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Biomedical subjects

J Knoll

Publications and source records attributed to J Knoll.

At least 91 records · Page 5Linked to original sources
PubMed1985

Analysis of the analgesic and anti-inflammatory effects of rimazolium, a pyrido-pyrimidine derivative, compared with that of prostaglandin synthesis inhibitors and morphine.

The analgesic, anti-inflammatory and gastrointestinal effects of rimazolium, morphine and prostaglandin synthesis inhibitors were compared in a battery of tests. Rimazolium, morphine and indomethacin all inhibited carrageenin-induced inflammation; however, the onset of action was different. The first (histamine-serotonin) phase was inhibited by rimazolium, the second (kinin) phase by morphine and the third (prostaglandin) by indomethacin. The chemoluminescence of leucocytes was inhibited by morphine and indomethacin but was unaffected by rimazolium. Prostaglandin-mediated pain (ACh, ATP, acetic acid writhing) was inhibited by all three types of compound; however, pain reaction where prostaglandins (PGs) are not involved (MgSO4 writhing) was inhibited by rimazolium and morphine, but not (or only slightly) by PG synthesis inhibitors. Gastric lesions produced by indomethacin were depressed by rimazolium and aggravated by morphine. These results suggest different mechanisms of anti-inflammatory and analgesic action of rimazolium, morphine and PG synthesis inhibitors.

Animals↗
PubMed1985

Satietin, a blood-borne, highly selective and potent anorectic glycoprotein.

Satietin, a 50 000 dalton anorectic glycoprotein, was isolated from human serum. Its isoelectric point is 7.0. It contains 14-15% amino acids and 70-75% carbohydrates. Its biological activity survives digestion with proteases and boiling. Satietin is a highly potent anorectic substance. The intracerebroventricular administration of 10-20 micrograms satietin suppresses food intake in rats during the first day of feeding after deprivation of food for 96 h to half of the amount eaten by untreated controls (ID50). The onset of the effect can be detected within 30 min, the peak effect is reached within an hour. The effect lasts 24-30 h. Satietin acts both at intravenous and subcutaneous administration (ID50 = 0.5-0.75 mg/kg) to rats deprived of food for 96 h. The peak effect is reached within an hour and lasts over 24 h. In contrast to the anorectic drugs in clinical use and to the endogenous anorectic substances (like cholecystokinin and calcitonin), satietin proved to be highly selective in suppressing food intake. Considering that satietin is widely distributed in the world of vertebrates, its concentration in the blood is amazingly high, its site of effect is in the central nervous system and it induces satiety without having any other detectable central or peripheral effect, the hypothesis was put forward that satietin may play the role of a rate limiting blood-borne satiety signal in the negative feed-back of food intake, i.e. serving as the essential chemical link connecting the gastrointestinal tract and the brain in the regulation of feeding.

Animals↗
PubMed1985

Satietin, a blood-borne glycoprotein in the regulation of food intake.

Satietin and satietin-D, two closely related 50,000 dalton anorectic glycoproteins were isolated from human serum. The isoelectric point of satietin is 7.0, it contains 14-15% amino acids and 70-75% carbohydrates. Satietin-D has an isoelectric point of 3.0, a protein content of 20-22% and a carbohydrate content of 55-60%. Both satietin and satietin-D are potent, long-acting and highly selective suppressants of food intake in the rat. The hypothesis was forwarded that satietin and satietin-D may belong to a system which brings into being the rate-limiting blood-borne satiety signalization in the negative feedback of food intake.

Animals↗
PubMed1984

Molecular weight measurement of human satietin.

Attempts were made to estimate the actual molecular weight of satietin, an endogenous food intake inhibitor, by means of classical and high-performance gel filtration and gel electrophoresis. Satietin, which proved to be a glycoprotein, was isolated from human plasma. Sephacryl S-300 gel and TSK-GEL G 3000 SW columns were used as media for gel filtration and gel electrophoresis in the presence of sodium dodecyl sulphate (SDS-PAGE), respectively. A relatively good correlation was established between the molecular weight measurements carried out by different methods, although satietin as a carbohydrate-rich glycoprotein gave an underestimated value by gel filtration when the calibration graphs were constructed with simple proteins. The molecular weight of satietin was determined to be about 43,000 daltons by SDS-PAGE and 29,000 daltons by gel filtration when using a buffer containing 1% of sodium dodecyl sulphate.

Chromatography, Gel↗
PubMed1984

L-deprenyl plus L-phenylalanine in the treatment of depression.

