The Italian way of osteoporosis.
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Adult↗
Biomedical subjects
N Montanaro
Publications and source records attributed to N Montanaro.
FARMAGUIDA: a databank for the analysis of the Italian drug market and drug utilization in general practice.
FARMAGUIDA, a databank of drugs marketed in Italy (2,596 pharmaceutical substances corresponding to 10,448 products), permits analysis of the nature and value of the drugs prescribed. It contains coded pharmaceutical and administrative information, an original classification, as well as indicators of the therapeutic status of each drug. The FARMAGUIDA classification was built hierarchically according to a three-level pattern: the first level (42 categories) corresponds to major pharmacological groups; the second level (157 groups) gathers drugs having similar clinical indications and/or pharmacological actions; and the third level (246 subgroups) classifies drugs according to chemical structure and/or the mechanism of action. Drugs not falling into well-established pharmacotherapeutic criteria (e.g. neurotropics or liver protectants) are classified into separate subgroups. Two larger groupings were also formulated: THER (11 headings), a utilization-oriented arrangement in which each heading also contained the corresponding placebo-like drugs, and PHARM (14 headings), a rational pharmacological arrangement, in which all placebo-like drugs were relegated into a separate set. The following quality indicators were created: DOC, which defines five degrees of documentation of clinical efficacy according to major textbooks of pharmacology and therapeutics; CLASS, which groups DOC values for a more simple evaluation of prescription data; PREP, which distinguishes monocomponent preparations from fixed-dose combinations, and also provides coded information about the rationale for the combination; HOSP, which hallmarks drugs that should be reserved for in-patients, e.g. anti-pseudomonal antibiotics. The composition of the list of reimbursable drugs, the Italian National Formulary (NF; 5782 products in 1990) was analyzed according to the FARMAGUIDA classification and indicators.(ABSTRACT TRUNCATED AT 250 WORDS)
Data Collection↗
Drug utilization in general practice: prescribing habits of National Formulary drugs by GPs of Emilia Romagna (Italy) in 1988 and 1989.
Two years of prescriptions for all the drugs included in the Italian National Formulary by 3,866 general practitioners, in a region of Northern Italy of almost 4 million inhabitants, were analysed to determine the pattern of drug use. The data (official code and proprietary name of the drug, number of packages prescribed, price of the drug, dispensing pharmacy, and date of dispensing) were collected monthly by retail pharmacies and were recorded and organized in database files. Quantitative and qualitative profiles of prescription patterns were studied for all the major therapeutic areas. Overall drug prescriptions averaged 600 DDD/1,000 inhabitants/day. Comparison of 1988 and 1989 data showed only a slight increase in total drug prescriptions, but greater changes were detected in certain drug groups, especially those recently marketed. Overprescription of well-documented drugs, such as H2-antagonists, ACE-inhibitors, calcium antagonists and the HMG-CoA-reductase inhibitors, in comparison to other countries was shown. There was frequent prescribing of drugs devoid of documentation of their clinical efficacy, which were mainly given for clinical conditions lacking a specific treatment, or as placebos for minor disorders. The data demonstrate the need for educational intervention to improve the quality of drug prescribing habits in primary health care in Italy.
Drug Prescriptions↗
Effect of chronic treatment with dizocilpine (MK-801) on the behavioral response to dopamine receptor agonists in the rat.
The D2 or D1 dopamine receptor blockers (-)-sulpiride or SCH 23390 antagonized, in a dose dependent manner, the hypermotility induced by the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (0.25 mg/kg IP). MK-801 induced hyperactivity was not detected when rats were observed on days 7, 14 or 21 of 21 daily injections of MK-801. This lack of hyperactivity was also noted 5 days after the last administration of the repeated treatment with MK-801. The hypermotility induced by the D2 dopamine receptor agonist LY 171555 (0.3 mg/kg IP) was reduced 5 days following repeated treatment (21 days) with MK-801, while no change in the behavioral responses to the selective D1 agonist, SKF 38393, or the mixed D1/D2 agent apomorphine was detected. The results, although suggesting the involvement of dopaminergic pathways in the behavioral effect of MK-801, are conflicting with regard to the underlying mechanisms and to the adaptive changes of dopaminergic system following repeated NMDA receptor blockade.
