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Clozapine (Clozaril) is an antipsychotic agent with a risk of agranulocytosis of 1 to 2 percent. Its manufacturer requires that the white-cell count
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Drug treatment of schizophrenia has undergone significant changes since 1990 with the introduction of clozapine, the first of the second-generation “atypical”
The bad news was that Clozaril causes agranulocytosis in 2 per cent of all cases - an alarmingly high level for such a serious reaction. With agranulocytosis, the
Use in those with a history of clozapine-induced agranulocytosis or severe granulocytopenia; use with other agents known to suppress bone marrow function .
Only your doctor can determine if it is safe for you to continue taking Clozaril. The most feared side effect is agranulocytosis, a dangerous drop in the number of a
Major histocompatibility complex associations with clozapine-induced agranulocytosis. The USA experience. Drug Saf 1992; 7 Suppl 1:7.
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Clozapine, considered to be an effective treatment for refractory schizophrenia, carries a significant risk of agranulocytosis, a rare but
DrugCite - Agranulocytosis associated with Clozapine, Clozaril, Cyclophosphamide, Plavix, Mabthera, And Seroquel.
Given the relative protection from agranulocytosis when clozapine is discontinued before moderate leukopenia worsens, the principle question
Clozapine carries a black box warning for drug induced agranulocytosis. Agranulocytosis occurs in about 1% of patients who take clozapine during the first 6
Case report of agranulocytosis with olanzapine after clozapine. It is well known that clozapine can induced leukopenia, even agranulocytosis, which is
Clozaril prescribing, clozaril forum, clozaril agranulocytosis, clozaril information and clozaril homelife. Clozaril patient information leaflet,
Summary and Introduction: Although clozapine appears to be an effective drug for schizophrenia, its use is limited due to risk of agranulocytosis.
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Even though it does not produce some of the disturbing side effects of other antipsychotic medications, Clozaril may cause agranulocytosis,
A study of drug interactions between Diazepam, Temazepam, Clozaril, Lithium Count Decreased, Psychotic Disorder, Neutropenia, Insomnia, Agranulocytosis
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Patients who are to receive CLOZARIL should be warned about the significant risk of developing agranulocytosis. Patients should be advised to report
AGRANULOCYTOSIS. BECAUSE OF A SIGNIFICANT RISK OF AGRANULOCYTOSIS, A. POTENTIALLY LIFE-THREATENING ADVERSE EVENT, CLOZARIL®
Agranulocytosis: The most dangerous potential side effect of clozapine is agranulocytosis, a potentially life-threatening blood disorder in which the white blood
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Clozapine was introduced in Europe in 1975.As a result of reports from Finland, where 16 patients out of 2260 exposed (0.7%) developed agranulocytosis and 8
risk of agranulocytosis was estimated to be between 1% and 2%. Current estimates from the Clozaril National Reg- istry7 suggest that the incidence of risk is as
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Agranulocytosis, defined as an ANC of less than 500/mm 3 , has been estimated to occur in association with CLOZARIL ® (clozapine) use at a
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CLOZARIL should not be used simultaneously with other agents having a well- known potential to cause agranulocytosis or otherwise suppress bone marrow
With proper WBC/ANC monitoring and reporting, Clozaril-induced agranulocytosis can be reversible, if detected early. Prescribers and pharmacies must be
adverse effects of clozapine, including agranulocytosis, seizures, sedation, delirium, obsessive-compulsive symptoms, hypotension, tachycardia, weight gain ,
schizophrenia not treated with clozapine is much higher than the mortality from agranulocytosis in the patients treated with clozapine2,3. With periodic blood
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The natural history of clozapine-induced agranulocytosis has for the mechanism by which clozapine produces agranulocytosis. In this instance the evidence
The UK Clozaril Patient Monitoring Service (CPMS) was developed in order to manage the risk of agranulocytosis associated with clozapine. It is available 24
CLOZARIL is contraindicated in patients with myeloproliterative disorders, or a history of. CLOZARIL-induced agranulocytosis or severe granulocytopenia.
