Extrapiramidal syndrom, anticholinergic effects and orthostatic hypotension induced by antipsycotic drugs under everyday practice conditions in Italy:

the PPHSS Study

Segni extrapiramidali, effetti anticolinergici ed ipotensione ortostatica indotti da farmaci antipsicotici in condizioni di pratica clinica quotidiana: lo studio PPHSS
ARRIGO F.G. CICERO, MATILDE FORGHIERI*, DOMENICO F. CUZZOLA, FEDERICA CIPRESSI*, ROSSANA ARLETTI
Biomedical Department - Pharmacology Section, University of Modena and Reggio, Italy *Villa Rosa Home Care, Modena, Italy

SUMMARY. Introduction. The main aims of our study are to describe the pattern of use of conventional and atypical antipsychotics and the prevalence of related side effects in a large population of severe psychiatric patients under everyday clinical practice conditions. Material and methods. The Psychiatric Patients Health Status Study (PPHSS) is an epidemiological transversal study on the general health condition of a large population of severe Italian psychiatric subjects (M: 584, F: 1006, mean age: 51.05 18.82 years) admitted for the first time in a psychiatric clinic from June 1996 to June 2000 because of uncontrolled psychiatric symptoms. For this report, we selected from the general PPHSS database only the data relative to the 924 prescriptions of not overdosed antipsychotics at the admission in the clinic (390 relative to men, 534 relative to women, mean age = 47.32 17.80 years). Results. Orthostatic hypotension has been observed in the 24.40% of those assuming butirrophenones, 44.94% of those phenotiazines, 62.36% of those dibenzodiazepins and 31.58% of subjects treated with benzisoxazols. Anticholinergic symptoms have been reported by 26.98% of patients taking butirrophenones, 34.32% of those phenotiazines, 26.88% of those dibenzotiazepins, 19.30% of subjects that assume benzisoxazols. Extrapiramidal disorders have been observed in the 23.81% of those assuming butirrophenones, 6.91% of those phenotiazines, 3.22% of those dibenzotiazepins, 5.26% of subjects treated with benzisoxazols. Conclusions. Our conclusion is that in the studied population of free-living severe psychiatric patients, a great part of them developed one or more adverse effect (ADEs) related to the assumption of antipsychotic drugs. Among older neuroleptics, haloperidol seems to be globally the most safe, while among new antipsychotics risperidone appears to be less often associated to ADEs. KEY WORDS: antipsychotics, pharmacoepidemiology, extrapiramidal effects, side effects. RIASSUNTO. Introduzione. Il principale scopo del nostro studio la descrizione del pattern di impiego e la prevalenza di effetti collaterali correlati alluso di antipsicotici convenzionali ed atipici in una vasta popolazione di pazienti psichiatrici gravi in condizioni di pratica clinica quotidiana. Materiali e metodi. Lo Psichiatric Patients Health Status Study (PPHSS) uno studio epidemiologico trasversale sulle condizioni di salute generale di 1590 pazienti psichiatrici severi (M: 584, F: 1006; et media = 51.0518.82 anni) ricoverati per la prima volta in una casa di cura psichiatrica nel periodo giugno 1996-giugno 2000 per scarso controllo della sintomatologia psichiatrica. Per questo lavoro, abbiamo selezionato dal database PPHSS i dati relativi a 924 prescrizioni non sovradosate di antipsicotici allammissione in clinica (390 relativa a uomini, 534 a donne, et media -47.3217.80 anni. Risultati. Ipotensione ortostatica stata osservata nel 24.40% di coloro i quali assumevano butirrofenoni, 44.94% di quelli in trattamento con fenotiazine, 62.36% di quelli con dibenzodiazepine e 31.58% dei soggetti trattati con benzisossazoli. Disturbi extrapiramidali sono stati osservati nel 23.81% dei casi in trattamento con butirrofenoni, 6.91% di quelli con fenotiazine, 3.22% di quelli con dibenzodiazepine e 5.26% dei soggetti trattati con benzisossazoli. Conclusioni. Le nostre conclusioni sono che nella popolazione studiata di pazienti psichiatrici severi free-living, una gran parte di essi manifesta uno o pi reazioni (ADEs) correlate allassunzione di antipsicotici. Fra i vecchi neurolettici il pi generalmente sicuro sembra essere laloperidolo, mentre fra gli antispicotici pi recenti il risperidone quello meno spesso associato ad eventi avversi. PAROLE CHIAVE: antipsicotici, farmacoepidemiologia, disturbi extrapiramidali, effetti collaterali.
E-mail: afgcicero@tiscalinet.it

