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| ID | Type | Description | Link |
|---|---|---|---|
| IIR | Other Grant/Funding Number | Bayer Pharmaceutical |
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| Name | Class |
|---|---|
| University of Pennsylvania | OTHER |
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This double-blind pilot study will evaluate the anti-inflammatory and analgesic effects of an over-the-counter (OTC) regimen of naproxen sodium versus acetaminophen in patients receiving one or two (adjacent) dental implants. It will also confirm that naproxen sodium in the OTC dosage range is a good alternative to immediate-release opioid formulations, which are subject to misuse, abuse and diversion in this patient population.
Placement of dental implants is a frequently performed outpatient surgical procedure, with United States dentists currently placing implants in approximately 500,000 patients per year.This procedure has become the gold standard for replacing missing teeth due to its high level of predictability and patient acceptance, with long-term success rates greater than 95%. Thus, the number of patients opting for this procedure over dentures and fixed bridges continues to increase. In the period between 1999 and 2000 only 0.7% of the USA population had missing teeth with implants in contrast to 5.7% between 2015 and 2016 It is estimated that by 2026, if the current pace of dental implant placement continues, approximately 17% of the population will have dental implants.
Dental implant surgery involves the incision of gingival tissue to expose the underlying bone, followed by the creation of a precise bony cavity where the implant will be placed using a specialized surgical drill, and lastly the screwing of the implant into bone using a specialized handpiece Thus, it is not surprising that post-surgical pain is a common sequela following dental implant surgery. Patients often experience post-surgical pain for several days after the placement of one to three dental implants, but at a pain intensity level that is generally less than that of dental impaction surgery. This post-surgical pain is inflammatory in nature; thus, NSAIDs have demonstrated efficacy and are the preferred analgesics in this patient population. Postoperative administration of intranasal ketorolac (SPRIX®) and oral acetaminophen 325 mg plus codeine 30 mg have both demonstrated efficacy.
The soft tissue and bony trauma associated with dental implant surgery upregulates inflammatory mediators both locally and systemically. Elevated levels of interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-1β have been observed in gingival crevicular fluid (GCF) from the implant site and the adjacent teeth one week after surgery. Prostaglandin E2 has been measured in the GCF of teeth surrounding implant sites employing similar methodology. Additionally, standard periodontal flap and bony recontouring surgery, which shares many similarities to dental implant surgery, induces an upregulation in immunoreactive prostaglandin E2 and leukotriene B4 levels at the surgical site. Dental implant surgery also increases cytokine levels in plasma, indicative of a systemic inflammatory response. Thus, in addition to being a model to study the efficacy and tolerability of OTC analgesics, dental implant surgery also appears to be an excellent model to study the anti-inflammatory properties of NSAIDs such as naproxen sodium.
Therefore, the investigators propose to initiate a double-blind, pilot study to evaluate the anti-inflammatory and analgesic effects of an OTC regimen of naproxen sodium versus acetaminophen in dental implant surgery patients. Notably, the vast majority of these patients are over the age of 45, a patient demographic that is rarely captured in postsurgical dental pain studies. Compared to dental impaction surgery patients, implant surgery patients possess more comorbidities such as hypertension, hyperlipidemia and hyperglycemia Thus, while dental impaction patients are typically on few if any drugs, polypharmacy is more of the norm in dental implant surgery patients. Performing a controlled study with OTC naproxen sodium in this population will provide the opportunity to confirm that its short-term use is generally safe and effective in these older, more medically complex patients. It will also confirm that naproxen sodium in the OTC dosage range is a good alternative to immediate-release opioid formulations, which are subject to misuse, abuse and diversion in this patient population.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Naproxen sodium | Experimental | Naproxen sodium 440 mg followed by naproxen sodium 220 mg q 8h (max 660 mg/day) |