The acquistare sconto clozaril mechanism of CLOZARIL-induced agranulocytosis is nonetheless, it is possible that causative factors may
Clozapine often increases weight. There is a FDA warning that it (infrequently) causes life-threatening agranulocytosis. It sometimes causes
Clozapine can cause reversible neutropenia, which may progress to a potentially fatal agranulocytosis. Other potentially serious adverse effects of clozapine
clozapine is an atypical antipsychotic with superior efficacy in the treatment of refractory schizophrenia. but it can cause agranulocytosis, which occurs in one to
Clozapine does, however, have a number of safety issues unique to it amongst the currently available antipsychotic drugs. Safety issues. 1. Agranulocytosis The
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BECAUSE OF A SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFE -THREATENING ADVERSE EVENT, CLOZARIL ® (CLOZAPINE)
clinical trials, CLOZARIL was associated with a 1% to 2% incidence of agranulocytosis, a potentially fatal blood disorder, which, if caught early, can be reversed.
Clozapine (Includes Clozaril) ↔ Agranulocytosis. Severe Potential Hazard, High plausibility. Applies to: Neutropenia. The use of
What is AGRANULOCYTOSIS INDUCED BY CLOZAPINE? Mr What will tell you the definition or meaning of AGRANULOCYTOSIS INDUCED BY CLOZAPINE.
Agranulocytosis. Background. Agranulocytosis, defined as an ANC of less than 500/mm3, has been estimated to occur in association with CLOZARIL(clozapine)
Because of the risk of agranulocytosis and granulocytopenia associated with the use of clozapine, Azur Pharma acquired the FazaClo® Patient Registry.
BECAUSE OF A SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFE-THREATENING ADVERSE EVENT, CLOZARIL®
After drug was administered, patient experienced the following problems/side effects: agranulocytosis, fatigue, insomnia, vomiting, weight decreased. Clozaril
One to two percent of patients who take clozapine will develop a condition called agranulocytosis, in which the white blood cell count drops dramatically.
Long-term patient monitoring for clozapine-induced agranulocytosis and neutropenia in Korea: when is it safe to discontinue CPMS? (PMID:16933201). Abstract
(clozapine). 25mgand 100mg Tablets. Clozaril® can cause agranulocytosis. Its use should be limited to patients: • with schizophrenia who are non-responsive to
Because of a significant risk of agranulocytosis, a potentially life-threatening adverse effect, clozapine should be reserved for the use in the treatment of severely
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BACKGROUND Clozapine can cause reversible agranulocytosis and neutropenia. This study documents the occurrence of blood dyscrasias and identifies
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Because of a significant risk of agranulocytosis, a potentially life-threatening adverse event, Clozaril (Clozapine) should be reserved for use in (1) the treatment
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10-18-10, 01:29 PM. Clozaril is an EXTREMELY POWERFUL DRUG and can, in very rare cases, cause agranulocytosis, which is a rapid drop
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Although clozapine causes agranulocytosis sig- nificantly more frequently than other antipsychotic drugs, with required hematological monitoring of the white
clozapine-induced agranulocytosis and to detect leukopenic events among patients taking clozapine. In other countries (e.g. in Europe), restrictions have been
When deaths were reported from Clozaril-induced agranulocytosis, the drug was withdrawn from general use. Clozaril was not made available in the United
In clinical trials conducted prior to approval of Clozaril in the U.S., the use of Clozaril was associated with a 1-2% incidence of agranulocytosis, a potentially fatal
The Clozaril National Registry (CNR) was created to help protect patients from developing potentially fatal agranulocytosis secondary to treatment with the
nia.1,2 Clozapine is, however, associated with an in? creased risk of agranulocytosis, an acute and potentially life-threatening condition in which the number of
Myeloproliferative disorders. Uncontrolled epilepsy. Severe or history of clozapine-induced agranulocytosis, or granulocytopenia. Paralytic ileus. Severe CNS
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Free radical scavenging enzyme activity and related trace metals in clozapine- induced agranulocytosis: a pilot study. J Clin Psychopharmacol. 1995 Oct Linday
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In patients taking Clozaril, agranulocytosis is less than 1 %. It is a decrease in white blood cells. It also causes cardiac problems(myocarditis).
It is only prescribed in resistant schizophrenia. Main problem associated with Clozaril is Agranulocytosis or reduction in white cells in blood.
