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Biomedical subjects

J Knoll

Publications and source records attributed to J Knoll.

At least 73 records · Page 4Linked to original sources
PubMed1988

Analgesic profile of rimazolium as compared to different classes of pain killers.

1,6-Dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-homopyrimidazol (rimazolium, MZ-144) proved to be effective in all the analgesic assays used (independently of the nociceptive stimulus applied) (hot plate, tail flick, writhing tests, Randall-Selitto test, tail clip, surgical pain) differing in this respect from the nonsteroidal antiinflammatory analgetics. The analgesic, antiinflammatory and gastrointestinal effects of rimazolium, morphine and prostaglandin synthesis inhibitors were compared. The prostaglandin (PG) mediated pain (acetylcholine-, adenosine triphosphate- and acetic acid-induced writhing) was inhibited by all the three types of compounds, however, pain reaction where PGs are not involved (MgSO4-writhing) was inhibited only by rimazolium and morphine but not, or only slightly, by PG synthesis inhibitors. While the analgesic effect of rimazolium alone was not reversed by naloxone, the full analgesia evoked by the ineffective doses of morphine and rimazolium combinations was completely naloxone reversible (pA2 = 8.6). In addition, rimazolium produced weak analgesia by intrathecal administration, and its concomitant s.c. administration enhanced the analgesic effect of intrathecally administered morphine. Furthermore, chronic treatment with rimazolium failed to influence its analgesic activity, and no tolerance developed and no naloxone precipitated withdrawal syndrome could be seen. In addition, rimazolium did not substitute for morphine in morphine dependent rats, after morphine withdrawal, thus indicating that rimazolium lacks the capacity of producing opiate-like physiological dependence. Also rimazolium fails to show any indication of narcotic-like abuse liability by any of clinical assessments. Rimazolium, morphine and indometacin inhibited the carrageenin-induced edema formation. Gastrointestinal lesions produced by indometacin were depressed by rimazolium and enhanced by morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1987

Serum lipids, lipid peroxides and the care of children with high risk atherosclerotic family history.

Children of parents who had their first acute myocardial infarction (AMI) before the age of 45 years were investigated and divided into 2 groups. Group 1 consisted of 12 children: both their parents or one parent and grandparents suffered from AMI. Group 2 consisted of 55 children, each of whom had one parent with AMI. Serum levels of total cholesterol (TC) and lipid peroxide (LP) were higher in these children and HDL-cholesterol values were lower than those of 39 control children. The extent of serum TC and HDL-C differences was similar in both high risk groups but the serum LP level was significantly higher in group 1 than in group 2. The serum free cholesterol (FC) level was higher in group 1 than in controls. Children were treated according to a program giving advice on diet, physical exercise and health education for 1 year. At the end of this period the serum HDL-C level increased in both groups, while LP and TC levels decreased. The high serum FC level did not change.

Adolescent↗
PubMed1987

R-(-)-deprenyl (Selegiline, Movergan) facilitates the activity of the nigrostriatal dopaminergic neuron.

(-)Deprenyl, when administered continuously in small doses (0.25 mg/kg/day), facilitates the activity of the nigrostriatal dopaminergic neuron because of its highly characteristic complex spectrum of pharmacologic activity: it is a highly potent and selective inhibitor of B-type MAO; it inhibits the reuptake of dopamine; it inhibits dopamine autoreceptors; it enhances scavenger function. 1) (-)Deprenyl treatment decreased significantly the activity of the cholinergic interneurons. In a series of experiments the acetylcholine (ACh) content was found to be 0.69 nmole/mg protein in the striatum of untreated rats, whereas a significantly higher amount of ACh (0.86 nmol/mg protein) was found in the rat striatum after two week pretreatment with (-)deprenyl, and the fractional rate constant (kb) of ACh efflux from the cholinergic interneurons of the striatum decreased significantly in the (-)deprenyl-treated group from 9.1 +/- 0.8 to 6.2 +/- 0.55. 2) The (-)deprenyl-induced increase of the dopaminergic tone in the striatum was proved by measurements of the activity of the nigrostriatal dopaminergic neuron. Whereas the striatum of untreated rats contained 52.7 +/- 1.6 nmole/g dopamine (DA) and the turnover rate (TRDA) was found to be 13.7 +/- 1.3 nmole/g/hr, the striatum of rats pretreated with 0.25 mg/kg (-)deprenyl daily for 28 days contained significantly higher amount of DA (81.77 +/- 5.7 nmole) and the turnover rate increased significantly to 24.44 +/- 1.1. Using the Glowinski-Iversen preparation we found that from the striata of untreated rats 200.0 +/- 25.8 pmole/g/min DA was released to KCl stimulation, whereas the amount of DA released to stimulation from the striata of rats pretreated with (-)deprenyl for 3 weeks increased significantly to 1452.2 +/- 183.1 pmole/g/min. 3) (-)Deprenyl inhibits the uptake of dopamine into the nigrostriatal dopaminergic neuron. In a new series of experiments we found that 420 +/- 21 pmole/g protein 3H-DA was taken up within 5 minutes in the striatum slices of untreated rats. Pretreatment of the rats with 0.25 mg/kg (-)deprenyl daily for two weeks decreased significantly the uptake of DA to 284 +/- 28 pmole/mg. 4) In a new series of experiments we found that the striata of untreated rats emitted 404.2 +/- 36.2 pmole/g/min ACh to ouabain stimulation but the striata dissected from rats pretreated with 6-hydroxy-dopamine (6-OHDA) released 811.4 +/- 49.2 pmol/g/min (p less than or equal to 0.001).

