Last reviewed by Editorial Team on August 27th, 2018.
What is Dexlansoprazole?
Dexlansoprazole is the Generic name for the gastric acid reducing drug, which belong to the class of proton pump inhibitors (PPIs). Chemically, it is R-enantiomer of lansoprazole. The main action of this drug is reducing acid content in stomach. It is used for erosive esophagitis, dyspepsia and heartburn associated with gastro esophageal reflux disease (GERD).
In addition dexlansporazole may be also prescribed to treat stomach ulcers. Never use this medicine for any off-label purposes unless directed by your doctor. This drug comes in the form of a delayed-release capsule in doses of 30 and 60 mg and disintegrating (dissolving) tablet in dose of 30 mg to be taken by mouth.
It is not available over the counter (OTC) and should be only given under prescription of registered medical practitioner. It is most commonly available under the brand names Dexilant and Kapidex. It is originally manufactured by Takeda Pharmaceuticals.
Dexlansoprazole special formulation – Dexalansoprazole DDR
Dexlansoprazole is manufactured using (DDR) – dual delayed-release technology with two types of pH-dependent granules. First type immediately releases drug with a peak concentration occurring within 1–2 hours after use. The second type slowly releases drug, producing a second peak 4-5 hours after administration.
What is Dexlansoprazole chemical name, class, molecular formula and weight?
Chemical name – 2-[(R)-[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole-d4. Dexlansoprazole belong to the group of benximidazoles compounds.
Pharmacologically, dexlansoprazole belongs to the class of proton pump inhibitors, functioning as an acid secretion reducer in the stomach. It inhibits the proton pump irreversibly and hence it provides longer relief.
Molecular formula – C16H14F3N3O2S
Molecular Weight – 360.362 g/mol
Dexlansoprazole 3D formula:
What are the inactive ingredients in dexlansoprazoles capsules?
Inactive ingredients: sugar spheres, magnesium carbonate, sucrose, low-substituted hydroxypropyl cellulose, titanium dioxide, hydroxypropyl cellulose, hypromellose 2910, talc, methacrylic acid copolymers, polyethylene glycol 8000, triethyl citrate, polysorbate 80, and colloidal silicon dioxide.
The capsule shell is made of hypromellose, carrageenan and potassium chloride. Based on the capsule shell color, blue contains FD&C Blue No. 2 aluminum lake; gray contains black ferric oxide; and both contain titanium dioxide
What are PPI? Is dexlansoprazole PPI?
PPI or Proton Pump Inhibitors seem to be one of the most common prescription drugs across the globe. They are usually suggested for diseases related to hydrochloric acid. Their popularity stems from the high efficacy in inhibiting gastric acid secretion, selectivity of action and few adverse reactions. The discovery of PPIs radically changed the therapeutic approach to diseases caused by excessive secretion of acidic gastric juices.
At present, PPIs are the most widely used and the strongest-acting anti secretive drugs. The above mentioned high efficacy in inhibition of the production of gastric hydrochloric acid is rooted in the effect of the drug on the basic as well as stimulated gastric secretion.
The mechanism of action of these proton pump inhibitors relies on the inhibitory effect on the activity of the enzyme H/K ATPase (hydrogen/ potassium Adenosine triphosphatase), more commonly known as the proton pump is found in the parietal cells of the mucosa of stomach.
This enzyme, in particular is involved in hydrochloric acid secretion, hydrolysis of ATP and exchange of cytoplasmic H+ ions for the K+ ions present in secretory canaliculus, resulting in secretion of HCl into the gastric lumen.
Benzimidazole compounds such as dexlansoprazole act as inhibitors of the proton pump and occur in the form of pro – drugs. In the acidic environment, a high degree of activation is exhibited by the proton pump inhibitors. The PPIs pass through the liver and reach the gastric parietal cells which have undergone activation by a meal.