|
| Acetaminophen | Active Comparator | Acetaminophen 1000 mg followed by acetaminophen 1000 mg q 6h (max 3000 mg/day according to Tylenol package insert) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Naproxen | Drug | 440 mg by mouth immediately after completion of implant surgery followed by 220 mg 12 hours later. Then 220 mg every 8 hours for the next two days. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Pain Intensity Scores on Numeric Pain Intensity Scale 0-6 Hours | Median maximum pain intensity scores where 0 = no pain and 10 = worst possible pain | Up to 6 hours |
| Pain Intensity Scores From 6 Through 72 Hours (Multi-dose Phase) | Pain intensity scores where 0 = no pain and 10 = worst possible pain | 6-72 hours Post initial Dose |
| Peak Plasma IL-6 Concentrations | Plasma IL-6 concentrations 6 hours after treatment measured by ELISA | 6 hours |
| Plasma IL-6 Change From Baseline | Percent change in plasma IL-6 levels at 6 hours after treatment relative to baseline | 6 hours post dose |
| Measure | Description | Time Frame |
|---|---|---|
| Rescue Analgesic Use | Number of patients requiring opioid rescue medication (tramadol) during inpatient phase (0-6 hours) in each treatment group | 0-6 hours |
| Rescue Medication Use Outpatient Phase (6-72 Hours) |
Not provided
Inclusion Criteria:
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Elliot V Hersh, DMD, MS, PhD | University of Pennsylvania | Principal Investigator |
| Katherine N Theken, PharmD, PhD | University of Pennsylvania School of Dental Medicine and Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pennsylvania School of Dental Medicine | Philadelphia | Pennsylvania | 19104-6030 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23904576 | Background | Moore PA, Hersh EV. Combining ibuprofen and acetaminophen for acute pain management after third-molar extractions: translating clinical research to dental practice. J Am Dent Assoc. 2013 Aug;144(8):898-908. doi: 10.14219/jada.archive.2013.0207. | |
| 32286125 | Background | Hersh EV, Moore PA, Grosser T, Polomano RC, Farrar JT, Saraghi M, Juska SA, Mitchell CH, Theken KN. Nonsteroidal Anti-Inflammatory Drugs and Opioids in Postsurgical Dental Pain. J Dent Res. 2020 Jul;99(7):777-786. doi: 10.1177/0022034520914254. Epub 2020 Apr 14. |
| Label | URL |
|---|---|
| 17 Dental Implant Industry Statistics and Trends. | View source |
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IPD will not be shared. This is a pilot, exploratory study.
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Subjects scheduled in University of Pennsylvania School of Dental Medicine Periodontics Clinic to receive the surgical placement of one or two dental implants.
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| ID | Title | Description |
|---|---|---|
| FG000 | Naproxen Sodium | Naproxen: 440 mg by mouth immediately after completion of implant surgery followed by 220 mg 12 hours later. Then 220 mg every 8 hours for the next two days. Tramadol: 50 mg by mouth every 6 hours as needed for pain |
| FG001 | Acetaminophen | Acetaminophen: 1000 mg by mouth immediately after the completion of implant surgery followed by 1000 mg every 6 hours for 3 days after surgery with a maximum daily dose of 3000 mg. Tramadol: 50 mg by mouth every 6 hours as needed for pain |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
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| ID | Title | Description |
|---|---|---|
| BG000 | Naproxen Sodium | Naproxen: 440 mg by mouth immediately after completion of implant surgery followed by 220 mg 12 hours later. Then 220 mg every 8 hours for the next two days. Tramadol: 50 mg by mouth every 6 hours as needed for pain |
