Risk of atrial fibrillation among bisphosphonate users: a multicenter, population-based, Italian study.

UNLABELLED: Bisphosphonate treatment is used to prevent bone fractures. A controversial association of bisphosphonate use and risk of atrial fibrillation has been reported. In our study, current alendronate users were associated with a higher risk of atrial fibrillation as compared with those who had stopped bisphosphonate (BP) therapy for more than 1 year. INTRODUCTION: Bisphosphonates are widely used to prevent bone fractures. Controversial findings regarding the association between bisphosphonate use and the risk of atrial fibrillation (AF) have been reported. The aim of this study was to evaluate the risk of AF in association with BP exposure. METHODS: We performed a nested case-control study using the databases of drug-dispensing and hospital discharge diagnoses from five Italian regions. The data cover a period ranging from July 1, 2003 to December 31, 2006. The study population comprised new users of bisphosphonates aged 55 years and older. Patients were followed from the first BP prescription until an occurrence of an AF diagnosis (index date, i.e., ID), cancer, death, or the end of the study period, whichever came first. For the risk estimation, any AF case was matched by age and sex to up to 10 controls from the same source population. A conditional logistic regression was performed to obtain the odds ratio with 95% confidence intervals (CI). The BP exposure was classified into current (<90 days prior to ID), recent (91-180), past (181-364), and distant past (≥365) use, with the latter category being used as a reference point. A subgroup analysis by individual BP was then carried out. RESULTS: In comparison with distant past users of BP, current users of BP showed an almost twofold increased risk of AF: odds ratio (OR) = 1.78 and 95% CI = 1.46-2.16. Specifically, alendronate users were mostly associated with AF as compared with distant past use of BP (OR, 1.97; 95% CI, 1.59-2.43). CONCLUSION: In our nested case-control study, current users of BP are associated with a higher risk of atrial fibrillation as compared with those who had stopped BP treatment for more than 1 year.

Comparative safety profiles of intravitreal bevacizumab, ranibizumab and pegaptanib: the analysis of the WHO database of adverse drug reactions.

PURPOSE: The purpose of this study is to conduct a comparative analysis of the suspected adverse drug reactions (ADRs) associated with intravitreal bevacizumab, ranibizumab and pegaptanib in the WHO database in order to have a real-life information on these drugs, which now is only based on data coming from clinical trials. METHODS: ADR reports for intravitreal use of bevacizumab, ranibizumab and pegaptanib from January 2002 to December 2012 were selected from the WHO-VigiBase. Reporting odds ratio (ROR) with confidence interval of 95 % and p value was calculated. The analysis was performed for drug-reaction pairs. The Medical Dictionary for Regulatory Activities (MedDRA) terminology for ADRs was used. RESULTS: The analysis was performed on 3180 reports corresponding to 7753 drug-reaction pairs. Significant RORs for endophthalmitis and uveitis (1.90, 95 % confidence interval (CI) 1.48-2.43, and 10.62, 6.62-17.05, respectively) were retrieved for bevacizumab, and cerebrovascular accident and myocardial infarction produced significant ROR (1.54, 1.14-2.10 and 1.73, 1.18-2.53, respectively) for ranibizumab. Pegaptanib was significantly associated with visual impairment (1.98, 1.12-3.5, p = 0.02), nausea (3.29, 1.57-6.86, p < 0.001), vomiting (2.91, 1.2-7.07, p = 0.01) and drug hypersensitivity (8.75, 3.1-24.66, p < 0.001). CONCLUSIONS: Our data showed an elevated disproportionality for cardiovascular ADRs in patients treated with ranibizumab and for infective ocular reactions in those treated with bevacizumab. No relevant safety issues were identified for pegaptanib. These findings suggest bevacizumab as a suitable choice for AMD therapy due to its effectiveness similar to that of ranibizumab, its favourable safety profile and for its lower cost.

Assessing the risk of osteonecrosis of the jaw due to bisphosphonate therapy in the secondary prevention of osteoporotic fractures.

