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The purpose of this study is to test the combined effect of melatonin and donepezil on improving sleep and behavior in children with Autism Spectrum Disorders. Melatonin is a natural neurohormone that helps regulate sleep and wake cycles. Donepezil is used to improve mental function for people with Alzheimer's disease. Children with Autism Spectrum Disorders are more likely to have problems sleeping than other children. This difficulty has been linked to daytime behavioral problems and family stress.
The goal of the present exploratory investigation is to see if there is a suggestion of a large additive or synergistic effect of melatonin and donepezil given together. Individually both medications improve sleep, but appear do so in different ways, with melatonin altering circadian rhythm and donepezil altering the characteristics of REM sleep. In this pilot investigation we will examine whether their combined effects on sleep lead to a large improvement in the behavior of children with ASD. Combined pharmacotherapy is very common in clinical practice, but is rarely studied in research (Comer et al. 2010). These two medications are both well tolerated and there is no negative drug interaction between the two. This investigation will use an RCT as well as a set of exploratory analyses to assess the combined effects of these two medications compared to placebo in terms of behavioral and sleep measures. In addition we will collect exploratory biomarkers (e.g., digit ratio, the ratio of the lengths different fingers as a measure of the balance of sex hormones during embryonic development) to relate to the various sleep and behavioral measures. A positive signal from this study may be used to guide a follow-up study with greater numbers of study subjects and statistical power.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group A | Other | Run-In Phase: Placebo. Phase 1 & Phase 2: Melatonin and donepezil (melatonin 3mg and donepezil 1.25-5mg based on age/weight each night) for 10 weeks Wash-Out Phase: no active or placebo medication. Note: Dosage of study drug varies with age/weight. Younger children (<12 years or < 80 lbs. weight start at a lower dose of donepezil (1.25 mg/night) and increase to 2.5 mg/night after one week. Older children (>= 12 years or >= 80 lbs weight) start at 3 mg donepezil and increase to 5 mg after one week. The dose of melatonin remains stable at 3 mg throughout for both groups. |
|
| Group B | Other | Run-In Phase: Placebo. Phase 1: Placebo. Phase 2: Melatonin and donepezil (melatonin 3mg and donepezil 1.25-5mg based on age/weight each night) or placebo for 5 weeks Wash-out Phase: no active or placebo medication. Note: Dosage of study drug varies with age/weight. Younger children (<12 years or < 80 lbs. weight start at a lower dose of donepezil (1.25 mg/night) and increase to 2.5 mg/night after one week. Older children (>= 12 years or >= 80 lbs weight) start at 3 mg donepezil and increase to 5 mg after one week. The dose of melatonin remains stable at 3 mg throughout for both groups. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Melatonin and Donepezil | Drug | 10 weeks of active study medication in Group A during Phase 1 & Phase 2. 5 weeks of active study medication in Group B during Phase 2. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Aberrant Behavior Checklist (ABC) Lethargy/Social Withdrawal Subscale | Subscale of the Aberrant Behavior Checklist (ABC). Subscales were derived by factor analysis (n=927). The checklist was first developed for use with severely mentally retarded individuals. More recently it has become widely used in research with children with autism. The ABC checklist is considered sensitive to drug effects. The Lethargy/Social Withdrawal subscale contains items such as: "Listless, sluggish, inactive" ; "Withdrawn, prefers solitary activities"; "Does not try to communicate by words or gestures"; "Shows few social reactions to others". The subscale consists of 16 items, each rated on a 4 point scale (0 = not at all, 3 = severe). Possible scores range from 0 to 48. Higher scores mean more lethargy and/or more social withdrawal. | Subscale rating was made by parent/caregiver every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks. |
| Measure | Description | Time Frame |
|---|---|---|
| Aberrant Behavior Checklist (ABC) Stereotypic Behavior Subscale. | Subscale of the Aberrant Behavior Checklist (ABC). Subscales were derived by factor analysis (n=927). The checklist was first developed for use with severely mentally retarded individuals. More recently it has become widely used in research with children with autism. The ABC Checklist is considered sensitive to drug effects. The Stereotypic Behavior subscale contains items such as: "Meaningless, recurring body movements" ; "Odd, bizarre in behavior"; "Waves, shakes the extremities repeatedly"; "Rocks body back and forth". The subscale consists of 7 items, each rated on a 4 point scale (0 = not at all, 3 = severe). Possible scores range from 0 to 21. Higher scores mean more stereotyped behavior. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jill Miller-Horn, MD, MS | Stony Brook University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stony Brook University | Stony Brook | New York | 11794 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21851192 | Background | Buckley AW, Sassower K, Rodriguez AJ, Jennison K, Wingert K, Buckley J, Thurm A, Sato S, Swedo S. An open label trial of donepezil for enhancement of rapid eye movement sleep in young children with autism spectrum disorders. J Child Adolesc Psychopharmacol. 2011 Aug;21(4):353-7. doi: 10.1089/cap.2010.0121. | |
| 22430453 | Background |
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Most patients were recruited from the clinical practice of the Principal Investigator. We also posted flyers in the hospital outpatient clinics and sent "Dear Physician" recruitment letters to other pediatric neurologists and psychologists in our catchment area.
