Critical notes on the specificity of drugs in the study of metabolism and functions of brain monoamines.
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Animals↗
Biomedical subjects
S Garattini
Publications and source records attributed to S Garattini.
Disposition of D-fenfluramine in lean and obese rats.
The anorectic drug D-fenfluramine (D-F) was administered as single i.v. doses of 1.25 and 6.25 mg/kg to lean female Sprague-Dawley and lean and obese female Zucker rats. Blood samples were collected serially and analysed by electron capture gas-liquid chromatography for D-F and its main metabolite, D-norfenfluramine (D-NF). At the lowest dose the disappearance of D-F followed an apparent first-order process with mean elimination half-life (T1/2) of approximately 2 h in female Sprague-Dawley and 4 h in lean and obese Zucker rats. Mean absolute steady-state volume of distribution (Vss) was the same in the lean female of both strains but total clearance (Cl) was significantly lower in the Zucker rats. Therefore elimination T1/2 of D-F was longer in female Zucker than Sprague-Dawley animals. Obese rats presented lower relative Cl and Vss but no change in absolute Cl and Vss and elimination T1/2 of the drug. Intra- and inter-strain differences were observed in hepatic microsomal protein and P-450 content. As in the case of D-F the elimination T1/2 of D-NF was also longer in Zucker than Sprague-Dawley rats. No differences were observed between lean and obese rats but in all cases the elimination T1/2 of the metabolite was much longer than that of its parent drug. After larger doses (6.25 mg/kg) the kinetics of the drug were not linear. The apparent Cl declined changing the metabolite-to-parent drug ratios in all types of rats, but more evidently in Zucker than Sprague-Dawley rats and in obese than lean animals. Inter- and intra-strain differences in D-F and D-NF kinetics should be considered in neurochemical studies of the drug and extrapolation of data across animal species requires consideration of dose dependence in the rat.
Animals↗
Biochemical hypotheses on antidepressant drugs: a guide for clinicians or a toy for pharmacologists?
The development of knowledge about the mechanism of action of tricyclic and the so-called 'atypical' antidepressants (AD) is reviewed. The discovery of clinically active antidepressants with little or no effect on noradrenaline or serotonin uptake has disproved the widely accepted concept that inhibition of monoamine uptake is a prerequisite for antidepressant activity. Another serious objection to this hypothesis is that blockade of monoamine uptake occurs in a matter of minutes after administration while 2-3 weeks of repeated treatment are necessary for the clinical AD effect. Nevertheless, the effect of repeated treatment with AD is compatible with the hypothesis that changes in central monoamine transmission are involved in the clinical activity of these drugs. Major changes in monoamine function after repeated treatment with AD include: desensitization and reduced density of noradrenaline receptors coupled to the adenylcyclase system, opposite changes in the sensitivity of alpha 1 (increased) and alpha 2-adrenoreceptors (decreased), down regulation of serotonin2 receptors and complex changes in the behavioural and electrophysiological responsiveness to serotonin agonists, subsensitivity of presynaptic dopamine receptors and enhanced activity of the mesolimbic dopamine system, decreased and increased density of GABA-A and GABA-B receptors respectively and down regulation of [3H]benzodiazepine binding. It remains to be clarified whether some of these changes have larger roles than others or whether they all contribute to the AD activity. An important role of dopamine in the activity of AD drugs is suggested by findings in the forced swimming test, whereas both catecholamines seem to be involved in the attenuation of escape deficit provoked by inescapable shock (learned helplessness).(ABSTRACT TRUNCATED AT 250 WORDS)
Antidepressive Agents↗
Response to flavone acetic acid (NSC 347512) of primary and metastatic human colorectal carcinoma xenografts.