Animals↗
NMDA antagonists interact with 5-HT-stimulated phosphatidylinositol metabolism and impair passive avoidance retention in the rat.
The NMDA receptor antagonists APV (5 micrograms/10 microliters/rat i.c.v.) or ketamine (12.5 mg/kg i.p.), administered 5 min before training, decreased the retention of a passive avoidance conditioning. In hippocampal or cortical slices of APV- and ketamine-treated rats, 5-HT-stimulated phosphoinositide metabolism was potentiated. It is suggested that excitatory amino acids could modulate the mechanism operative in signal transduction of serotonin; this interaction could play a role in memory retention.
2-Amino-5-phosphonovalerate↗
Repeated treatment with (-)-sulpiride plus a low dose of SCH 23390 displays wider neuroleptic activity without inducing dopaminergic supersensitivity.
Combined treatment with (-)-sulpiride plus a low dose of the D1 receptor antagonist SCH 23390, unlike (-)-sulpiride given alone, blocked rat striatal dopaminergic transmission. Five days after the withdrawal of 21-day repeated administration of the combined treatment, no increase in apomorphine-induced stereotyped behaviour was observed. The results suggest that the combination of a D2 blocker and a low dose of a D1 blocker produces a wider spectrum of neuroleptic activity without an overt risk of inducing dopaminergic behavioural supersensitivity.
Animals↗
Extreme insulin resistance due to anti-insulin receptor antibodies: a direct demonstration of autoantibody secretion by peripheral lymphocytes.
A 59-year-old woman with systemic lupus erythematosus was found to have marked hyperglycemia, extreme insulin resistance and abnormally high plasma immunoreactive insulin. Her circulating erythrocytes displayed a dramatic decrease of 125I-labeled insulin binding. Both the whole serum and purified IgG fraction strongly inhibited the binding of radiolabeled insulin to control erythrocytes. These results suggested, although indirectly, the existence of antibodies to insulin receptors in the serum of the patient. To directly investigate this issue, we used an enzyme-linked solid-phase immunoassay which allows the detection and enumeration of lymphocytes secreting antibodies towards insulin receptors. Peroxidase-conjugated anti-human immunoglobulin is used to reveal the binding of antibodies to insulin receptor-coated dishes. We demonstrated that the patient's mononuclear cells, when briefly incubated in Petri dishes with partially purified insulin receptor, were able to secrete immunoglobulins of G class specifically directed to the antigen. Moreover, only a fraction of the whole population of anti-insulin receptor antibodies was directed towards the insulin binding region of the receptor, seemingly corresponding to the auto-antibodies detected with conventional binding-inhibition assay.
Antibody-Producing Cells↗
Synergistic blockade of some dopamine-mediated behaviours by (-)-sulpiride and SCH 23390 in the rat.
Several studies have indicated that the D2 dopamine receptors mediate the antidopaminergic activity of the neuroleptics; nevertheless, the selective blocker (-)-sulpiride weakly inhibits dopamine-mediated behaviour. The present study investigated whether the concomitant injection of doses of the D1 antagonist SCH 23390, which by themselves are without effect, would enable (-)-sulpiride to express fully neuroleptic activity in the rat. The benzamide YM 09151-2 that strongly inhibits dopamine-mediated behaviour was also studied. Rats receiving different doses of (-)-sulpiride, YM 09151-2 and SCH 23390 given alone or in combination were tested for exploratory activity, apomorphine-induced stereotyped behaviour and hyperactivity elicited by the D2 agonist LY 171555. When given alone, (-)-sulpiride (10, 20 and 40 mg/kg IP) had no effect on exploratory activity and stereotypy. When (-)-sulpiride was administered in combination with an ineffective dose of SCH 23390 (5 micrograms/kg) both responses were significantly inhibited. The combined administration of subthreshold doses of (-)-sulpiride (2.5 mg/kg) and SCH 23390 (2.5 micrograms/kg) significantly inhibited hypermotility induced by LY 171555. Moreover, the combined administration of ineffective doses of YM 09151-2 with subthreshold doses of SCH 23390 strongly inhibited all the behavioural responses. The results indicate that SCH 23390 allowed (-)-sulpiride to exhibit a wider spectrum of neuroleptic activity and potentiated the antidopaminergic activity of YM 09151-2.