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| ID | Title | Description |
|---|---|---|
| FG000 | Group A | Group A received an initial 5 week Run-In Period where other medications were withdrawn, and Placebo medication was given. Instructions for improving sleep hygiene were given during this phase. This Run-In Period was followed by Phase 1 (5 weeks) with active study medication (donepezil and melatonin) with dose based on subject age/weight. This was followed by Phase 2 (5 weeks) with continued study medication. At the conclusion of Phase 2, study medication was discontinued and a variable washout period (2-12 weeks) followed, ending with the next scheduled clinic visit with the Principal Investigator. |
| FG001 | Group B | Group B received an initial 5 week Run-In Period where other medications were withdrawn, and Placebo medication was given. Instructions for improving sleep hygiene were given during this phase. This Run-In Period was followed by Phase 1 (5 weeks)where Placebo medication was continued. This was followed by Phase 2 (5 weeks) with active study medication (donepezil and melatonin) with dose based on subject age/weight. At the conclusion of Phase 2, study medication was discontinued and a variable washout period (2-12 weeks) followed, ending with the next scheduled clinic visit with the Principal Investigator. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Run-In Phase (5 Weeks) |
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| Phase 1 (5 Weeks) |
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| Phase 2 (5 Weeks) |
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| Wash-Out Phase (2-12 Weeks) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Group A | Melatonin and donepezil (melatonin 3mg and donepezil 1.25-5mg based on age/weight each night) or placebo for 15 weeks Melatonin and Donepezil: The duration depends on group assignment. Placebo: The duration depends on group assignment. |
| BG001 | Group B |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Aberrant Behavior Checklist (ABC) Lethargy/Social Withdrawal Subscale | Subscale of the Aberrant Behavior Checklist (ABC). Subscales were derived by factor analysis (n=927). The checklist was first developed for use with severely mentally retarded individuals. More recently it has become widely used in research with children with autism. The ABC checklist is considered sensitive to drug effects. The Lethargy/Social Withdrawal subscale contains items such as: "Listless, sluggish, inactive" ; "Withdrawn, prefers solitary activities"; "Does not try to communicate by words or gestures"; "Shows few social reactions to others". The subscale consists of 16 items, each rated on a 4 point scale (0 = not at all, 3 = severe). Possible scores range from 0 to 48. Higher scores mean more lethargy and/or more social withdrawal. | Participants who completed the trial. | Posted | Median | Full Range | score on a scale | Subscale rating was made by parent/caregiver every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks. |
Overall study - Baseline thru Visit 4, a maximum of 27 weeks. This includes a 5 week run-in period with Placebo, 10 weeks of active study drug (Group A) vs. an additional 5 weeks of placebo followed by 5 weeks of active study drug (Group B), and 2-12 weeks of follow-up, ending with the next scheduled clinic visit with the Principal Investigator. There was no post-study follow-up.
The parent/guardian was queried about adverse events at each study visit. These events were discussed with the Principal Investigator and the study coordinator.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Group A | Melatonin and donepezil (melatonin 3mg and donepezil 1.25-5mg based on age/weight each night) or placebo for 15 weeks Melatonin and Donepezil: The duration depends on group assignment. Placebo: The duration depends on group assignment. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| difficulty falling asleep | Nervous system disorders | Non-systematic Assessment |
No statistical comparisons were undertaken due to the small sample size in the two groups. Study enrollment/completion proved insufficient to permit any conclusions to be drawn. Enrollment/completion was likely limited because of the study requirement that all prior sleep medications, including melatonin, be discontinued as a condition for study participation.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ruth A. Reinsel Ph.D., Clinical Research Associate II | Stony Brook Medicine Dept. of Neurology | (631) 638-2087 | ruth.reinsel@stonybrookmedicine.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 23, 2020 | Jul 25, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000067877 | Autism Spectrum Disorder |
| D012893 | Sleep Wake Disorders |
| ID | Term |
|---|---|
| D002659 | Child Development Disorders, Pervasive |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D008550 | Melatonin |
| D000077265 | Donepezil |
| ID | Term |
|---|---|
| D014363 | Tryptamines |
| D007211 | Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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The study is conducted in 2 main phases, supplemented by an initial Run-In Phase and a Final Wash-Out Phase.