SUMMARY: There is evidence that the use oral bisphosphonates can lead to osteronecrosis of the jaws (ONJ). Although the occurrence of ONJ appears rare among oral bisphosphonates (BPs) users, it is important to know that it exists and can be opportunely minimized. INTRODUCTION: The purpose of this study is to evaluate the association between BPs prescribed for the secondary prevention of osteoporotic fractures and the occurrence of ONJ. METHODS: An Italian record linkage claims database with a target population of around 18 million individuals (6 million over 55 years of age) constituted the data source. We conducted a nested case-control study within a cohort of individuals aged 55+ years old, who were discharged from hospitals with a primary diagnosis of incident osteoporotic fracture. The date related to the discharge diagnosis of ONJ was the index date. Conditional logistic regression for matched data was fitted to estimate the odds ratio (OR) along with 95 % confidence intervals (95 % CI) for the likely association between use of BPs and the risk of ONJ. RESULTS: Any one of the 61 ascertained cases of ONJ (incidence rate, 36.6 per 100,000 person-years) was matched to 20 controls for a total of 1120 controls. When the exposure to BPs was modeled according to recency (i.e., exposure time window prior to the index date) of use, the adjusted OR (95 % CI) for current users was 2.8 (1.3-5.9) against never users. The cumulative use of BPs has shown to increase the incidence of ONJ among patients with primary osteoporotic fractures, although not statistically significant risk has been observed. CONCLUSIONS: Although the risk of BP-related ONJ appears low in non-oncological indications, it is important to be aware that it exists and to know how it may be predicted and possibly minimized.

Use of anti-asthmatic drugs in Italy: analysis of prescriptions in general practice in the light of guidelines for asthma treatment.

UNLABELLED: Our aim was to analyse anti-asthmatic drug utilisation in primary health care in a Northern Italian region in the light of guidelines for asthma treatment. METHODS: We collected all prescriptions for anti-asthmatic agents reimbursed in 1998 in six local health authorities (overall population: 1,909,192 inhabitants) of Emilia Romagna (Northern Italy). The asthmatic cohort was defined as the population of subjects aged 20-44 years receiving at least one prescription of an anti-asthmatic agent devoid of indications for transient respiratory diseases. In order to include routine users, the asthmatic cohort was restricted to those subjects with at least one prescription in the first quarter of 1998. Anti-asthmatic agents were classified according to their therapeutic role as follows: maintenance therapy for mild-moderate asthma (Mm); maintenance therapy for severe asthma (Ms); quick relief for mild attack (Qm) and quick relief for severe attack (Qs). RESULTS: The asthmatic cohort included 11,518 subjects; of these, 47% received only one prescription in 1998. The most frequent regimens were Mm+Qm (25%) and Qm alone (23%). Some regimens appeared not to be in accordance with international recommendations. The main reasons were lack of drugs for quick relief (36%), use of long-term beta(2)-adrenoceptor agonists (Ms drugs) without quick-relief or anti-inflammatory agents (10% of the cohort and 56% of the recipients of Ms drugs) and presence of fixed-dose combinations (27%). In 76% of the patients treated with Mm drugs (mainly inhaled steroids), the total amount of drugs prescribed over the 1-year period covered less than 150 days. CONCLUSIONS: The use of anti-asthmatic drugs in general practice in Italy does not seem to comply with the international recommendations especially with regard to the use of quick-relief agents. Active interventions to implement guidelines and monitor the choice of drug regimens are warranted.

The therapeutic course as a measure complementary to defined daily doses when studying exposure to antibacterial agents.

OBJECTIVE: The defined daily dose (DDD) method may not provide accurate information about exposure to antibacterial agents, owing to their short-term use and the consequently high turnover of subjects. This study was addressed to evaluate whether the number of "therapeutic courses" could offer additional information. METHODS: Prescription data of antibacterial agents (ATC J01) in Ravenna, Italy (350,000 inhabitants), were studied in 1998. All the prescriptions issued within 10 days were considered as belonging to one therapeutic course (TC). The following measures were compared: DDD/1000 inhabitants/year, number of exposed subjects/1000 inhabitants/year and number of TC/1000 inhabitants/year. In order to compare the number of 10-day TCs with the number of DDDs, the latter was divided by 10 (DDD10). The intensity of drug treatment was also evaluated as the average number of DDDs per TC (therapeutic intensity). RESULTS: Sixty-one percent of the subjects received only one prescription in 1998. Among the second prescriptions, 69% were issued after a time interval greater than 21 days. The overall prevalence of use was 329 per 1000 inhabitants, the TCs were 525 per 1000 inhabitants and DDD10/1000 inhabitants/year were 470. The therapeutic intensity varied with the age classes (being lowest in the elderly) and with the individual antibiotics used. Two or more antibacterials were used within the same TC in 7% of the cases. CONCLUSION: The measures considered in this study provided different estimates of exposure to antimicrobial agents. The combined analysis of DDDs and TCs may offer a more reliable information about exposure to antimicrobial agents.

Pattern of antibiotic use in primary health care in Italy.