| BG001 | Acetaminophen |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | Pain Intensity Scores on Numeric Pain Intensity Scale 0-6 Hours | Median maximum pain intensity scores where 0 = no pain and 10 = worst possible pain | Medium Greatest Pain Intensity Scores from 0-6 hours Following Dosing With Naproxen Sodium or Acetaminophen | Posted | Median | Inter-Quartile Range | score on a scale | Up to 6 hours |
|
One week
Does not differ from clinicaltrials.gov
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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 | Naproxen Sodium | Naproxen sodium 440 mg followed by naproxen sodium 220 mg q 8h (max 660 mg/day) Naproxen: 440 mg by mouth immediately after completion of implant surgery followed by 220 mg 12 hours later. Then 220 mg every 8 hours for the next two days. Tramadol: 50 mg by mouth every 6 hours as needed for pain |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | General disorders | Naproxen sodium | Non-systematic Assessment | Occurred during outpatient dosing with naproxen sodium |
Research study as described in the results manuscript only evaluated 30 subjects but it is the first of it's kind. Our analysis was not powered to comprehensively evaluate the clinical and demographic factors that influence the local and systemic inflammatory response to implant placement surgery or drug response. In addition, we excluded smokers and patients with diabetes, autoimmune diseases, or other comorbidities that might influence the inflammatory response to implant placement surgery.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Elliot V Hersh DMD, MS, PhD. Professor of Oral Surgery and Pharmacology | University of Pennsylvania School of Dental Medicine | 215-898-9686 | evhersh@upenn.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 | Jul 23, 2022 | Mar 10, 2024 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Aug 5, 2022 | May 7, 2024 | ICF_002.pdf |
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| ID | Term |
|---|---|
| D059787 | Acute Pain |
| ID | Term |
|---|---|
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D009288 | Naproxen |
| D000082 | Acetaminophen |
| D014147 | Tramadol |
| ID | Term |
|---|---|
| D009280 | Naphthaleneacetic Acids |
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
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Double blind, randomized, active-controlled, two arms
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Administration of naproxen or acetaminophen will be masked by over-encapsulation
|
| Acetaminophen | Drug | 1000 mg by mouth immediately after the completion of implant surgery followed by 1000 mg every 6 hours for 3 days after surgery with a maximum daily dose of 3000 mg. |
|
|
| Tramadol | Drug | 50 mg by mouth every 6 hours as needed for pain |
|
|
Number of patients requiring opioid rescue medication during outpatient phase in both treatment groups
| 6-72 hours |
| Peak GCF IL-1β Levels | Levels of IL-1β in gingival crevicular fluid measured at 24 hours after treatment | 24 hours post-dose |
| COX-1 Activity Percent of Baseline (Pre-surgery) | Cyclooxygenase (COX)-1 activity was evaluated ex vivo by quantifying serum thromboxane B2 levels | 6 hours post dose |
| COX-2 Activity | COX-2 activity was evaluated ex vivo by quantifying plasma prostaglandin (PG)E2 levels following lipopolysaccharide (LPS) stimulation in whole blood, | 6 hours post-dose |
| Peak GCF IL-8levels | Levels of IL-8 in gingival crevicular fluid measured at 24 hours after treatment | 24 hours post-dose |
| 25315314 | Background | Deeb GR, Deeb JG, Agarwal V, Laskin DM. Use of transalveolar sutures to maintain vestibular depth and manipulate keratinized tissue following alveolar ridge reduction and implant placement for mandibular prosthesis. J Oral Maxillofac Surg. 2015 Jan;73(1):48-52. doi: 10.1016/j.joms.2014.07.022. Epub 2014 Jul 30. |
| 8329098 | Background | Schmitt A, Zarb GA. The longitudinal clinical effectiveness of osseointegrated dental implants for single-tooth replacement. Int J Prosthodont. 1993 Mar-Apr;6(2):197-202. |
| 8329097 | Background | Zarb GA, Schmitt A. The longitudinal clinical effectiveness of osseointegrated dental implants in posterior partially edentulous patients. Int J Prosthodont. 1993 Mar-Apr;6(2):189-96. |