The Run-In phase (5 weeks) - All subjects receive Placebo and instructions about how to improve sleep hygiene. This allows us to evaluate a) response to placebo and b) the effect of improved sleep hygiene in the absence of study drug in both groups.
Phase 1 (5 weeks) - Group A receives study drug (donepezil & melatonin). Group B receives Placebo. Here we assess the benefit of study drug vs. Placebo in a parallel group design.
Phase 2 (5 weeks) - Both groups receive study drug (donepezil & melatonin). Here we assess the effect of switching from Placebo to study drug in Group B, and the effect of an extra 5 weeks of study drug in Group A.
Wash-Out Phase (variable length, 2-12 weeks) - study drug is discontinued.
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| Placebo | Other | For both groups: 5 weeks of Placebo in the Run-In Phase. For Group B: an addition 5 weeks of Placebo in Phase 1. |
|
| Subscale rating was made by parent/caregiver every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks. |
| Sleep Duration (Hours) | A brief seven item questionnaire adapted from the Children's Sleep Habits Questionnaire (CSHQ). This parental questionnaire assesses sleep behaviors in children. It has been validated in children with ASD, correlates with polysomnographic recordings, and has been used successfully in previous studies of melatonin with such children. The CSHQ items chosen for this study come from the subscales found to be most often disturbed in children with autism. | Rating was made by parent/caregiver every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks. |
| Clinical Global Impressions Scale, Clinician Impression of Global Improvement | Measured by the Clinical Global Impressions Scale. The Clinician Impression of Global Improvement is a single item rated as follows: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse. Thus, higher scores indicate a change for the worse. Note: This measure was not evaluated at Baseline. | Rating was made by clinician every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks. |
| Clinical Global Impressions Scale, Parent Reported Global Improvement | Parent Impression of Global Improvement is a single item rated as follows: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse. Thus, higher scores indicate a change for the worse. Note: This measure was not evaluated at Baseline. | Rating was made by parent every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks. |
| Cidav Z, Marcus SC, Mandell DS. Implications of childhood autism for parental employment and earnings. Pediatrics. 2012 Apr;129(4):617-23. doi: 10.1542/peds.2011-2700. Epub 2012 Mar 19. |
| 17252887 | Background | Malow BA, Marzec ML, McGrew SG, Wang L, Henderson LM, Stone WL. Characterizing sleep in children with autism spectrum disorders: a multidimensional approach. Sleep. 2006 Dec;29(12):1563-71. doi: 10.1093/sleep/29.12.1563. |
| 19398354 | Background | Richdale AL, Schreck KA. Sleep problems in autism spectrum disorders: prevalence, nature, & possible biopsychosocial aetiologies. Sleep Med Rev. 2009 Dec;13(6):403-11. doi: 10.1016/j.smrv.2009.02.003. Epub 2009 Apr 24. |
| 22522199 | Background | Taylor MA, Schreck KA, Mulick JA. Sleep disruption as a correlate to cognitive and adaptive behavior problems in autism spectrum disorders. Res Dev Disabil. 2012 Sep-Oct;33(5):1408-17. doi: 10.1016/j.ridd.2012.03.013. Epub 2012 Apr 21. |
| 18078449 | Background | Wasdell MB, Jan JE, Bomben MM, Freeman RD, Rietveld WJ, Tai J, Hamilton D, Weiss MD. A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res. 2008 Jan;44(1):57-64. doi: 10.1111/j.1600-079X.2007.00528.x. |
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Melatonin and donepezil (melatonin 3mg and donepezil 1.25-5mg based on age/weight each night) or placebo for 15 weeks Melatonin and Donepezil: The duration depends on group assignment. Placebo: The duration depends on group assignment. |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| ABC Lethargy/Social Withdrawal | Subscale of the Aberrant Behavior Checklist (ABC). The checklist is widely used in research with children with autism. It is considered sensitive to drug effects. The Lethargy/Social Withdrawal subscale contains items such as: "Listless, sluggish, inactive" ; "Withdrawn, prefers solitary activities"; "Does not try to communicate by words or gestures"; "Shows few social reactions to others". The subscale consists of 16 items, each rated on a 4 point scale (0 = not at all, 3 = severe). Possible scores range from 0 to 48. Higher scores mean more lethargy and/or more social withdrawal. | Median | Full Range | units on a scale |
|