The antidepressive efficacy of 1-deprenyl (5-10 mg daily) plus 1-phenylalanine (250 mg/day) has been evaluated in 155 unipolar depressed patients. Both oral and intravenous administration showed beneficial effects in 90% of outpatients and 80.5% of inpatients. It is concluded that this combined treatment has a potent antidepressive action based on the accumulation of 1-phenylethylamine in the brain.

Depressive Disorder↗
PubMed1984

Satietin; a 50,000 dalton glycoprotein in human serum with potent, long-lasting and selective anorectic activity.

Satietin, a 50,000 dalton anorectic glycoprotein was isolated from human serum. Its isoelectric point is 7.0. It contains 14-15% amino acids and 70-75% carbohydrates. Its biological activity survives digestion with proteases and boiling. Satietin is a highly potent anorectic substance. The intracerebroventricular administration of 10-20 micrograms satietin suppresses food intake in rats during the first day of feeding after deprivation of food for 96 hours to half of the amount eaten by untreated controls (ID50). The onset of the effect can be detected within 30 minutes, the peak effect is reached within an hour. The effect lasts 24-30 hours. Satietin acts both at intravenous and subcutaneous administration (ID50 = 0.5-0.75 mg/kg) in rats deprived of food for 96 hours. The peak effect is reached within an hour and lasts over 24 hours. In contrast to the anorectic drugs in clinical use and to the endogenous anorectic substances (like cholecystokinin and calcitonin) satietin proved to be highly selective in suppressing food intake. Considering that satietin is widely distributed in the world of vertebrates, its concentration in the blood is amazingly high, its site of effect is in the central nervous system and it induces satiety without having any other detectable central or peripheral effect, the hypothesis was forwarded that satietin may play the role of a rate limiting blood-borne satiety signal in the negative feedback of food intake, i.e. serving as the essential chemical link connecting the gastrointestinal tract and the brain in the regulation of feeding.

Animals↗
PubMed1984

Satietin, a blood-borne anorectic glycoprotein, as the putative rate-limiting satiety signal in the negative feed-back of food intake.

Satietin, a 50,000 dalton anorectic glycoprotein, was isolated from human serum. Its isoelectric point is 7.0. It contains 14-15% amino acids and 70-75% carbohydrates. Its biological activity survives digestion with proteases and boiling. Satietin is a highly potent anorectic substance. The intra-cerebroventricular administration on 10-20 micrograms satietin suppresses food intake in rats during the first day of feeding after deprivation of food for 96 hours to half of the amount eaten by untreated controls (ID50). The onset of the effect can be detected within 30 minutes, the peak effect is reached within an hour. The effect lasts 24-30 hours. Satietin acts both in intravenous and subcutaneous administration (ID50 = 0.5-0.75 mg/kg) in rats deprived of food for 96 hours. The peak effect is reached within an hour and lasts for 24 hours. In contrast to the anorectic drugs in clinical use and to the endogenous anorectic substances (like cholecystokinin and calcitonin) satietin proved to be highly selective in suppressing food intake. Since satietin is widely distributed in the world of vertebrates, its concentration in the blood is amazingly high, its site of effect is in the central nervous system and it induces satiety without having any other detectable central or peripheral effect, the hypothesis was forwarded that satietin may play the role of a rate limiting blood-borne satiety signal in the negative feed-back of food intake, i.e., serving as the essential chemical link connecting the gastrointestinal tract and the brain in the regulation of feeding.

Animals↗
PubMed1983

(-)-Deprenyl a selective MAO "B' inhibitor, increases [3H]imipramine binding and decreases beta-adrenergic receptor function.

In rats, a selective inhibition for 3 weeks of monoamineoxydase (MAO) type B elicited by daily doses of pargyline (2.5 mumol/kg) or (-)-deprenyl (1 mumol/kg) attenuated the NE dependent stimulation of cortical adenylate cyclase and reduced the number of brain recognition sites for beta-adrenergic receptor ligands. Similar actions were not elicited by a comparable dose regimen of (+)-amphetamine. Hence the inhibition of MAO B mimicks responses that are typically elicited by antidepressants. The molecular nature of the mechanisms involved cannot be understood, however, these mechanisms may not be identical for pargyline and (-)-deprenyl because this drug but not pargyline increased the number of [3H]imipramine recognition sites. Even high daily doses of pargyline (100 mumol/kg, for 3 weeks) failed to change [3H]imipramine binding though they still down regulated beta-adrenergic recognition sites, the NE stimulation of adenylate cyclase and the Bmax of [3H]mianserin and [3H]spiroperidol binding.

Animals↗
PubMed1983

Fragile (X) X-linked mental retardation I: relationship between age and intelligence and the frequency of expression of fragil (X)(q28).