Animals↗
Behavioral and biochemical expression of D1-receptor supersensitivity following SCH 23390 repeated administrations.
In this study concomitant changes of behavioral and biochemical responses in rats repeatedly treated with SCH 23390 were evaluated. Apomorphine-induced stereotyped behavior was increased in D1-supersensitive rats, in contrast no change in the behavioral response to the pure D1-agonist SKF 38393 was detected. Parallel biochemical studies indicated that the enhancement in striatal dopamine (DA) metabolite concentration due to the administration of spiroperidol plus SKF 38393 was not potentiated in SCH 23390 repeatedly treated rats. The results show that the expression of D1-supersensitivity could depend on the stimulation of D2-receptors.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Changes in behavioural responses to the combined administration of D1 and D2 dopamine agonists in normosensitive and D1 supersensitive rats.
The selective D1 receptor stimulant SKF 38393 dose-dependently increased grooming time in rats without affecting locomotor activity or eliciting stereotyped behaviour. The selective D2 receptor agonist LY 171555 induced a dose-dependent increase in rat motility, a marked decrease in grooming time and a low occurrence of stereotyped behaviour. Concurrent administration of the two selective agonists induced high-degree stereotyped responses and reductions in locomotor and grooming behaviours. Rats withdrawn from repeated treatment with the selective D1 receptor blocker SCH 23390 (0.05 mg/kg twice daily for 21 days; 7 days of washout) did not exhibit any change of locomotor and grooming responses to threshold doses of LY 171555 and SKF 38393 given alone or in combination. On the contrary, a significantly greater occurrence of high-degree stereotyped responses to the combination of the two selective agonists was observed. The data support the view that D1 and D2 receptors have a cooperative role in the generation of stereotypies and suggest that D1 receptor supersensitivity needs D2 stimulation to be revealed.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Neuroleptic-induced reduction of quipazine-elicited head-twitches in rats: possible involvement of striatal dopaminergic supersensitivity.
Rats were treated with a single large dose of various neuroleptic compounds and, 5-7 days after, they were assayed for either behavioral sensitivity to apomorphine (hypermotility and stereotyped behavior) or head-twitch response to the mixed serotonin-dopamine agonist quipazine. The animals withdrawn from chlorpromazine, fluphenazine, haloperidol, metoclopramide and the D1 selective blocker SCH 23390, showed enhanced hypermotility and/or stereotyped responses to apomorphine and reduced head-twitch response to quipazine. The rats withdrawn from thioridazine, (-)-sulpiride and sultopride responded to apomorphine only with enhanced hypermotility while their response to quipazine was either unchanged or even increased. The results are discussed in terms of dopaminergic brain areas and/or receptor subtypes involved in the modulation of the head-twitch response to quipazine. We concluded that an enhancement of dopaminergic tone at the striatal level could be related to the reduced head-twitch response to quipazine.
Animals↗
Responses to selective D-1 and D-2 agonists after repeated treatment with selective D-1 and D-2 antagonists.