Aging↗
PubMed1987

1,6-Dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido(1,2-a)- pyrimidine-3-carboxamide (Ch-127) protects against the intestinal damage in rats caused by two weeks' daily administration of indomethacin.

1,6-Dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido 1,2-a pyrimidine-3-carboxamide (Ch-127) significantly inhibited the intestinal ulceration induced by a single dose of indomethacin (15 mg/kg p.o.). Moreover, indomethacin produced 75% lethality in the dose of 3.5 mg/kg p.o. administered daily for 2 weeks. The concurrent daily administration of Ch-127 (50 mg/kg p.o. +25 mg/kg s.c.) with indomethacin prevented the gastrointestinal mucosa from histologically detectable changes, and none of the animals died. The 80% lethality following the daily administration of naproxen (60 mg/kg p.o.) for two weeks was also significantly decreased by combining it with Ch-127 (50 mg/kg p.o.).

Animals↗
PubMed1986

The pharmacology of (-)deprenyl.

(-)Deprenyl (Selegilinum hydrochloricum, Jumex, Eldepryl) developed in the early sixties as a new spectrum, potent, irreversible MAO blocker (Knoll et al., 1965) was introduced as the first selective inhibitor of B-type MAO (Knoll and Magyar, 1972). In striking contrast to MAO inhibitors which strongly potentiate the pressor effect of tyramine, (-)deprenyl was described to inhibit the tyramine-induced release of noradrenaline in vascular smooth muscle (Knoll et al., 1968). The peculiar pharmacological spectrum of (-)deprenyl allowed its use as an adjuvant to the levodopa therapy of Parkinson's disease (for review see Birkmayer and Riederer, 1985). Levodopa therapy revolutionized the medication of Parkinson's disease, but severe side-effects forced the search for adjuvants with a levodopa-sparing effect. Peripheral decarboxylase inhibitors are now efficiently used for this purpose. It was reasonable to expect further potentiation and prolongation of the effect of levodopa in parkinsonians with concurrent administration of MAO inhibitors. A number of irreversible inhibitors of this type were tested in combination with levodopa, and potentiation of the antiakinetic effect of the latter was demonstrated; however, the supervention of distressing side-effect (greatly increased involuntary movements, hypertensive reactions, toxic delirium) terminated any further work along this line. There was a concensus that to give MAO inhibitors concurrently with levodopa was contra-indicated. This conclusion was called in question, however, by the development of deprenyl. (-)Deprenyl is a safe MAO inhibitor which can be given concurrently with levodopa and a peripheral decarboxylase inhibitor for the long run without the supervention of any distressing side-effects. For details regarding the pharmacology of (-)deprenyl we refer a number of reviews (Knoll 1976, 1978, 1980, 1982, 1983, 1986). The aim of this paper is to give a brief survey of the most important experimental data which demonstrate that (-)deprenyl facilitates dopaminergic tone in the brain in a peculiar manner and gives a satisfactory explanation for the observation that long-term (-)deprenyl treatment prolongs the life span of parkinsonian patients significantly (Birkmayer et al., 1985).

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

[Medicamentous strategy for improving the quality of life in the senescence].