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INTRODUCTION Antipsychotic drugs are primarily used to treat signs and symptoms of psychoses ranging from schizophrenia, psychotic depression, psychotic mania, paranoia, psychosis associated with dementia, delirium, and other non-psychotic conditions as agitation, marked mood instability and aggressive behavior even in absence of overt psychotic symptoms (1). The past decade has an unprecedented development of new antipsychotics defined as atypical because they separate the antipsychotic therapeutic effect from extrapiramidal side effects and because their effect on the serotonin receptors (2). Conventional antipsychotics are efficacious in controlling active symptoms, assaultive behaviour and severe agitation, but novel antipsychotics are able to improve negative and cognitive symptoms as well, causing less adverse effects (3). However, the treatment with atypical antipsychotic drugs is much more expensive than that with conventional neuroleptics and they are absolutely not safe (4). Moreover, most part of available data on antipsychotic safety comes from randomised clinical trials with pre-selected patients: trials normally exclude the more problematic patients, those taking more than one drug and that are often affected by different diseases at the same time, that is like to say those that more often require complicate treatments (5). Furthermore, the report of several studies is more concerned about the beneficial effects than about the side effects of the drugs (6). The consequence is that the trials safety results are not directly extensible to the setting of the current clinical practice (7). In the setting of increasing concern about drug safety, the main aims of our study are to describe the pattern of use of conventional and atypical antipsychotics and the prevalence of related side effects in a large population of severe psychiatric patients under everyday clinical practice conditions.

ta of all the subjects. The psychiatric diagnoses (Table 1) have been formulated by psychiatrists following the DSM IV criteria (8). The available pharmacological informations regard the drugs assumed by the patients at the admission in the psychiatric clinic (commercial formulation, chemical name, dose and route of administration) and the main objective adverse drug effects (ADE) referred by the patients and codified by the medical doctor who sampled the data. Adverse events have been classified as ADE according to the WHO definition (9). To evaluate the prevalence of the main adverse drug effects, we selected from the general PPHSS database only the data relative to the 924 prescriptions of not overdosed antipsychotics at the admission in the clinic (390 relative to men, 534 relative to women, mean age = 47.32 17.80 years). The dose taken from the patients was the one needed to control the psychiatric symptoms. Antipsychotics were grouped in Benzamides, Butirrophenones, Dibenzotiazepins, Tioxantenes, Diphenylbuthylpiperidine, Phenotiazines and Benziosoxazols (Table 2). Then we grouped Diphenylbuthylpiperidine and Tioxantenes as Others and we excluded them from the data analysis because of their small representativity. The ADE were grouped in orthostatic hypotension (orthostatic systolic blood pressure value <105 mmHg), extrapiramidal and anticholinergic effects, hyperprolactinemia related syndrome and hemathological disorders (with special attention to agranulocytosis). The statistical analysis was carried out with the help of SPSS 8.0 software, version for Window 98. Continous data were compared with the Student t-test for unpaired sample. A chi-square test followed by the Fishers exact test was carried out to compare the percentages. A p value less than 0.05 has been considered as significant (10).

RESULTS Three patients treated with Haloperidol and four treated with Promazine at full dosage developed one or more sign of hyperprolactinemia related syndrome that needed to be pharmacologically countracted with Bromocriptine. No significant emathological disorder has been observed in the studied population. The assumption of antipsychotics has been often associated to orthostatic hypotension without overall significant differences among the drug classes (p=0.129). However, comparing the single drug classes, arterial hypotension resulted significantly more frequent in Phenotiazines (44.94%) and Dibenzotiazepins (44.09%) taking subjects than in others. The only drug not associated with this common ADE was Chlorperazine, while hypotension was rare with Clozapine (Table 3). Women developed orthostatic

PATIENTS AND METHODS

The Psychiatric Patients Health Status Study (PPHSS) is an epidemiological transversal study on the general health condition of a large population of severe Italian psychiatric subjects (M: 584, F: 1006, mean age: 51.05 18.82 years) admitted for the first time in a psychiatric clinic from June 1996 to June 2000 because of uncontrolled psychiatric symptoms. The PPHSS database contains anagraphic data, personal and familial historical informations, anthropometric data, clinical and laboratory da-