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Agranulocytosis, defined as an ANC of less than 500/mm3, has been estimated to occur in association with CLOZARIL® (clozapine) use at a
Fazaclo ODT for patients. Patients who are to receive CLOZARIL should be warned about the significant risk of developing agranulocytosis. Patients should be
“treat- ment-resistant” patients. Despite its advantages, the use of clozapine has been hampered due to a 1-2% incidence of drug- induced agranulocytosis. The
(1992) Abt et al. Drug safety an international journal of medical toxicology and drug experience. This paper describes a statistical analysis of the simultaneous
Appendix 5: Narratives of fatal outcomes associated with Clozaril use and the development of agranulocytosis. Appendix 6:Algorithm for criteria for changes in
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Pharmacodynamic -Related Interactions. The mechanism of CLOZARIL-induced agranulocytosis is unknown; nonetheless, the possibility that
Approximately one percent of patients who take Clozaril develop a condition called agranulocytosis, in which white blood cells drop dramatically, causing
(1991) Fischer et al. Molecular Pharmacology. Read by researchers in: 100% Medicine. The use of clozapine, a unique antipsychotic drug, has been restricted
Alvir JM, Liebermann JA, Saffermann AZ, Schwimmer JL, Schaaf JA: Clozapine- induced agranulocytosis. Incidence and risk factors in the United States.
Clozapine can cause life threatening agranulocytosis in 0.8 percent of the patients veloped Clozapine induced agranulocytosis which was not reported to the
A serious adverse reaction which may occur with Clozaril therapy is granulocytopenia/ agranulocytosis. In view of this risk the use of Clozaril should be limited to
Carbolith and Clozapine interaction - Serious agranulocytosis; Carbolith and Clozaril interaction - Serious agranulocytosis; Cibalith-S and
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Agranulocytosis induced by clozapine is thought to be mediated either through Evidence that clozapine-induced agranulocytosis is immune-mediated comes
key words — clozapine; agranulocytosis; neutropenia. INTRODUCTION. It is reported that the rate of agranulocytosis induced by the use of
Approximately 3% of patients treated with clozapine will develop neutropenia ( around 1% will progress to agranulocytosis) which makes them vulnerable to
When deaths were reported from Clozaril-induced agranulocytosis, the medication was withdrawn from gen- eral use. Clozaril was not made available in the
cell (WBC) count monitoring frequency on the rate of clozapine-associated agranulocytosis using data from Clozaril National Registry (CNR). In addition, the
of troubling side effects, including the risk of agranulocytosis and metabolic
Clozapine (Clozaril®, Clopine®) is an atypical antipsychotic that is effective for treatment-resistant schizophrenia. It causes agranulocytosis in up to 1% of
Agranulocytosis: The most dangerous potential side effect of clozapine is agranulocytosis, a potentially life-threatening blood disorder in which
Patient must be registered due to risk of agranulocytosis, 800-507-8334 Teva Clozapine Registry. Register a patient with Teva Clozapine Registry: Online form
The primary harmful side effect of Clozaril, an antipsychotic agent, is agranulocytosis. An established computerized database was modified and
Clozaril may lead to agranulocytosis. Agranulocytosis is a very serious blood condition when the body fails to produce enough white blood
Contraindications, Warnings, and Precautions: Clozaril may cause three very serious medical conditions, including agranulocytosis, seizures and orthostatic
It has been reported that Neutropenia or agranulocytosis with myeloid hypocellularity develops in a small subset (1 to 5%) of Clozapine-treated patients 14.
The test is intended to be used as an adjunct to existing clinical information to aid in determining the risk of developing clozapine-induced agranulocytosis, and
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Because of the significant risk of agranulocytosis and seizure associated with its use, CLOZARIL should be used only in patients who have failed to respond
what is agranulocytosis? learn about the definition of agranulocytosis. the greatest risk of agranulocytosis are clozaril (clozapine) and tegretol ( carbamazepine) .