The striatum, in which the nigrostriatal dopaminergic neurons terminate, contains the highest amount of dopamine DA) in the brain. DA, released in the striatum, plays the rate limiting role in the control of motor functions by continuously inhibiting the release of acetylcholine (ACh) from the cholinergic interneurons of the caudate nucleus. DA content of the human caudate nucleus decreases by 13% per decade over the age of 45. Parkinson's disease seems to be a kind of selective, highly accelerated 'premature aging' of the nigrostriatal dopaminergic system, and the DA content of this neuron system shrinks within a short time to less than 10% of the normal level in the premorbid state. Clinical symptoms occur when the striatum loses more than 70% of its DA content. The chemical lesioning of the nigrostriatal dopaminergic neuron in the rat by 6-OH-dopamine (6-OHDA) leads to an increase of cholinergic activity in the striatum. The striatum taken from a rat pretreated with 6-OH dopamine is a useful experimental model for the rapid screening of compounds with potential therapeutic benefit in Parkinson's disease. A more specific neurotoxin than 6-OHDA is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which kills the cells in the substantia nigra with high specificity and induces rapidly parkinsonian-like condition in men and monkeys. (-)Deprenyl, the selective inhibitor of B-type MAO protects the striatum from the neurotoxic effects of 6-OHDA and MPTP. The amount of ACh released from the striatum of the rat increases from 372.8 +/- 31.4 to 746.5 +/- 44.0 pmol/g/min in 6-OHDA treated rats, it remains normal (371.1 +/- 34.7) if (-)deprenyl is given 30 minutes before 6-OHDA administration, hut is further increased (956.3 +/- 79.3 pmol/g/min), if clorgyline os injected 30 minutes before 6-OHDA. (-)Deprenyl prevents in a similar manner the neurotoxicity of MPTP in monkeys, whereas clorgyline, the selective inhibitor of MAO-A, is ineffective. The most important effect of deprenyl in the brain is the sensitization of dopaminergic neurons to physiological and pharmacological influences without eliciting 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.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1986

Long-term administration of (-)deprenyl (selegiline), a compound which facilitates dopaminergic tone in the brain, leaves the sensitivity of dopamine receptors to apomorphine unchanged.

The effect of repeated administration of the MAO-B enzyme blocker (-)deprenyl on the apomorphine (APO) sensitivity of dopamine (DA) receptors was investigated in rats, and compared to the effect of other drugs influencing the dopaminergic system. APO was given either in a high dose (0.1-0.6 mg/kg), which induces stereotyped behaviour or in a smaller one (0.02 mg/kg) causing sedation. Repeated administration of all the other drugs investigated (except (-)deprenyl), i.e. haloperidol, d-amphetamine, (1 mg/kg s.c., respectively) and the MAO-A blocker clorgyline (0.25 mg/kg s.c.) altered the efficiency of APO on the stereotypy. Haloperidol, clorgyline (0.5 mg/kg s.c.) and imipramine (10 mg/kg i.p.) attenuated the APO-sedation. The long-lasting administration of (-)deprenyl (0.25 mg/kg s.c., daily for 42 days) however, left the effects of APO unchanged, demonstrating that (-)deprenyl facilitates the dopaminergic tone in the rat brain without altering the sensitivity of DA receptors.

Animals↗
PubMed1985

[Bioavailability of isosorbide dinitrate and isosorbide-5-mononitrate under steady-state conditions].

The relative bioavailability of isosorbide dinitrate (ISDN) and its mononitrate metabolites (IS-2-MN, IS-5-MN) was determined under repetitive dose conditions in 8 healthy volunteers using a randomised, crossover design. Reference drugs were non-sustained release ISDN (Isoket 20) and IS-5-MN (Ismo 20). The relative bioavailability of ISDN after Iso Mack Retard was 69%, for two development products 78% and 79%, and 87% for Isoket Retard. The bioavailability of IS-2-MN and IS-5-MN in sustained release preparations was 6-16% and 1-17% lower, respectively. Whereas the sum total for the area under the concentration-time curve (ISDN and metabolites) for Iso Mack Retard 20 mg was also significantly lower, there was no significant difference in this parameter between Isoket retard 20 and Isoket 20. Taking IS-5-MN non-retard as reference, the bioavailability of IS-5-MN and total nitrate in all ISDN preparations examined was significantly lower.

Adult↗
PubMed1985

The facilitation of dopaminergic activity in the aged brain by (-)deprenyl. A proposal for a strategy to improve the quality of life in senescence.

In the aging brain there is a loss of neurons compensated for by a proliferation of glial cells. Because of the increased B-type monoamine oxidase (MAO) activity present in the glia, dopaminergic and 'trace aminergic' modulation in the brain declines in senescence. The significant increase of the incidence of depression in the elderly, the age-dependent decline in male sexual vigor and the frequent appearance of parkinsonian symptoms in the latter decades of life might be attributed to a decrease of dopamine and 'trace amines' in the brain. The outlines of a drug strategy to counteract these biochemical lesions of aging by chronic administration of (-)deprenyl (Jumex, Eldepryl), a selective inhibitor of B-type MAO, which facilitates dopaminergic and 'trace-aminergic' activity in the brain, are forwarded. The restitution and long-term maintenance of full scale sexual activity in aged male rats continuously treated with (-)deprenyl and the clinical observation that this drug prolongs in a statistically significant manner, the duration of the Parkinson's disease support the view that (-)deprenyl may improve deteriorating functions due to dopamine deficiency in the aging brain.