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Table 1. Prevalence of psychiatric diseases diagnoses formulated in a specialist setting following the DSM-IV criteria in the study population who received a prescription for an antipsychotic drug. Diagnosis Depressive syndromes Anxious syndromes Psychoses Schizophrenia/ Schizoaffective disorders Personality disorders Alcoholism Addiction Anorexia Dementia Total Men 97 (24.87%) 26 (6.67%) 77 (19.74%) 29 (7.44%) 38 (9.74%) 51 (13.08%) 23 (5.90%) 0 (0%) 49 (12.56%) 390 (100%) Women 155 (29.03%) 46 (8.62%) 119 (22.28%) 17 (3.18%) 34 (6.37%) 17 (3.18%) 25 (4.68%) 29 (5.43%) 92 (17.23%) 534 (100%) Total 252 (27.27%) 72 (7.79%) 196 (21.21%) 46 (4.98%) 72 (7.79%) 68 (7.36%) 48 (5.20%) 29 (3.14%) 141 (15.26%) 924 (100%)

Table 2. Distribution of antipsychotic prescription in the studied population. Antipsychotic class Benzamides Butirrophenones Dibenzotiazepins Benzisoxazols Phenotiazines Antipsychotic drug Amisulpride L-sulpiride Tiapride Haloperidol Clozapine Clotiapine Olanzapine Risperidone Chlorpromazine L-Mepromazine Promazine Perfenazine Tioridazine Men 6 (1.54%) 24 (6.15%) 18 (4.62%) 88 (22.56%) 12 (3.08%) 30 (7.69%) 12 (3.08%) 24 (6.15%) 21 (5.38%) 27 (6.92%) 7 (1.79%) 49 (12.56%) 54 (13.86%) 18 (4.62%) 390 (100%) Women 15 (2.81%) 54 (10.11%) 15 (2.81%) 101 (18.91%) 6 (1.12%) 18 (3.37%) 15 (2.81%) 33 (6.18%) 3 (0.56%) 18 (3.37%) 29 (5.43%) 71 (13.30%) 126 (23.60%) 30 (5.62%) 534 (100%) Total 21 (2.27%) 78 (8.44%) 32 (3.57%) 189 (20.45%) 18 (1.95%) 48 (5.19%) 27 (2.92%) 57 (6.17%) 24 (2.60%) 45 (4.87%) 36 (3.90%) 120 (12.99%) 180 (19.48%) 48 (5.20%) 924 (100%)

Others* Total Others = Rare prescriptions ( 15)

Table 3. Number and percentage of cases of arterial hypotension (ortosthatic systolic blood pressure < 105 mmHg) in patients treated with antipsichotics in relation to the drug prescriptions. Antipsychotic class Benzamides Butirrophenone Dibenzotiazepins Benzisoxazols Phenotiazines Antipsychotic drug Amisulpride L-sulpiride Tiapride Haloperidol Clozapine Clotiapine Olanzapine Risperidone Chlorpromazine L-Mepromazine Promazine Perfenazine Tioridazine Men 0 (0.00%) 4 (16.67%) 3 (16.67%) 19 (21.59%) 3 (25.00%) 12 (40.00%) 1 (8.33%) 7 (29.17%) 13 (61.90%) 15 (55.55%) 3 (42.86%) 11 (22.45%) 15 (27.78%) 106/372 (28.49%) Women 3 (20.00%) 6 (11.11%) 3 (20%) 27 (26.73%) 2 (33.33%) 12 (80.00%) 8 (53.33%) 9 (27.27%) 2 (66.67%) 5 (27.28%) 12 (41.38%) 35 (49.29%) 66 (52.38%) 194/504 (37.69%) Total 3 (15.00%) 10 (12.82%) 6 (18.75%) 46 (24.34%) 4 (27.78%) 27 (56.25%) 9 (33.33%) 18 (28.07%) 15 (62.50%) 20 (44.44%) 20 (55.55%) 46 (38.33%) 81 (45%) 296/876 (33.79%)

Total

hypotension significantly more often than men (p=0.012) and in a more severe way (Mean men stand-

ing systolic blood pressure = 77.66 11.76 mmHg Vs. Mean women standing blood pressure = 72.73 12.11