| ABC Stereotypic Behavior | Subscale of the ABC Checklist, which is considered sensitive to drug effects. The Stereotypic Behavior subscale contains items such as: "Meaningless, recurring body movements" ; "Odd, bizarre in behavior"; "Waves, shakes the extremities repeatedly"; "Rocks body back and forth". The subscale consists of 7 items, each rated on a 4 point scale (0 = not at all, 3 = severe). Possible scores range from 0 to 21. Higher scores mean more stereotyped behavior. | Median | Full Range | units on a scale |
|
| Sleep Duration (hours) | As measured by the Child's Sleep Habits Questionnaire (CSHQ). | Median | Full Range | hours |
|
| ID |
|---|
| Title |
|---|
| Description |
|---|
| OG000 | Group A | Melatonin and donepezil (melatonin 3mg and donepezil 1.25-5mg based on age/weight each night) or placebo for 15 weeks Melatonin and Donepezil: The duration depends on group assignment. Placebo: The duration depends on group assignment. |
| OG001 | Group B | Melatonin and donepezil (melatonin 3mg and donepezil 1.25-5mg based on age/weight each night) or placebo for 15 weeks Melatonin and Donepezil: The duration depends on group assignment. Placebo: The duration depends on group assignment. |
|
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| Secondary | Aberrant Behavior Checklist (ABC) Stereotypic Behavior Subscale. | Subscale of the Aberrant Behavior Checklist (ABC). Subscales were derived by factor analysis (n=927). The checklist was first developed for use with severely mentally retarded individuals. More recently it has become widely used in research with children with autism. The ABC Checklist is considered sensitive to drug effects. The Stereotypic Behavior subscale contains items such as: "Meaningless, recurring body movements" ; "Odd, bizarre in behavior"; "Waves, shakes the extremities repeatedly"; "Rocks body back and forth". The subscale consists of 7 items, each rated on a 4 point scale (0 = not at all, 3 = severe). Possible scores range from 0 to 21. Higher scores mean more stereotyped behavior. | Participants who completed the trial. | Posted | Median | Full Range | score on a scale | Subscale rating was made by parent/caregiver every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks. |
|
|
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| Secondary | Sleep Duration (Hours) | A brief seven item questionnaire adapted from the Children's Sleep Habits Questionnaire (CSHQ). This parental questionnaire assesses sleep behaviors in children. It has been validated in children with ASD, correlates with polysomnographic recordings, and has been used successfully in previous studies of melatonin with such children. The CSHQ items chosen for this study come from the subscales found to be most often disturbed in children with autism. | Participants who completed the trial. | Posted | Median | Full Range | hours | Rating was made by parent/caregiver every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks. |
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| Secondary | Clinical Global Impressions Scale, Clinician Impression of Global Improvement | Measured by the Clinical Global Impressions Scale. The Clinician Impression of Global Improvement is a single item rated as follows: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse. Thus, higher scores indicate a change for the worse. Note: This measure was not evaluated at Baseline. | Participants who completed the trial. | Posted | Median | Full Range | units on a scale, where 4=no change | Rating was made by clinician every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks. |
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| Secondary | Clinical Global Impressions Scale, Parent Reported Global Improvement | Parent Impression of Global Improvement is a single item rated as follows: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse. Thus, higher scores indicate a change for the worse. Note: This measure was not evaluated at Baseline. | Participants who completed the trial. | Posted | Median | Full Range | units on a scale, where 4=no change | Rating was made by parent every 5 weeks for a total of 5 times. Due to small N, only the endpoint of the study is reported here. Study endpoint (Visit 5) was after at least 18 wks, including 2 wks of washout, up to a maximum of 27 wks. |
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| 0 |
| 4 |
| 0 |
| 4 |
| 2 |
| 4 |
| EG001 | Group B | Melatonin and donepezil (melatonin 3mg and donepezil 1.25-5mg based on age/weight each night) or placebo for 15 weeks Melatonin and Donepezil: The duration depends on group assignment. Placebo: The duration depends on group assignment. | 0 | 8 | 0 | 8 | 2 | 8 |
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| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006571 | Heterocyclic Compounds |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D007189 | Indans |
| D007192 | Indenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D010880 | Piperidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D011083 | Polycyclic Compounds |