The antitumour activity of flavone acetic acid (FAA) was evaluated against two human colorectal carcinoma (HCC) lines, HCC-P2988 and HCC-M1410, transplanted into nude mice. On repeated i.v. injection of 200 mg kg-1 every 4 days FAA was moderately active against the s.c. growing HCC-P2988. HCC-M1410 transplanted s.c. was almost unresponsive in the same experimental conditions. In contrast, FAA (200 mg kg-1 i.v. every 4 days, repeated three times) significantly reduced liver tumour colonies produced by the HCC-M1410 cells injected intrasplenically into nude mice. These findings suggest that FAA has potential activity against human colorectal carcinoma, particularly against liver metastases.
Animals↗
Catecholamine receptor binding in rat kidney: effect of aging.
Binding to several receptors was compared in kidneys from 3- and 24-month-old rats. In crude membrane preparations of aged rat kidneys, the number of beta 2-adrenergic receptors was significantly reduced but the number of total beta-adrenoceptors was unchanged. The high-affinity alpha 1-adrenoceptor component was significantly reduced in old rats, whereas the low-affinity component was unchanged. The number of alpha 2-adrenoceptors showed a non-significant decrease. 3H-spiperone binding sites were similar in young and old rats. For each receptor binding the KD values were the same in young and old animals. The D1 dopamine receptor was significantly reduced in old rats. In our experiments, age-related changes of specific binding sites in the kidney were selective for some receptors studied and did not seem to be due to general aging-induced membrane modifications. Moreover, the renal and central receptors were sensitive to aging differently in the same animal model.
Aging↗
Steroids and cytotoxic drugs in the treatment of membranous glomerulopathy.
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Chlorambucil↗
The need to compare the effectiveness of the available antidepressant drugs.
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Antidepressive Agents↗
Clinical pharmacokinetics of oral buspirone in patients with impaired renal function.
12 patients with mild to moderate impairment of renal function and 12 healthy subjects each received 20mg buspirone as a single dose in this acute study. Six anuric patients with chronic renal failure were given two 20mg doses of buspirone, the first 2 days before haemodialysis (between dialyses) and the second during hemodialysis (2 hours before dialysis began). The differences between the median pharmacokinetic values of buspirone for healthy subjects, patients with mild to moderate renal impairment, and anuric patients were not statistically significant. Similarly, there were no significant differences between values in mild to moderate renal failure vs healthy subjects. Some of the median pharmacokinetic values for the active buspirone metabolite 1-(2-pyrimidinyl)-piperazine (1-PP), however, differed significantly for anuric patients, compared with healthy subjects or patients with mild to moderate renal impairment. When assessed between and during haemodialysis, the anuric patients had significantly (p less than 0.05) greater pharmacokinetic median values: half-life (t 1/2) = 15.2 vs 9.8 hours; area under the concentration-time curve (AUC) = 604 vs 404 nmol/L.h; and mean residence time (MRT) = 9.28 vs 6.96 hours. No firm recommendation for specific dosage can be made based on the present data. However, it does appear that in patients with mild to moderate renal impairment, the pharmacokinetics of buspirone and its active metabolite 1-PP are similar to those in individuals with normal renal function. For anuric patients higher concentrations of the 1-PP metabolite are attained while they are not undergoing haemodialysis. A dosage reduction of 25 to 50% might be necessary when buspirone is given to anuric patients.
Administration, Oral↗
Disposition of (-)-fenfluramine and its active metabolite, (-)-norfenfluramine in rat: a single dose-proportionality study.