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mmHg; p = 0.048). Only 20% of the women treated with L-sulpiride and Clotiapine, 41.67% of those treated with Promazine and 6.98% of those treated with Perfenazine required a specific medical treatment to tolerate symptoms caused by arterial hypotension. Anticholinergic symptoms have been also often lamented from patients taking antipsychotics, with overall significant differences among the drug classes (p = 0.041). One more time, comparing the single drug classes, anticholinergic symptoms were more frequent among subjects taking Phenotiazines (34.32%; p = 0.039) and significantly less frequent in those assuming Benzamides (15.27%; p = 0.042) (Table 4). Women developed arterial anticholinergic symptoms significantly more often than men (p = 0.039). 10.52%, 25.00%, 20%, 11.11%, 36.67% and 8.45% of subjects assuming respectively L-sulpiride, Clozapine, Olanzapine, LPromazine, Perfenazine and Tioridazine required a

specific medical treatment to tolerate anticholinergic symptoms. An extrapiramidal syndrome has been diagnosed in association with the 11.18% of the antipsychotic prescriptions without any significant difference among sexes (p = 0.098) (Table 5). 60%, 75% and 50% of those assuming respectively Haloperidol, L-Mepromazine and Promazine required a specific treatment to attenuate extrapiramidal signs.

DISCUSSION Compliance may be defined as the extent to which a patients behaviour conforms to medical advice. There are many factors that affect compliance, such as the cost of medications and the inadequacy of physicians explications to patients of the importance of continu-

Table 4. Number and percentage of cases of anticholinergic symptoms in patients treated with antipsychotics in relation to the drug prescriptions. Antipsychotic class Benzamides Butirrophenone Dibenzotiazepins Benzisoxazols Phenotiazines Antipsychotic drug Amisulpride L-sulpiride Tiapride Haloperidol Clozapine Clotiapine Olanzapine Risperidone Chlorpromazine L-Mepromazine Promazine Perfenazine Tioridazine Men 2 (33.33%) 5 (20.83%) 3 (16.17%) 22 (25.00%) 1 (8.33%) 7 (23.33%) 5 (41.67%) 5 (20.83%) 8 (67.26%) 6 (22.22%) 2 (28.57%) 8 (16.33%) 22 (40.74%) 97/372 (26.07%) Women 3 (20.00%) 14 (25.93%) 2 (20.00%) 29 (28.71%) 2 (33.33%) 5 (27.78%) 5 (33.33%) 7 (21.21%) 3 (100%) 12 (66.67%) 7 (24.14%) 22 (30.99%) 49 (38.89%) 161/504 (31.94%) Total 5 (23.81%) 19 (24.36%) 6 (18.75%) 51 (26.98%) 3 (16.17%) 12 (25.00%) 10 (37.04%) 11 (21.05%) 11 (45.83%) 18 (40.00%) 9 (25.00%) 30 (25.00%) 71 (39.44%) 258/876 (29.45%)

Total

Table 5. Number and percentage of cases of extrapiramidal disorders in patients treated with antipsychotics in relation to the drug prescriptions. Antipsychotic class Benzamides Butirrophenone Dibenzotiazepins Benzisoxazols Phenotiazines Antipsychotic drug Amisulpride L-sulpiride Tiapride Haloperidol Clozapine Clotiapine Olanzapine Risperidone Chlorpromazine L-Mepromazine Promazine Perfenazine Tioridazine Men 1 (16.67%) 1 (4.17%) 1 (5.55%) 21 (23.86%) 1 (8.33%) 0 (0%) 1 (8.33%) 1 (4.17%) 2 (9.52%) 2 (7.41%) 1 (14.29%) 2 (4.08%) 2 (3.70%) 36/372 (9.68%) Women 2 (13.33%) 2 (3.70%) 1 (6.67%) 25 (24.75%) 0 (0%) 1 (5.55%) 0 (0%) 2 (6.06%) 0 (0%) 1 (5.55%) 3 (10.34%) 2 (2.82%) 4 (3.17%) 42/504 (8.33%) Total 3 (14.29%) 6 (7.69%) 2 (6.25%) 45 (23.81%) 1 (5.55%) 1 (2.08%) 1 (3.70%) 3 (5.06%) 2 (0.8%) 12 (2.67%) 4 (11.11%) 4 (3.33%) 6 (3.33%) 98/876 (11.19%)