The most feared side effect of Clozaril is agranulocytosis, a dangerous drop in the number of a certain kind of white blood cell. Symptoms
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AGRANULOCYTOSIS. BECAUSE OF A SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY. LIFE-THREATENING ADVERSE EVENT, CLOZARIL®
The approved labeling for Clozaril states: "Because of the significant risk of agranulocytosis and seizure associated with its use, Clozaril should be used only in
[1][2] The FDA also requires clozapine to carry five black box warnings for agranulocytosis, seizures, myocarditis, for "other adverse
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However, clozapine was temporarily withdrawn in the 1970s following fatal cases of agranulocytosis. Patients treated with clozapine must have regular blood
This paper traces the histor y of clozapine's discover y and development in Europe, its part in the 1975 Finnish agranulocytosis scare, and its subsequent volatile
At least 6000 patients now receive clozapine, and no deaths from agranulocytosis have occurred under the CPMS. A proposal by the US Department of Veteran
Background: Therapy of schizophrenia with clozapine is associated with the unpredictable development of severe neutropenia and agranulocytosis in 1% to 2%
Clozaril has at least two serious side effects: 1 out of 20 patients suffers from convulsive seizures, and 1 or 2 out of 100 suffer from agranulocytosis.
History of a drop in white blood cell count (agranulocytosis/granulocytopenia) caused by clozapine or other medicines (except cancer
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agranulocytosis in subjects receiving clozapine. Method Data from l2 760 subjects registered to receive clozapine from january I990 to April l997 were analysed.
Patients with a history of drug-induced agranulocytosis or severe granulocytopenia or myeloproliferative disorders. Clozapine should not be
Even though it does not produce some of the disturbing side effects of other antipsychotic medications, Clozaril may cause agranulocytosis, a potentially lethal
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To study the adverse reactions other than the well known agranulocytosis of clozapine use in. Ireland, spread over a decade. The long duration of the study can
To the Editor: Clozapine can cause life-threatening agranulocytosis in up to 0.8% of patients treated with this medication +(1). This limits the
adverse reaction, clozapine-induced agranulocytosis (CA), is sented in the group of patients, 9 of 66 (14%), when com- associated with different HLA types and
Due to the significant risk of agranulocytosis and seizure associated with its use, clozapine should be limited to treatment-resistant schizophrenic patients who
In addition to agranulocytosis, Clozaril also lowers one's blood pressure. In my case, I had to stop taking a hypertension medication because my blood pressure
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NEUTROPENIA AND AGRANULOCYTOSIS. Clozapine (Clopine®, Clozaril®) has drastically improved the lives of many patients with resistant schizophrenia,
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More recent data from the Clozaril. National Registry in the U.S. has also shown that the incidence of agranulocytosis on clozapine, and fatality resulting from it
Acetazolamide, propoxyphene, sodium bicarbonate, or thiazide diuretics (eg, hydrochlorothiazide) bec.
Unfortunately, it has been difficult to study the long term safety of clozapine use, though one study of 172 children found that the risk of agranulocytosis was
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Clozaril may cause agranulocytosis, a potentially lethal disorder of the white blood cells, which is why individuals prescribed this medication should have blood
Because of the significant risk of agranulocytosis and seizure associated with its use, CLOZARIL should be used only in patients who have
Major ones are Agranulocytosis (bone marrow toxicity) and Myocarditis ( inflammation of the heart). More. Dr. Douglas Severance answered: Clozapine is an
Because of drug-induced agranulocytosis, it is dispensed only under rigid guidelines. Overdose has been rare. Presented here is a case of clozapine overdose
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Patients taking clozapine are at increased risk of potentially life-threatening agranulocytosis. The labeling has required white blood cell
Clozapine is usually used as a last resort in patients who have not responded to other anti-psychotic treatments due to its danger of causing agranulocytosis as
Myocarditis with antipsychotics: recent cases with clozapine [Clozaril) .. .. 9. Drug-induced neutropenia and agranulocytosis 10. (Dysport) - severe
While drug interactions, benign ethnic neutropenia, and medical comorbidity can often contribute to clozapine-induced agranulocytosis, most
We had reported that the drug adverse reaction, clozapine-induced agranulocytosis (CA), is associated with different HLA types and HSP70
(clozapine), the physician should be thoroughly familiar with the details of this prescribing information. BOXED WARNING. 1. AGRANULOCYTOSIS. BECAUSE
Clozapine can cause neutropenia and agranulocytosis. In the UK, the Clozaril Patient Monitoring System (CPMS) was set up to ensure patients receive regular
AGRANULOCYTOSIS. BECAUSE OF A SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFE-THREATENING ADVERSE EVENT , CLOZARIL®
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Agranulocytosis occurs in about 1% of patients taking clozapine.3,4 Neutropenia is seen in about 3%.4 The risk of both agranulocytosis and
The FDA requires blood testing for patients taking clozapine. The FDA also requires clozapine to carry five black box warnings for agranulocytosis, seizures,
agranulocytosis and olanzapine. Clozapine (sold as Clozaril, Azaleptin, Leponex , Fazaclo, Froidir ; Denzapine, Zaponex in the UK; Klozapol in
concerns about agranulocytosis, clozapine was introduced to the United States in 1990 for use in patients suffering from treatment-refractory schizophrenia.