1. The disposition of (-)-fenfluramine, (-)-F, was studied in rats after i.v. and oral administration (1.25 to 12.5 mg/kg). Whole blood-to-plasma ratio and the protein binding (determined by equilibrium dialysis) of the compound and its main active metabolite, (-)-norfenfluramine (-)-NF, were investigated. 2. The bound fraction of both compounds (about 40%) was constant in the concentration range of 1-10 nmol/ml. The whole blood to plasma concentration ratios of (-)-F and (-)-NF were larger than unity and were constant over this dose range. 3. The drug followed apparent first-order kinetics, at doses up to 6.25 mg/kg. The mean half-lives of the parent drug and its metabolite were about 1 and 12 h respectively. The volume of distribution of (-)-F was large and total body clearance approached liver blood flow. 4. Oral doses were rapidly absorbed from the rat gastrointestinal tract. Bioavailability of the drug was about 20%. Urinary excretion of unchanged drug (3-4% of dose) and its metabolite (about 20%) were similar after i.v. and oral administration. 5. After larger doses (12.5 mg/kg) the kinetics of (-)-F were nonlinear. The AUC increased, but not in proportion to the dose, and kinetic parameters were modified. 6. Brain concentrations reflected the dose-related changes observed in (-)-F and (-)-NF blood concentrations, and patterns of brain distribution and subcellular localization of the drug and its metabolite were modified at the highest dose tested.
Administration, Oral↗
Tertatolol ameliorates renal function in rats with chronic renal failure.
Tertatolol is a new beta-blocking agent which induces renal vasodilation in experimental animals and humans and increases glomerular filtration rate (GFR), diuresis and natriuresis. The mechanisms underlying renal effects of tertatolol are not known. Our aims were to establish whether tertatolol influences renal function by a systemic or by an intrarenal effect and to assess whether tertatolol could maintain GFR in chronic renal failure. Tertatolol but not propranolol when given as i.v. bolus injection at the dose of 25 and 50 micrograms/kg. b.w. induces a significant increase in GFR and perfusate flow rate (PFR) in an isolated perfused kidney model [GFR: tertatolol, 25 micrograms/kg; preinjection: 0.477 +/- 0.077 ml/min/g of kidney; 30 min postinjection: 0.996 +/- 0.114 ml/min/g of kidney. Tertatolol (50 micrograms/kg) preinjection: 0.517 +/- 0.040 ml/min/g of kidney; 30 min postinjection: 0.879 +/- 0.035 ml/min/g of kidney. Propranolol (500 micrograms/kg) preinjection: 0.574 +/- 0.045 ml/min/g of kidney; 30 min postinjection: 0.538 +/- 0.029 ml/min/g of kidney. PFR: tertatolol, 25 micrograms/kg, preinjection: 30.00 +/- 0.79 ml/min; 30 min postinjection: 36.20 +/- 2.58 ml/min. Tertatolol (50 micrograms/kg) preinjection: 29.30 +/- 1.44 ml/min; 30 min postinjection: 38.01 +/- 1.87 ml/min. Propranolol (500 micrograms/kg) preinjection: 28.70 +/- 1.04 ml/min; 30 min postinjection: 28.30 +/- 0.91 ml/min]. In the same preparation tertatolol significantly increases urine flow rate and Na+ excretion [urine flow rate: tertatolol (25 micrograms/kg) preinjection: 28.28 +/- 4.10 microliter/min; 60 min postinjection: 38.23 +/- 6.74 microliter/min. Tertatolol (50 micrograms/kg) preinjection: 24.02 +/- 0.63 microliter/min; 60 min postinjection: 33.18 +/- 2.07 microliter/min.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Progress in assessing the role of serotonin in the control of food intake.