Members of eight Saskatchewan families with fragile (X) X-linked mental retardation were studied in an attempt to relate frequency to age and intelligence. The mean IQ of 37 affected men was 35 (range 10-66). The mean IQ of 32 carriers was 88 (range 57-119), and the mean IQ of 13 females who remain at risk for being carriers, have no affected sons, and who failed to demonstrate the fra(X) was 100 (range 78-126). We demonstrated a significant inverse relationship between age and frequency of the fra(X) in carriers and in affected males. However, we demonstrated a more highly significant inverse relationship between frequency of the fra(X) and IQ in carriers but to a lesser extent in affected males. Of 32 carriers, only 3 (9.4%) did not demonstrate the fra(X) after addition of 5-fluoro-2'-deoxyuridine (FUdR) to the folic acid and thymidine-reduced culture medium. From these data we would recommend that chromosome studies in individuals at risk for fra(X) X-linked mental retardation be carried out at the youngest age and that the addition of FUdR to culture medium is useful in carrier identification. It is clear that, in at least the carriers, a lower expression of the fra(X) is highly significantly correlated to higher intelligence.

Adolescent↗
PubMed1983

Deprenyl (selegiline): the history of its development and pharmacological action.

Deprenyl inhibits MAO-B selectively in different animal species and in man. Its safety margin is remarkable. We were able to block MAO-B activity in the brain selectively in vivo in four species (mouse, rat, cat, dog) with s.c. administration of 0.17-0.31% of LD50. The usual oral dose range in clinical practice, 5-20 mg daily (0.05-0.2 mg/kg), is about ten times lower than the orally active dose in the rat. Deprenyl proved to be safe drug in man. Neither hypertensive reactions nor the need for any special dietary care were ever encountered during long-term (2-8 years) daily administration of the drug. The most important effect of deprenyl in the brain is the sensitization of dopaminergic neurons to physiological and pharmacological influences, but in contrast to levodopa or bromocrytine, deprenyl does not elicit an acute increase in dopaminergic activity. The effect of deprenyl is due, on the one hand, to the inhibition of MAO-B and, on the other hand, to inhibition of the uptake of dopamine. In agreement with its peculiar spectrum of pharmacological activity, deprenyl proved to be a useful adjuvant to levodopa alone or in combination with a peripheral decarboxylase inhibitor. In addition, a supplement of deprenyl in Parkinson's disease led to significant prolongation of the duration of the illness. This has not been observed so far with other antiparkinsonian drugs. The dopamine content of the human caudate nucleus decreases by 13% per decade over the age of 45. The hypothesis has been put forward that the significant increase of incidence of depression in the elderly, the age-dependent decline in male sexual vigour and the frequent appearance of parkinsonian symptoms in the later decades of life might be attributed to a decrease of dopamine and 'trace amines' in the brain. The possibility of countering these biochemical lesions of ageing by long-term administration of deprenyl, a selective inhibitor of MAO-B which facilitates dopaminergic and 'trace-aminergic' activity in the brain, and is a safe drug in man, is considered in detail.

Aging↗
PubMed1982

Direct evidence that eseroline possesses morphine-like effects.

The opiate-like effects of eseroline, a physostigmine derivative, were studied in different tests. The antinociceptive effect of eseroline given s.c. and intracerebrally could be detected in the rat hot plate test and was reversed by naloxone. The apparent pA2 values of naloxone demonstrated with eseroline and morphine were found to be equal, suggesting an effect on similar receptors. Eseroline also had opiate agonist activity on the isolated longitudinal muscle strip of guinea pig ileum and isolated nictitating membrane of the cat: presynaptically, it inhibited the contractions evoked by stimulation and its effect was antagonized by naloxone. Eseroline reduced acetylcholine release from the myenteric plexus of the longitudinal muscle strip when the cholinesterases had been inhibited by physostigmine. In addition, it was also found that eseroline antagonized the inhibitory effect of normorphine in the longitudinal muscle strip and potentiated the effect of exogenous acetylcholine on smooth muscle, both effects being attributed to its anticholinesterase activity. The analgesic effect of eseroline was not related to its anticholinesterase activity.

Acetylcholine↗
PubMed1982

The analysis of post-tetanic potentiation in guinea-pig ileum longitudinal muscle strip.