| 30075090 | Background | Elani HW, Starr JR, Da Silva JD, Gallucci GO. Trends in Dental Implant Use in the U.S., 1999-2016, and Projections to 2026. J Dent Res. 2018 Dec;97(13):1424-1430. doi: 10.1177/0022034518792567. Epub 2018 Aug 3. |
| 24564610 | Background | Bockow R, Korostoff J, Pinto A, Hutcheson M, Secreto SA, Bodner L, Hersh EV. Characterization and treatment of postsurgical dental implant pain employing intranasal ketorolac. Compend Contin Educ Dent. 2013 Sep;34(8):570-6. |
| 20467629 | Background | Alissa R, Sakka S, Oliver R, Horner K, Esposito M, Worthington HV, Coulthard P. Influence of ibuprofen on bone healing around dental implants: a randomised double-blind placebo-controlled clinical study. Eur J Oral Implantol. 2009 Autumn;2(3):185-99. |
| 17190305 | Background | Hashem AA, Claffey NM, O'Connell B. Pain and anxiety following the placement of dental implants. Int J Oral Maxillofac Implants. 2006 Nov-Dec;21(6):943-50. |
| 17274712 | Background | Al-Khabbaz AK, Griffin TJ, Al-Shammari KF. Assessment of pain associated with the surgical placement of dental implants. J Periodontol. 2007 Feb;78(2):239-46. doi: 10.1902/jop.2007.060032. |
| 28864284 | Background | Samieirad S, Afrasiabi H, Tohidi E, Qolizade M, Shaban B, Hashemipour MA, Doaltian Shirvan I. Evaluation of caffeine versus codeine for pain and swelling management after implant surgeries: A triple blind clinical trial. J Craniomaxillofac Surg. 2017 Oct;45(10):1614-1621. doi: 10.1016/j.jcms.2017.06.014. Epub 2017 Jul 5. |
| 23772674 | Background | Emecen-Huja P, Eubank TD, Shapiro V, Yildiz V, Tatakis DN, Leblebicioglu B. Peri-implant versus periodontal wound healing. J Clin Periodontol. 2013 Aug;40(8):816-24. doi: 10.1111/jcpe.12127. Epub 2013 Jun 18. |
| 9796154 | Background | Aboyoussef H, Carter C, Jandinski JJ, Panagakos FS. Detection of prostaglandin E2 and matrix metalloproteinases in implant crevicular fluid. Int J Oral Maxillofac Implants. 1998 Sep-Oct;13(5):689-96. |
| 8997678 | Background | O'Brien TP, Roszkowski MT, Wolff LF, Hinrichs JE, Hargreaves KM. Effect of a non-steroidal anti-inflammatory drug on tissue levels of immunoreactive prostaglandin E2, immunoreactive leukotriene, and pain after periodontal surgery. J Periodontol. 1996 Dec;67(12):1307-16. doi: 10.1902/jop.1996.67.12.1307. |
| 26171113 | Background | Li S, Yang Y, Yu C, Yao Y, Wu Y, Qian L, Cheung CW. Dexmedetomidine Analgesia Effects in Patients Undergoing Dental Implant Surgery and Its Impact on Postoperative Inflammatory and Oxidative Stress. Oxid Med Cell Longev. 2015;2015:186736. doi: 10.1155/2015/186736. Epub 2015 Jun 15. |
| 11780571 | Background | Pietruski JK, Pietruska MD, Stokowska W, Pattarelli GM. Serum levels of interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8) in patients treated with dental implants. Rocz Akad Med Bialymst. 2001;46:28-37. |
| 31116832 | Background | Aghaloo T, Pi-Anfruns J, Moshaverinia A, Sim D, Grogan T, Hadaya D. The Effects of Systemic Diseases and Medications on Implant Osseointegration: A Systematic Review. Int J Oral Maxillofac Implants. 2019 Suppl;34:s35-s49. doi: 10.11607/jomi.19suppl.g3. |
| 37266144 | Result | Theken KN, Chen M, Wall DL, Pham T, Secreto SA, Yoo TH, Rascon AN, Chang YC, Korostoff JM, Mitchell CH, Hersh EV. A randomized, double-blind pilot study of analgesic and anti-inflammatory effects of naproxen sodium and acetaminophen following dental implant placement surgery. Front Pharmacol. 2023 May 17;14:1199580. doi: 10.3389/fphar.2023.1199580. eCollection 2023. |
Acetaminophen: 1000 mg by mouth immediately after the completion of implant surgery followed by 1000 mg every 6 hours for 3 days after surgery with a maximum daily dose of 3000 mg. Tramadol: 50 mg by mouth every 6 hours as needed for pain |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Body Mass Index (BMI) | Mean | Standard Deviation | BMI (kg/m^2) |
|
| Length of Surgery | Implant surgery length from administration of local anesthetic to placement of last suture | Mean | Standard Deviation | Minutes |
|
Acetaminophen 1000 mg followed by acetaminophen 1000 mg q 6h (max 3000 mg/day according to Tylenol package insert)
Acetaminophen: 1000 mg by mouth immediately after the completion of implant surgery followed by 1000 mg every 6 hours for 3 days after surgery with a maximum daily dose of 3000 mg.