This study was aimed at achieving a better understanding of the functional role of D-1 and D-2 receptors in some dopamine-mediated behaviors. Hypermotility, grooming behavior and stereotyped behavior were induced, respectively, by LY 171555 (D-2 agonist), SKF 38393 (D-1 agonist) and apomorphine (mixed agonist). Acute pretreatment either with the D-1 selective antagonist SCH 23390 (0.02 mg/kg) or with the D-2 receptor blocker YM 09151-2 (0.02 mg/kg, IP) blocked all these behaviors, suggesting the existence of functional interactions between D-1 and D-2 receptors. Striatal membranes prepared from rats receiving repeated administrations with SCH 23390 (0.05 mg/kg, twice daily for 21 days) showed an increase in the number of D-1 but not of D-2 receptors. On the contrary the repeated treatments with YM 09151-2 increased only the Bmax values of D-2 receptors. While the D-1 supersensitive rats showed only enhancement of apomorphine-induced stereotyped behavior, the D-2 supersensitive rats exhibited an increase of both apomorphine-elicited stereotypy and LY 171555-elicited hypermotility. SKF 38393-induced grooming was unaffected by any pretreatments. Moreover when D-2 supersensitive rats were acutely pretreated with SCH 23390, the enhancement of apomorphine-induced stereotyped behavior was abolished. It is concluded that the behavioral expression of D-1 receptor supersensitivity requires the simultaneous activation of D-1 and D-2 receptors.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Molecular mechanisms in the action of minaprine.
1. Minaprine is a pyridazine derivative endowed with antidepressant activity, however biochemical studies following repeated administrations are still lacking. 2. Rats were administered with minaprine (10 mg/kg i.p.) twice daily for 3 weeks. 3. In minces from the frontal cortex of rats receiving minaprine the NE-induced cAMP accumulation is reduced suggesting that, similarly to other antidepressant treatments, minaprine attenuates the beta-adrenergic receptor function. 4. The selective lesion of the serotonergic axons abolished such attenuation. 5. In synaptic plasma membranes prepared from rats repeatedly treated with pargyline (at doses which block MAO tipo A and B) but not with minaprine, the number of 5HT1C and 5HT2 receptors was reduced. 6. Repeated administrations of minaprine but not of pargyline increased the Bmax values of [3H]-imipramine binding. In 5, 7-DHT lesioned rats minaprine failed to increase the number of the residual [3H]-imipramine recognition sites. 7. The authors conclude that the increase in the number of [3H]-imipramine recognition sites is unrelated to the IMAO activity of minaprine. 8. The presence of 5HT axons on which [3H]-imipramine recognition sites are located is an absolute requirement for the clinical efficacy of minaprine. 9. The action of minaprine in the regulation of the synthesis and/or of the release of an endogenous substance that is important in mediating brain beta-adrenergic function is discussed.
Adenylyl Cyclases↗
Enhanced stereotyped response to apomorphine after chronic D-1 blockade with SCH 23390.
Rats were treated for 21 days with the selective D-1 blocker SCH 23390 (0.1 mg/kg SC). Threshold doses of apomorphine for hypermotility (0.15 mg/kg SC) and for stereotyped response (0.25 mg/kg SC) were given 7, 21, 35, and 77 days after discontinuation of the chronic treatment. The rats always showed enhanced stereotyped response to the higher dose of apomorphine but never any change in their motility response to the lower dose of dopamine agonist. This finding may represent a behavioral correlate of the reported supersensitivity of D-1 receptors induced by SCH 23390.
Animals↗
Behavioral differentiation between pharmacokinetic and pharmacodynamic components of the interaction of antidepressants or neuroleptics with methamphetamine.
This study proposes a method capable of separating the pharmacodynamic from the pharmacokinetic component in the methamphetamine (MA) hyperactivity potentiation induced by antidepressants. Several antidepressants and neuroleptics, other centrally-acting drugs and the inhibitor of hepatic drug metabolism SKF 525-A were studied. The motility counts taken between 10 and 20 min after MA injection were considered as an index of pharmacodynamic interaction and the whole duration of the hyperactivity syndrome as an index of pharmacokinetic interaction. The duration of MA effect was prolonged by some of the drugs studied and left unchanged by the others regardless of their clinical classification. On the contrary, our evaluation of the intensity of MA effect produced a sharp differentiation between classical neuroleptics and typical antidepressants: the former antagonized and the latter potentiated MA peak intensity. Only the D-2 blocking neuroleptics sulpiride and tiapride potentiated MA intensity. Regarding the specificity of our model, none of the compounds known to be devoid of clinical antidepressant or antipsychotic activity interacted with MA in such a way as to be included in either category. As to the sensitivity of the test, two "false negatives" were obtained: the neuroleptic clozapine and the antidepressant mianserin. Such exceptions were discussed taking into account their peculiar mechanisms of action.