There is evidence that serotonin inhibits food intake, particularly intake of carbohydrate and that induced by activation of catecholamine-containing neurons in different brain circuits. An agent that has contributed considerably to the hypothesis of a role of serotonin in feeding is fenfluramine, used as an anorexigenic drug in obese people. Experiments using synaptosomal preparations for studying monoamine uptake and release have shown that d-norfenfluramine preferentially releases serotonin from a reserpine-insensitive compartment. Studies on brain monoamine release and metabolism in intact animals have shown that d and l isomers of fenfluramine at relatively low doses have a specific action on brain serotonin and catecholamines, respectively. Several findings suggest that d-fenfluramine and d-norfenfluramine cause anorexia by increasing the availability of serotonin at postsynaptic receptors. Evidence has recently been provided that d-fenfluramine uses preferentially serotonin1 sites, particularly of the serotonin1B type, in the rat brain to cause anorexia in this animal species. Activation of serotonin1A sites by agents such as 8-OH-DPAT and buspirone instead has been shown to cause overeating. It is suggested that serotonin1B sites in the hypothalamus and serotonin1A sites in the serotonin neurons of the midbrain raphe nuclei mediate these effects. Evidence is provided that [3H]d-fenfluramine binding to rat brain membranes is different from serotonin uptake sites ([3H]imipramine binding) and serotonin receptors. It is, however, displaced by some drugs using serotonin to cause anorexia, raising the possibility that it is somewhat related to serotonin mechanisms involved in feeding control. These studies provide evidence that the serotoninergic system in the brain is a likely target for drugs affecting food intake and suggest new ways to develop novel and potent strategies for the treatment of clinical hyperphagia and anorexia.
Eating↗
Podophyllotoxin derivatives VP-16 and VM-26.
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Animals↗
Effect of etidronate disodium on the interactions between malignancy and bone.
This study was designed to assess the capacity of etidronate disodium (etidronate) to affect neoplastic involvement of bone by murine tumors. Using sublines of the Walker 256 carcinoma, differing in the pattern of bone involvement, etidronate was found to inhibit hypercalcemia caused by systemically acting humoral factors, to inhibit bone metastasis following inoculation of tumor cells into the abdominal aorta, and to reduce the invasion of bone adjacent to tumors. Etidronate was also found to prevent bone metastasis in syngeneic rat mammary carcinoma. Etidronate was found devoid of direct antineoplastic activity, whether administered intramuscularly, subcutaneously, or intravenously, in a series of murine tumors of different histologic varieties. At the same time, it was shown that etidronate did not modify the antineoplastic activity of any of the major chemotherapeutic agents used in these studies, nor did it demonstrate any degree of immunosuppression. The experimental models used for this study should prove useful in evaluating agents that may affect the various types of bone involvement seen in neoplastic disease. The drug's apparent lack of interference with the antineoplastic activity of standard cytotoxic agents and its lack of immunosuppressive activity suggest that it may be readily adaptable to combination chemotherapy regimens.
Animals↗
Prostaglandin and thromboxane synthesis by M5076 ovarian reticulosarcoma during growth: effects of a thromboxane synthetase inhibitor.
The five stable metabolites [prostaglandin F2 alpha (PGF2 alpha), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha)] of arachidonic acid (AA) via the cyclooxygenase pathway were measured by high-resolution gas chromatography-mass spectrometry in M5076 ovarian reticulosarcoma (M5) homogenates at various times after tumor implantation (Days 15, 18, 21, and 24). Vegetating tumor showed an active AA overall metabolism, which significantly increased during tumor growth. Synthesis of selected products (TXB2, PGD2, and PGE2) increased markedly over time (up to 10.6, 3.5, and 0.9 micrograms/g, respectively). The overall metabolic profile was TXB2 much greater than PGD2 greater than PGF2 alpha greater than 6-keto-PGF1 alpha greater than PGE2 on Day 15 and TXB2 much greater than PGD2 much greater than PGF2 alpha greater than 6-keto-PGF1 alpha on Day 24. TXB2 was also by far the most abundant product of in vitro-cultured M5 cells. Chronic treatment of M5-bearing mice with dazmegrel (UK-38,485), a selective thromboxane synthetase inhibitor (100 mg/kg p.o. daily, from Day 7 to killing), resulted in incomplete TXB2 synthesis inhibition, AA metabolism diversion toward the other prostaglandins, and no effects of tumor growth and metastasis. More frequent dazmegrel treatment (100 mg/kg p.o. every 8 h from Day 1 to killing) resulted in complete TXB2 synthetase inhibition, AA metabolism diversion, and increased tumor growth and metastasis. These data do not support the hypothesis of thromboxane synthetase inhibitors reducing tumor growth. However, since TXB2 suppression was accompanied by the production of other products possibly interfering in tumor growth, no conclusions on the effective role of TXA2 in malignancy can be drawn.