OBJECTIVE: The overuse and misuse of antibiotics have been related to the growing emergence of bacterial resistance. The aim of the present study was to assess the pattern of antibiotic use by Italian general practitioners (GPs) in the treatment of the most frequent infectious problems. METHODS: The study was performed with 131 GPs recruited on a voluntary basis from among the 181 GPs contacted in two Italian regions, Emilia Romagna and Umbria. GPs were requested to report all the infectious events encountered during six sample weeks on a special form, whether an antibiotic was administered or not. RESULTS: The GPs reported 7095 infectious cases, of which 5036 (77%) were respiratory-tract infections (RTIs) and 749 (11%) were urinary-tract infections (UTIs). Antibiotics were prescribed in 71% of the cases. The proportion of antibiotic-treated cases was highest in UTIs (97%), followed by lower respiratory-tract infections (LRTIs; 93%) and upper respiratory-tract infections (URTIs; 54%). Drugs belonging to 16 Anatomical Therapeutical Chemical groups (fourth level) were used. Wide-spectrum penicillins and macrolides ranked first (23%), followed by penicillins plus beta-lactamase inhibitors (15%), cephalosporins (15%) and fluoroquinolones (10%). The most prescribed antibiotics for the major disease groups were wide-spectrum penicillins for URTIs (36%), macrolides and cephalosporins for LRTIs (27% each) and fluoroquinolones for UTIs (46%). CONCLUSIONS: The present survey showed a high level of inappropriate use. In fact, a large number of infectious diseases, including infections commonly caused by viral agents, were treated with an anti-bacterial drug. Italian GPs had a tendency to preferentially prescribe wide-spectrum antibiotics and to use, in many cases, antibiotics that are rarely of choice in primary health care, such as cephalosporins and fluoroquinolones. In order to attain a more evidence-based prescription, local guidelines shared by specialists and GPs should be implemented.

Deviations from evidence-based prescribing of non-steroidal anti-inflammatory drugs in three European regions.

OBJECTIVE: We examined to what extent the evidence of the relative gastrointestinal toxicity with non-steroidal anti-inflammatory drugs (NSAIDs) was implemented in clinical practice in Bologna, Italy, Funen, Denmark, and Stockholm, Sweden, areas with accurate computerised information on prescriptions purchased by defined populations. METHODS: We ranked each NSAID by purchased volume in defined daily doses during September 1996 and compared it with the ranking of gastrointestinal complications from a meta-analysis of controlled epidemiological studies published between 1986 and 1994. We restricted our comparison to those NSAIDs that accounted for 90% of the use and within this DU90% segment we determined the proportion of "high risk" (azapropazone, ketoprofen, piroxicam) and "low risk" (ibuprofen, diclofenac) drugs with respect to gastrointestinal toxicity. RESULTS: In Funen, Denmark, we found the best NSAID profile (63% low risk/11% high risk) while Bologna, Italy, had the other extreme (26% low risk/38% high risk), with Stockholm, Sweden, in between (43% low risk/20% high risk). CONCLUSION: Our study suggests that factors other than evidence-based medicine had a dominating impact on the use of prescription NSAIDs in 1996.

Lack of adherence to lipid-lowering drug treatment. A comparison of utilization patterns in defined populations in Funen, Denmark and Bologna, Italy.

AIMS: The objective was to explore differences in lipid-lowering drug (LLD) prescribing in Italy and Denmark. METHODS: We used two geographical areas with computerized drug prescription records in defined populations, one in Funen, Denmark with 500 000 inhabitants, the other in Bologna, Italy with 400 000 inhabitants. Prescriptions for patients who had purchased a LLD from 1994 until 1996 were retrieved as well as coprescriptions of antidiabetic and cardiovascular drugs as markers for diabetes and cardiovascular disease. Only patients surviving and remaining in the area were included. Compliance was defined as percentage of DDDs purchased divided by the number of days within the time window. The limit between good and poor compliance was set at 82%. RESULTS: In Bologna, LLD consumption measured in DDD increased by 41% and in Funen by 129%. Annual prevalence increased from 36.9 to 46.3 users/1000 inhabitants from 1994 to 1996 and from 3.2 to 6.6 users/1000 inhabitants in Bologna and Funen, respectively. From 1995 to 1996, the incidence of use decreased slightly in Bologna from 19.3 to 18. 8/1000 inhabitants/year, whereas in Funen the incidence increased from 1.8 to 2.3/1000 inhabitants/year. In Bologna 48% and in Funen 91% of users persisted with treatment for 2 years or longer. In Bologna, 7% and in Funen 45% were good compliers. In Bologna, 61% and in Funen, 72% received other drugs indicating cardiovascular or diabetic comorbidity. CONCLUSIONS: Patterns of use differed substantially between the two areas. In contrast with Funen, where long-term use was common, Bologna LLD use was sporadic. Based on a higher rate of coprescription, LLDs seemed to be used for secondary prevention to a higher extent in Funen than in Bologna. In Funen it appeared that the correct patients, but an insufficient number of them, were being treated adequately according to guidelines. The higher discontinuation rate of lipid lowering drugs in the Bologna area indicates that a large proportion of patients use these drugs for too short a period of time to benefit from treatment. Since society's health care resources are limited it is difficult to justify public funding of these medications without at the same time giving appropriate attention to these problems.