Aged↗
PubMed1985

Increased life expectancy resulting from addition of L-deprenyl to Madopar treatment in Parkinson's disease: a longterm study.

In an open, uncontrolled study the longterm (9 years) effect of treatment with Madopar alone (n = 377) or in combination with l-deprenyl (selegiline, selective monoamine oxidase type B inhibitor) (n = 564) have been compared in Parkinsonian patients. In patients who lost their response to conventional Madopar therapy the addition of l-deprenyl resulted in a significant recouping of levodopa effect. The survival analysis revealed a significant increase of life expectancy in Madopar--l-deprenyl group regardless of the fact whether or not the significant demographic differences between the two groups were taken into account. Although the mechanism underlying this action of l-deprenyl is not known, the results are interpreted as indicating l-deprenyl's ability to prevent or retard the degeneration of striatal dopaminergic neurons. l-Deprenyl is the first anti-Parkinson drug having such a property. This hypothesis is not far fetched since l-deprenyl selectively prevents the degeneration of striatal dopaminergic neurons induced in animals by the illicit drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Since latter compound is known to cause Parkinsonism in man and primates or Parkinson-like neurochemical and pathological changes in other animals the implications of the present study involving monoamine oxidase activity and l-deprenyl are apparent.

Adult↗
PubMed1985

The anorectic effect of satietin is unrelated to carbohydrate metabolism.

The effect of satietin and amphetamine on the carbohydrate metabolism of free fed and food deprived rats was studied. Rats deprived of food for 96 hours maintained normal glucose and glucagon blood levels but the blood concentration of insulin dropped from 232.02 +/- 23.93 to 12.48 +/- 0.71 pmol/l. Amphetamine (500 micrograms/animal, intracerebroventricularly) left in normally fed rats the blood concentration of glucose, insulin and glucagon unchanged. The same treatment, however, increased the insulin concentration in the blood of food deprived rats from 11.37 +/- 4.43 to 73.47 +/- 8.29 pmol/l. Glucose and glucagon, as well as insulin levels remained unchanged in both normally fed and food deprived rats when treated with satietin (20 micrograms/rat, intracerebroventricularly). It was concluded that the anorectic effect of satietin is unrelated to carbohydrate metabolism.

Amphetamine↗
PubMed1985

The time-structure of the anorectic effect of satietin.

The influence of anorectic doses of satietin, calcitonin, fenfluramine and amphetamine on the amount of food eaten, on the time elapsed before taking the first tablet (latency) and on the time-structure of food intake during a one hour feeding session, divided into four 15-minute periods, was measured in rats after one day starvation with a pellet-detecting eatometer. In contrast to fenfluramine, amphetamine significantly increased the time elapsed before taking the first tablet, indicating the stimulation of a satiety mechanism by fenfluramine and the inhibition of a feeding mechanism by amphetamine. In this test satietin and calcitonin acted like fenfluramine. The time-course of food intake was significantly different in the amphetamine and fenfluramine-treated animals, the latter ate more during the first 15-minute period. Satietin and calcitonin acted like fenfluramine in this test, too. The results are consistent with the view that satietin acts by activating a satiety mechanism.

Amphetamine↗
PubMed1985

Differentiation of multiple analgesic opiate receptors.

In order to analyse opiate receptors mediating anti-nociception, the activity pattern of different opiates was determined by using hot-plate (45 degrees C and 56 degrees C), tail-flick and algolytic tests on rats, and the acetic acid stretching test on mice, for evaluation of analgesic activity. Potentiation of barbiturate anaesthesia, measurement of pupillary diameter, and a modification of pentetrazol convulsion, were used for evaluation of non-analgesic activity. The efficacy and affinity constant (pA2) of the proposed opiate A receptor agonist and B receptor antagonist drug N-cyclopropylmethyl-norazido-dihydroisomorphine (CAM) were determined. CAM produced several opiate agonist (morphine-like) effects, often stronger than morphine, in three of the analgesic tests and two of the non-analgesic tests. On the other hand CAM proved to be a very strong narcotic antagonist, as potent as naloxone as evidenced by identical pA2 values, in the algolytic, 45 degrees C hot-plate and pentetrazol tests, but not in the 56 degrees C hot-plate, tail-flick and acetic acid tests. The potency differences for the actions of morphine and CAM in a heat test (56 degrees C hot-plate) compared with a non-heat test (acetic acid stretching) were found to be 8.6 and 540 respectively. It is concluded that opiate analgesia might be mediated by at least two receptors classified in terms of the antagonistic or agonistic activity of CAM.

Analgesics, Opioid↗