Animals↗
Mechanism of action of anxiolytic drugs.
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Animals↗
Tianeptine, a selective enhancer of serotonin uptake in rat brain.
Tianeptine is a tricyclic agent provided with antidepressant activity in experimental models and in clinical trials. In vitro tianeptine and its two principal metabolites have no effects on monoamine uptake, release or neurotransmitter receptor binding. The biochemical effect of tianeptine in vivo after acute or repeated treatment indicates an enhanced serotonin uptake in cortex and hippocampus but not in mesencephalon, with no effect on noradrenaline or dopamine uptake. This enhanced serotonin uptake is not due to decrease in serotonin release, but is related to increase in the Vmax of the uptake carrier for serotonin. The fact that enhancers as well as inhibitors of serotonin uptake are provided with antidepressant activity challenge simple conclusion as to their mechanism of action. The possibility that increased serotonin uptake after repeated treatment may be related to the antidepressant activity exerted by these drugs, and drugs enhancing serotonin uptake might have antidepressant activity, with an earlier onset, is proposed.
Animals↗
Behavioural and biochemical studies on 6-methylamino-4,5,6,7-tetrahydrobenzothiazole (14.839JL), a new potent dopaminergic agonist.
6-Methylamino-4,5,6,7-tetrahydrobenzothiazole monochlorhydrate (14.839JL) is a new, potent dopaminergic agonist. The stereotypy induced by this drug was greater than that induced by an equivalent dose of apomorphine, was antagonized by pretreatment with sulpiride and counteracted the hypomotility induced by reserpine. Striatal levels of the dopamine metabolites homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) were significantly lowered for up to 4-6 h by doses from 0.05 to 1 mg/kg. The drug was also very effective in lowering prolactine secretion. 14.839JL displaced [3H]N-n-propylnorapomorphine [3H]NPA from striatal binding sites with an IC50 similar to dopamine (DA). Conversely, the ability of 14.839JL to displace 3H spiperone from its binding sites was 100 and 10 times lower than that of haloperidol and sulpiride, and similar to that of SCH 23390. Differently from the latter, however, 14.839JL did not modify adenylate cyclase activity. All these data suggest that 14.839JL is a new, potent, long-lasting direct DA agonist, probably acting on D2 receptors.
Adenylyl Cyclases↗
From fenfluramine racemate to d-fenfluramine. Specificity and potency of the effects on the serotoninergic system and food intake.
Experiments using the binding of various ligands for monoamines to rat brain membranes and synaptosomal preparations for studying monoamine uptake and release have shown that d-fenfluramine is more potent than the l isomer in inhibiting 5-HT uptake, whereas d-norfenfluramine preferentially releases 5-HT from a reserpine-insensitive compartment. Studies on brain monoamine metabolism in intact animals have shown that the d and l isomers of fenfluramine at relatively low doses have a specific action on brain 5-HT and catecholamines, respectively. Based on the different ability of metergoline and ritanserin to displace 5-HT2 binding to rat brain membranes and to antagonize d-fenfluramine's anorexia, evidence has been provided that d-fenfluramine preferentially uses 5-HT1 sites in the rat brain to cause anorexia in this animal species. Finally, characteristics, regional distribution, and pharmacological characterization of a high-affinity [3H]d-fenfluramine binding to rat brain membranes have been described. This binding appears to be different from 5-HT uptake sites ([3H]imipramine binding) and 5-HT receptors and is not regionally related to the endogenous levels of 5-HT in the rat brain. It is, however, preferentially displaced by some agents using 5-HT to cause anorexia in rats, raising the possibility that it is somewhat related to 5-HT mechanisms involved in feeding control.
Amines↗