Use of lipid-lowering drugs from 1990 to 1994: an international comparison among Australia, Finland, Italy (Emilia Romagna Region), Norway and Sweden.

OBJECTIVE: To compare the overall utilisation pattern of lipid-lowering drugs between 1990 and 1994 in Australia, Finland, Italy, Norway and Sweden as well as the pattern of use with respect to age and gender in Italy and Sweden. METHODS: Data were retrieved from regulatory authorities in each country for the 5-year period and analysed according to the ATC/DDD methodology (Anatomical Therapeutic Chemical classification/Defined Daily Doses). Utilisation was calculated as the DDDs for 1000 inhabitants per day for all drugs of the ATC category B04 (serum lipid-reducing agents). Data from Sweden and Italy were also compared with respect to gender and age. RESULTS: In 1994, Australia demonstrated the highest degree of utilisation (11.9 DDD) and the Nordic Countries the lowest (Sweden 5.6; Norway 4.9; Finland 4.0). In all countries except Italy, a steady increase was observed; in Italy, utilisation of these drugs reached a maximum in 1992 (11.5 DDD), but then underwent a reduction which was caused by restrictions in the reimbursement status in 1993 (10.4) and 1994 (6.7). Administration of statins increased in all countries, becoming the most used group of the B04 class. In 1988, the number of different drugs listed by each national health service ranged from 4 (Norway) to 16 (Italy); in 1994 it ranged from 6 (Norway) to 9 (Sweden). Analysis with respect to gender showed the opposite pattern in Sweden (males 4.6 and females 3.3 in 1992; 6.2 and 4.5, respectively, in 1994) than in Italy (males 10.8 and females 17.8 in 1992; 6.4 and 9.2, respectively, in 1994). Exposure was highest in people aged 60-69 years in both countries, followed by age group 50-59 in Sweden and 70-79 in Italy. CONCLUSIONS: Large variations in the utilisation of lipid-lowering drugs exist between countries, with Australia and Italy much higher than others. Of the drugs in the ATC category B04, the use of statins predominates in all countries, but to varying degrees. The large difference in the degree of drug utilisation with respect to age and gender between Italy and Sweden suggests major deviations from evidence-based medicine.

Use of benzodiazepines in the Italian general population: prevalence, pattern of use and risk factors for use.

This study was conducted to determine the prevalence and profile of use of benzodiazepines in the Italian population and risk factors for use. Between November 1992 and February 1993, 62 general practitioners submitted a validated self-administered questionnaire on health status and drug use to a randomised sample of 3100 subjects ( > or = 18 years of age, stratified by sex and age), of whom 2803 responded (response, rate 90.4%). Main outcome measures were point estimate (past-week) of all the drugs taken by each individual, dosage and length of use and source of the prescription. The overall past-week prevalence of use of benzodiazepines was 8.6% (5.0% males and 11.8% females). In the elderly ( > or = 65 years) 18.8% reported current use (9.0% males and 24.7% females). Fifty-six per cent of the persons exposed to a benzodiazepine were chronic users (daily, for more than 6 months), and 70.1% in subjects > or = 65 years. The average daily dose taken was relatively low: 61% of short-term users and 51% of chronic users used less than half a defined daily dose (DDD). Female sex, older age, unemployment and retirement were independently associated with the use of benzodiazepines. Benzodiazepine use in Italy appeared to be relatively high (about 9% of subjects reported current use 57% of whom were chronic users). Women were prescribed a benzodiazepine twice as often as men and one out of four elderly women was on treatment. Although the average dosage used was rather low, the high prevalence and the elevated proportion of chronic users should encourage drug information campaigns and educational interventions to promote a more conservative use of these drugs especially in the elderly.

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)

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.

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.

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.

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.

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.