Clozapine neutropenia and clozapine agranulocytosis seem to be 2 different conditons because the risk factors are different. Agranulocytosis occurs in about
About one or two people out of every 100 who take CLOZARIL will develop agranulocytosis. In this condition, the body 's ability to make white blood cells can be
Clozaril can cause agranulocytosis. This is a condition where the number of white blood cells are reduced. These cells are needed to fight infections. If you have
Neutropenia and potentially fatal agranulocytosis reported. must be registered with the Clozaril Patient Monitoring Service—takes several days to do this
Myocarditis seems to occur within 6 to 8 weeks of starting clozapine. Due to risk of agranulocytosis clozaril should not be combined with Carbamazepine.
Patients who are to receive CLOZARIL should be warned about the significant risk of developing agranulocytosis. They should be informed that weekly blood
One to two percent of patients who take clozaril will develop a condition called agranulocytosis, in which the white blood cell count drops
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Approximately one percent of patients who take clozapine develop a condition called agranulocytosis, in which white blood cells drop dramatically, causing
Does Clozaril cause Agranulocytosis? If so, who have it, when it happens and how? Find it out from a study of 967 Clozaril users.
study are: (1) to find out the incidence of clozapine induced neutropenia or agranulocytosis on Thai patients, (2) to compare results with other countries, and (3)
Special Precautions, Clozaril can cause agranulocytosis. Its use should be limited to treatment-resistant schizophrenic patients who have normal leukocyte
Clozapine is a new type of antipsychotic drug that is used to treat The drug can cause a very serious side effect, agranulocytosis (a large
Because of concern for the side effect of agranulocytosis (see side effects), clozapine should be reserved for patients who have failed to respond to other
Note: Do not initiate in patients with 1) history of myeloproliferative disorder or 2) clozapine-induced agranulocytosis or granulocytopenia. Weekly for 6 months
Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL,
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Clozapine-induced agranulocytosis (CiA) is a potentially life-threatening pharmacological adverse drug reaction, which limits a broader application of this highly
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To the editors: Clozapine (Clozaril), a dibenzodiazepine neuroleptic, is associated with a 1% to 2% incidence of drug-induced agranulocytosis.
Original Article from The New England Journal of Medicine — Clozapine-Induced Agranulocytosis -- Incidence and Risk Factors in the United
Clozaril is contraindicated in patients with paralytic ileus. In clinical trials, Clozaril was associated with a 1% to 2% incidence of agranulocytosis, a potentially
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mandate was to evaluate the impact of the current Clozaril monitoring system on the rate of agranulocytosis and consider whether reductions in monitoring
Although the mechanism of clozapine-induced agranulocytosis is unknown, it is possible that causative factors may interact synergistically to increase the risk
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Although clozapine was developed about 30 years ago and the initial results were promising, the development of several fatal cases of agranulocytosis resulted
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The most serious of clozapine's side effects is agranulocytosis. Other important side-effects include orthostatic hypotension and tachycardia, sedation, seizures,
Clozapine is of proven efficacy in treatment-resistant schizophrenia. Concerns regarding the possibility of neutropenia and agranulocytosis
Incidence of agranulocytosis in Europe prior to monitoring: 1 to 2% per year# Incidence of agranulocytosis during Clozaril clinical trials
Neutropenia and Agranulocytosis in Patients Receiving. Clozapine in the UK and Ireland. KARENATKIN,FRANCISKENDALLDUNCANGOULD
Do I always need to call the Clozaril National Registry to request registration and of agranulocytosis and whether further monitoring frequency reductions were
The mechanism for clozapine-induced agranulocytosis is unclear and may be the result of direct toxicity or an immune response. Predisposing factors for
Clozapine therapy requires special monitoring and surveillance requirements due to its potential for causing fatal agranulocytosis in ~1% of exposed patients
Carbamazepine may induce the metabolism of clozapine. Both carbamazepine and clozapine have been reported to induce agranulocytosis, although the exact
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The use of clozapine, a unique antipsychotic drug, has been restricted due to a 1- 2% incidence of drug-induced agranulocytosis. Metabolic activation of
Clozaril is associated with a condition which hinders the production of white blood cells, called agranulocytosis. Geodon, Seroquel, and Risperdal may be viable
CLOZARIL is contraindicated in patients with myeloprolilerative disorders, or a history of. CLOZARIL-induced agranulocytosis or severe granulocytopenia.