Tramadol: 50 mg by mouth every 6 hours as needed for pain
|
|
|
| Primary | Pain Intensity Scores From 6 Through 72 Hours (Multi-dose Phase) | Pain intensity scores where 0 = no pain and 10 = worst possible pain | Mean Pain Intensity Scores from 6-72 hours Following Around-the-Clock Dosing With Naproxen Sodium or Acetaminophen | Posted | Mean | Inter-Quartile Range | units on pain intensity scale | 6-72 hours Post initial Dose |
|
|
|
|
| Primary | Peak Plasma IL-6 Concentrations | Plasma IL-6 concentrations 6 hours after treatment measured by ELISA | Posted | Median | Inter-Quartile Range | pg/ml | 6 hours |
|
|
|
|
| Primary | Plasma IL-6 Change From Baseline | Percent change in plasma IL-6 levels at 6 hours after treatment relative to baseline | Posted | Median | Inter-Quartile Range | percentage change from baseline | 6 hours post dose |
|
|
|
|
| Secondary | Rescue Analgesic Use | Number of patients requiring opioid rescue medication (tramadol) during inpatient phase (0-6 hours) in each treatment group | Number of patients in each treatment group requiring opioid rescue medication (tramadol) during inpatient phase (0-6 hours) | Posted | Number | participants | 0-6 hours |
|
|
|
| Secondary | Rescue Medication Use Outpatient Phase (6-72 Hours) | Number of patients requiring opioid rescue medication during outpatient phase in both treatment groups | Posted | Number | participants | 6-72 hours |
|
|
|
| Secondary | Peak GCF IL-1β Levels | Levels of IL-1β in gingival crevicular fluid measured at 24 hours after treatment | Posted | Median | Inter-Quartile Range | pg/ml | 24 hours post-dose |
|
|
|
|
| Secondary | COX-1 Activity Percent of Baseline (Pre-surgery) | Cyclooxygenase (COX)-1 activity was evaluated ex vivo by quantifying serum thromboxane B2 levels | Posted | Median | Inter-Quartile Range | percentage of baseline blood levels | 6 hours post dose |
|
|
|
|
| Secondary | COX-2 Activity | COX-2 activity was evaluated ex vivo by quantifying plasma prostaglandin (PG)E2 levels following lipopolysaccharide (LPS) stimulation in whole blood, | Patient in each group surgically receiving one or two implants | Posted | Median | Inter-Quartile Range | percentage of baseline blood levels | 6 hours post-dose |
|
|
|
|
| Secondary | Peak GCF IL-8levels | Levels of IL-8 in gingival crevicular fluid measured at 24 hours after treatment | Posted | Median | Inter-Quartile Range | pg/ml | 24 hours post-dose |
|
|
|
|
| 0 |
| 15 |
| 0 |
| 15 |
| 1 |
| 15 |
| EG001 | Acetaminophen | Acetaminophen 1000 mg followed by acetaminophen 1000 mg q 6h (max 3000 mg/day according to Tylenol package insert) Acetaminophen: 1000 mg by mouth immediately after the completion of implant surgery followed by 1000 mg every 6 hours for 3 days after surgery with a maximum daily dose of 3000 mg. Tramadol: 50 mg by mouth every 6 hours as needed for pain | 0 | 15 | 0 | 15 | 2 | 15 |
|
| Agitation | Psychiatric disorders | Acetaminophen | Non-systematic Assessment | Patient felt on edge during in patient period after initial dose of acetaminophen 1000 mg. |
|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment | One patient after 1st dose, one patient as outpatient (multidose phase) |
|
| emesis | Gastrointestinal disorders | Non-systematic Assessment | Vomiting one episode each. One patient during as inpatient after first dose and one patient as outpatient during multi-dose phase |
|
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| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D000814 | Aniline Compounds |
| D000588 | Amines |
| D003511 | Cyclohexanols |
| D000441 | Hexanols |
| D005233 | Fatty Alcohols |
| D000438 | Alcohols |
| D004123 | Dimethylamines |
| D008744 | Methylamines |
| D008055 | Lipids |