue was slightly lower than that of subcutaneous adipose tissue. As age advanced beyond sexual maturity, the nitrogen content of intra-abdominal adipose tissue was steadily reduced, whereas that of subcutaneous tissue did not change. The L-hydroxyproline concentration of intra-abdominal adipose tissue was also lower than in subcutaneous adipose tissue. In male rats it rose in most adipose tissue sites when sexual maturity was reached, then fell with advancing age. In female rats the pattern of change was less consistent, but the l-hydroxyproline content of intra-abdominal adipose tissue was reduced as age increased.

A low molecular weight fraction of a polyphloretin phosphate (PPP) preparation simulated glycerol in a milieu designed for enzymatic assay of glycerol. It is suggested that a component of this PPP mixture is able to act as an alternative substrate for the ATP-glycerol transfer enzyme; it becomes phosphorylated and thus initiates the series of reactions resulting in a increased conversion of NADH to NAD and the observed changes in absorbance.

Il y a une connexion lineaire entre la concentration progressive de l'ethanol et l'inhibition de la lipolyse stimulec par le serum dans les cellules libres du tissu adipeux de rats affames. L'ethanol n'a pas affecte la decharge basale du glycerol.

A method is described for measuring the deoxyribonucleic acid (DNA) content of small samples of adipose tissue or free fat cells. Lipids and acid-soluble nucleotides are first removed by extraction with a cold diethyl ether-ethanol mixture containing 10 per cent. m/V of trichloroacetic acid. DNA is then measured by hydrolysing the nucleoprotein residue in a 5 per cent. solution of trichloroacetic acid at 90 °C for 20 min, followed by treatment with p-nitro-phenylhydrazine and measurement of the hydrazone at 560 nm.Several aspects of the method have been critically examined in order to determine the optimum conditions. The method is satisfactorily reproducible.