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clozapine should be introduced at the earliest opportunity''.2. A severe adverse effect of clozapine that limits its more widespread use is agranulocytosis.
Agranulocytosis for Customer Taking Clozapine (Clozaril) the client, The Teaching Points below outlines information for clients who take clozapine.
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Clozapine should not be used simultaneously with other agents having a well- known potential to cause agranulocytosis or otherwise suppress bone marrow
CLOZARIL is contraindicated in patients with myeloproliferative disorders, or a history of. CLOZARIL-induced agranulocytosis or severe granulocytopenia.
Every patient taking clozapine undergoes rigorous blood monitoring on a regular basis, but despite this vigilance a death from agranulocytosis has occurred in
Because of life threatening agranulocytosis (reduction of type of white cells called granulocytes in blood) Clozapine was withdrawn from the
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BECAUSE OF A SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFE-THREATENING ADVERSE EVENT, CLOZARIL® (CLOZAPINE) SHOULD
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clozapine has been limited because of infrequent but serious side effects, the most notable being agranulocytosis. In recent years, however, mandatory blood
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Clozapine was developed by Sandoz in 1961 , and introduced in Europe ten years later. In 1975 after reports of agranulocytosis leading to death in some
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Clozapine is generally considered the most toxic of the antipsychotic drugs. It causes agranulocytosis, a life-threatening depletion of white blood cells, in 1-2% of
Some investigators have suggested that the presence of HLA-B38 may predispose certain patients to the development of agranulocytosis during clozapine
Clozapine was developed by Sandoz in 1961, and introduced in Europe ten years later. In 1975, after reports of agranulocytosis leading to death in some
According to its label, “The mechanism of Clozaril-induced agranulocytosis is unknown; nonetheless, the possibility that causative factors may interact
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However, the presence of fever during clozapine therapy does not appear to predict agranulocytosis, NMS, or an increased rate of drug
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The clozapine protocol [1], whose main aim is to 'minimise the risk of any patients on Clozaril developing agranulocytosis' (p.3), unequivocally commands (p.17,
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Clozaril is not a cure. Even though it does not produce some of the disturbing side effects of other antipsychotic medications, Clozaril may cause agranulocytosis
The FDA requires weekly blood testing for patients taking clozapine.[1] The FDA also requires clozapine to carry five black box warnings for agranulocytosis,
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Agranulocytosis, defined as an ANC of less than 500/mm³, has been estimated to occur in association with CLOZARIL® (clozapine) use at a cumulative
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Objective: Define the incidence of clozapine-induced leukopenia, neutropenia, and agranulocytosis in patients with schizophrenia at Srinagarind Hospital.
Patients taking clozapine are at increased risk of potentially life-threatening agranulocytosis. The labeling has required white blood cell monitoring for these
Clozapine (Clozaril®) for GPs and care co-ordinators . Agranulocytosis/ neutropenia (patient may report symptoms of infection e.g, flu-like symptoms, sore
Background History: Although clozapine appears to be an effective drug for schizophrenia, its use is limited due to risk of agranulocytosis.
The goal of the program is to prevent clozapine induced agranulocytosis. This is accomplished by the early detection of leukopenia or granulocytopenia based
Clozapine was developed by Sandoz in 1961, and introduced in Europe ten years later. In 1975, after reports of agranulocytosis leading to
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