The effect of tetanus on the twitch responses of the longitudinal muscle-myenteric plexus preparation of the guinea-pig ileum to electrical stimuli was investigated in the presence of naloxone and indomethacin. Naloxone was used to prevent post-tetanic twitch inhibition due to the release of endogenous opiate ligands, and indomethacin to diminish pretetanic twitch height. Twitch contractions following tetanus were potentiated in the presence of both drugs. The optimal stimulation parameters for the manifestation of post-tetanic potentiation (PTP) were determined; tetanic stimulation: 30 Hz for 25 s. supramaximal impulse intensity; twitches: 0.04 Hz, low impulse intensity. PTP was also obtained when indomethacin was replaced by noradrenaline or adenosine, i.e. by drugs whose mechanism of action also includes a presynaptic effect. Postsynaptic changes in contractility cannot fully account for the observed PTP of twitches judging from the smaller effect of tetanus on acetylcholine-evoked contractions. The hypothesis of a presynaptic origin of PTP at this muscarinic synapse was corroborated in the experiments where acetylcholine stores were labelled with [3H] choline and the release of the label was increased during PTP. Furthermore, a bioassay showed that the output of endogenous acetylcholine in the post-tetanic interval was increased in the presence of naloxone plus indomethacin but not in their absence. The fact that PTP was also observed in the absence of any drug, if the tetanic stimulation was short (10 s) and of low impulse intensity, suggested its possible physiological significance.

Acetylcholine↗
PubMed1982

Effect of prostacyclin on cardiac transmembrane currents.

The relatively stable sodium salt of prostacyclin, PGI2-Na, kindly supplied by Chinoin Works (Budapest), was found to induce a dose-dependent increase in the inward-going membrane current of the sinoauricular fiber of the frog. Threshold concentration was 0.05 microgram/ml, and maximal effect was reached at a concentration of about 0.1 microgram/ml. Supramaximal concentrations of PGI2-Na evoked a maximal response, in contrast to primary prostaglandins, the dose-response curves of which decline at supramaximal values. The stimulatory effect of PGI2-Na was confined to the fast component of the inward current and was also readily demonstrable in the presence of Mn ions, i.e., with the slow channel blocked. The PGI2-Na was, however, ineffective in sodium-free medium (choline Ringer) or in the presence of 1 microgram/ml tetrodotoxin. Endogenous prostacyclin is likely to contribute to the regulation of cardiac cell membrane processes.

Animals↗
PubMed1982

Drugs affecting the tetrodotoxin-sensitive ("fast") sodium mechanism in the cardiac cell membrane.

Prostacyclin, a newer member of the prostaglandin family, has been shown to stimulate the fast sodium system in the heart. A stimulatory effect of celluline-A, a biological Ca complex obtained from frog skin, has been demonstrated on both the fast and slow depolarization mechanisms. Prostacyclin and celluline-A are capable of restoring the electrical excitability of the isolated cat auricle poisoned with 3.5 mM MnCl2, i.e., in a situation when epinephrine is ineffective. We conclude that the normal cardiac cell membrane is tuned in such a way that the contribution of both the fast and slow depolarization mechanisms is necessary to generate an action potential, which is the result of their synergistic action. But both of them have remarkable reserve capacity which can be mobilized by their respective stimulators. With this reserve capacity mobilized, either of the two mechanisms can generate an action potential on its own, without the contribution of the other. Epinephrine can mobilize the reserve capacity of the slow mechanism, and prostacyclin that of the fast one. Celluline-A is a potent stimulator of both depolarization mechanisms.

Animals↗
PubMed1982

Drugs affecting the calcium-dependent slow depolarization mechanism of the cardiac cell membrane.

Transmembrane action potentials were recorded from isolated electrically paced cat and guinea pig left auricles in Tyrode solution and in the presence of 25 mM K+ or tetrodotoxin (TTX). The overshoot (OS) was increased, and the plateau of the action potential (AP) was shortened by epinephrine (5 X 10(-6)M) and by celluline-A (an organic calcium complex obtained from frog skin). The maximum rate of depolarization (Vmax) was enhanced by serotonin (5-HT) (10(-6)M), prostaglandin F2 alpha (2.8 X 10(-6)M), and by celluline-A. After inactivation of the fast sodium channel by TTX (10(-5)M) or by partial depolarization (25 mM K+ Tyrode) of electrically driven cat and guinea pig left auricle, catecholamines (epinephrine and isoproterenol, 4 X 10(-7) to 5 X 10(-6)M), histamine (10(-6) to 10(-5)M), and celluline-A restored the electrical and mechanical activity. Prostaglandins (PGE1, PGF2 alpha, 1.4 X 10(-8)-2.8 X 10(-6)M), 5-HT (10(-6)-5 X 10(-6)M), and 4-aminopyridine (1.5 X 10(-4)M) were ineffective in such conditions. The beta-adrenergic blocking agent pindolol (4 X 10(-7)M) prevented only the effect of catecholamines; the H1 receptor blocker mepyramine (10(-5)M) antagonized only that of histamine, and D-600 (2 X 10(-6)M), a selective Ca channel blocker, prevented the restoring effect of catecholamines, histamine, and celluline-A.

4-Aminopyridine↗