Animals↗
Involvement of different dopamine receptors in rat diphasic motility response to apomorphine.
A critical dose of apomorphine (300 micrograms/kg SC) given immediately before placing rats into a novel environment produced a diphasic motility response (initial sedation followed by enhanced locomotion). Various neuroleptics having different clinical and/or pharmacological profiles were studied by using such a model. (-)-Sulpiride and sultopride preferentially antagonized apomorphine inhibition; haloperidol and tiapride antagonized both phases of apomorphine response at similar doses; chlorpromazine, fluphenazine, thioridazine, metoclopramide and SCH 23390 preferentially antagonized apomorphine stimulation. The results are discussed in terms of the dopamine receptor subtypes involved in the two phases of apomorphine effect. Apomorphine stimulation can be antagonized by D-1 as well as D-2 receptor blockade. A higher affinity for D-2 receptors seems a necessary requisite for the antagonism of apomorphine inhibition; moreover, the ability of neuroleptics to antagonize apomorphine inhibition seems to depend on the ratio of their presynaptic versus postsynaptic D-2 activity.
Animals↗
Reduced head-twitch response to quipazine of rats previously treated with methiothepin: possible involvement of dopaminergic system.
Methiothepin has been reported to induce an increase of specific binding sites for 3H-5TH 2-3 days following a single administration of a large dose. The present study was intended to ascertain whether methiothepin pretreatment would induce behavioral serotonergic supersensitivity, as assayed by evaluating head-twitch response to quipazine and L-5-hydroxytryptophan (L-5HTP). Methiothepin-pretreated rats exhibited a significantly reduced response after quipazine but not a significant change after L-5HTP. Such findings could be explained by considering that quipazine stimulates both serotonin and dopamine receptors and by hypothesizing that methiothepin also induced dopaminergic supersensitivity which hampered head-twitch behavior. Such an explanation was supported by the following findings. Rats tested 5 days after a large dose of haloperidol exhibited reduced head-twitch response to quipazine. Moreover, rats which had received a single administration of either haloperidol or methiothepin showed (1) more sustained spontaneous locomotor activity, and (2) enhanced stereotyped response to apomorphine.
5-Hydroxytryptophan↗
Antidepressant versus neuroleptic activities of sulpiride isomers on four animal models of depression.
The atypical neuroleptic sulpiride is also prescribed for depression because of its activating effect. However, such an effect does not necessarily imply an action identical to that of classical antidepressants, and a laboratory comparison of the neuroleptic and antidepressant activities of sulpiride may contribute to a better definition of its psychotherapeutic profile. Sulpiride isomers were studied in the rat in four behavioural models of depression which are thought to be influenced by neuroleptics in different ways. Desipramine (imipramine) and haloperidol were employed in each test as a standard antidepressant and neuroleptic, respectively. The four tests were: 1) prevention of apomorphine-induced sedation: 2) antagonism of apomorphine-induced hypothermia; 3) behavioural despair (swim test); 4) learned helplessness ( FR2 lever pressing escape). Desipramine ameliorated behaviour in all tests; haloperidol ameliorated the response to test 1, influenced that to test 2 in a neuroleptic-like way and worsened the responses to tests 3 and 4. (-)-Sulpiride worked in a similar way to haloperidol in all tests. (+)-Sulpiride significantly and dose-dependently ameliorated the responses to test 3 and was inactive in the others. No conclusion was drawn from test 1 owing to its lack of specificity; the results of the remaining tests indicated a neuroleptic profile of (-)-sulpiride and suggested a potential "antidepressant" activity of (+)-sulpiride which merits further investigation.
Animals↗