Total

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ously treating psychoses. A primary reason for poor compliance among patients receiving antipsychotic medications is ADEs, many of which are dose related (11), even if a further difficulty is that many antipsychotic drugs cause ADEs at therapeutic doses (12). Although physicians may often consider ADEs such as dizziness, low energy, or sedation as minor ADEs (even if they may greatly interfere with normal functioning), they cant ignore objective ADEs such as anticholinergic symptoms, extrapiramidal signs and arterial hypotension, which many patients find really unacceptable (13). Some risk factors for ADE that have been proposed include age (14), number of drug the patient is receiving (15) and factors that alter drug distribution or metabolism, such as renal or hepatic insufficiency, congestive heart failure, anaemia, and alcoholism (16). In our study the correlation between development of side effects and age seem to be confirmed as for anticholinergic symptoms and extrapiramidal syndrome, but not for orthostatic hypotension (Table 6): this effect could be related to the prevalence of hypertensive elderly found in our sample (17). It has also been suggested that a patient who is receiving specific drugs or drugs of a certain class may be prone to having an ADE; however, not much studies have been carried out on this subject on psychotics. The discrepancy between observed antipsychotic prescription and diagnosis formulated in a specialist setting could partially explain the high observed prevalence of ADE in our population. Moreover, even if no case of drug overdosing has been observed, the most part of patients took the highest dosage suggested for those drugs. Orthostatic hypotension has been observed in the 40% of those assuming Butirrophenones, 44.94% of those Phenotiazines, 62.36% of those Dibenzotiazepins, 31.58% of those Benzisoxazols and 14.39% of subjects treated with Benzamides. Anticholinergic symptoms have been reported by 26.98% of patients taking Butirrophenones, 34.32% of those Phenotiazines, 26.88% of those Dibenzotiazepins, 19.30% of

Table 6. Prevalence of the studied antipsychotic adverse effects in patients aged less and more of 65 years Age < 65 years Arterial hypotension Anticholynergic symptoms Extrapiramidal syndrome 363 (56.81%) 199 (31.14%) 77 (12.05%) Age 65 years 33 (29.20%) 59 (52.21%) 21 (18.58%)

those Benzisoxazols and 22.73% of subjects that assume Benzamides. Extrapiramidal disorders have been observed in the 23.81% of those assuming Butirrophenones, 6.91% of those Phenotiazines, 3.22% of those Dibenzotiazepins, 5.26% of those Benzisoxazols and 8.33% of subjects treated with Benzamides. We recognize that our study has several limitations which may hinder the generalizability of the results to other care settings. The main methodological problem was the simultaneous assumption of different psychiatric drugs by our patients (84.26% anxiolytics, 32.21% antidepressant drugs), that made difficult to discern the drug-effect relation: this is the reason because we have not considered the prevalence of sedation, the most common side effect of psychiatric drugs. For the same reason, some ADEs as anticholinergic syndrome and arterial hypotension could be over-estimated because of the concomitant use of these drugs. However, the prescription of anxiolytics and antidepressants is similar in the subjects assuming the different antipsychotics and this study reflects the real clinical world where physicians have to treat patients assuming at home simultaneously more than one psychodrug. Another issue is that an alternative approach not our focus in this study could be to take a specific patient group classified on the basis of the central acting drugs associated to antipsychotics; this way of addressing the problem may prove useful in future studies. Moreover, we could consider as ADEs only those effects who are instantaneously recognizable, while other important ADEs as weight increase were not objectivable, because based only on patient reported data. We had the same problem with sedation, an other main side effect of antopsychotic drugs, that has not been valuable, because the 79.33% of the considered subjects were treated with more than one central acting drugs with this common adverse effect at therapeutic doses. However, we think that the results of our studies could be considered interesting for two main reasons: they represent the population of patients taking antipsychotics out of specialist psychiatric clinics and because of the rarity of this kind of study carried out on free-living severe psychiatric patients. Our general conclusion is that in the studied population of free-living severe psychiatric patients a great part of them developed one or more adverse effect related to the assumption of antipsychotic drugs. According to literature data, new antipsychotics seem to be more safe than older neuroleptics, even if the letter are still widely prescribed at full dosage in patients who appear not to tolerate new antipsychotics.

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Even if benzamides are less often associated to ADEs, their employment in the treatment of psychoses is still not supported by a sufficient scientific evidence of efficacy (18). Among older neuroleptics, haloperidol seems to be globally the most safe, while among new antipsychotics risperidone appears to be less associated to ADEs. Because of the high prevalence of ADEs, physicians must consider more the quality-of-life issues in selecting antipsychotic drugs, psychiatric drugs association and drug doses.

8. 9. 10. 11.

12.

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