In the acidic pH of the stomach, the proton pump inhibitors undergo protonation and are converted to sulphenamide, which is the active form of the drug. The activity of the proton pump is inhibited by sulphenamide, therefore stopping the hydrogen ion transporation into the gastric lumen via covalent binding to the cysteine residue SH groups of the H/ K ATPase.
How Dexlansoprazole works in the body?
Dexlansoprazole is known to reduce the acid content in stomach. They inhibit proton pump located in parietal cells in stomach wall. They do this by irreversibly blocking the actions of an enzyme H+/K+ ATPase located in luminal membrane of parietal cells.
After discontinuation, the secretory activity returns after 2-3 days as synthesis of new proton pump requires minimum 18 hours. Its peak concentration reaches plateau level after continuous dosing. It is a hit and run drug i.e. its effect last longer even after it is eliminated by the body. It is available as delayed-release capsule.
What is the difference between dexlansoprazole and lansoprazole?
Dexlansoprazole is chemically related to the lansoprazole. It is the R-isomer of lansoprazole. Lasnoprazole is a racemic mixture of its (R)-(+) and (S)-(−)-enantiomers. It lasts longer than lansoprazole, thus it needs to be taken less often. Dexlansoprazole is manufactured using (DDR) – dual delayed-release technology with two types of pH-dependent granules while lansoprazole is not.
Studies proposed that racemic switches to pure enantiomeric of PPIs may improve the stereoselective pharmacokinetics, leading to better clinical results compared to racemic PPIs. For now, there are no adequate studies showing that dexlansoprazole is more effective and safer than lansoprazole.
Two trials published in the same Journals compared dexlansoprazole DDR with lansoprazole for their effects of healing of erosive esophagitis. Results showed that dexlansoprazole DDR in doses 60 mg and 90 mg (no labeled dose) were less efficient than lansoprazole 30 mg for healing erosive esophagitis.
However, placebo-controlled clinical trials found that dexlansoprazole DDR was highly effective for long-term therapy of healed erosive esophagitis but also for the symptomatic relief of nonerosive reflux disease – NERD. The higher doses of 60 mg of dexlansoprazole DDR did not show any advantage over the lower dose dexlansoprazole 30 mg for maintenance of healing or relief of GERD symptoms.
Studies comparing dexlansoprazole DDR with other proton pump inhibitors are lacking.
Dexlansoprazole Brand Names
Dexlansoprazole is available with the following brand names in the market:
- Dexilant solutab
Dexilant is one of the most trusted ones and is easily available at any pharmacy shop. There are no generic forms of dexlansoprazole on the market.
What are FDA approved indications for Dexlansoprazole?
- Erosive esophagitis, healing of all grades
- Erosive esophagitis, maintenance of healing
- Gastroesophageal reflux disease (GERD), symptomatic, non-erosive
Potential off-label uses of dexlansoprazole include healing and maintenance of gastric and duodenal ulcers, eradication of H.pylori, prevention of NSAID associated gastric ulcers. healing NSAID related and non-NSAID related gastric ulcers, and pathological hypersecretory conditions such as Zollinger-Ellison syndrome.
Dexlansoprazole delayed release capsules?
The delayed release capsules provide long duration of action and hence long term benefit. The drug remains in plasma for longer duration and thus offers sustained benefits.
Dexlansoprazole dual delayed release capsules?
The dual delayed release formulation results in Dexlansoprazole with two distinct peaks. The first peak occurs in initial hours i.e. 1-2 hours followed by second peak which occurs within 4-5 hours. This is responsible for longer action of drug.
Dexlansoprazole Dosage Forms and Strengths
Dexlansoprazole is available in following forms and strengths:
- Dexilant Capsule can be administered orally or via nasogastric route (60mg)
- Dexilant delayed release capsule (60mg) can be administered orally
- Dexilant Capsule can be administered orally or via nasogastric route (30mg)
- Dexilant Tablet can be administered orally (30mg)
- Kapidex Capsule can be administered orally (30mg)
Dexlansoprazole dosage for different indications
The general recommendations for dexlansoprazole dosage are following:
- Adult dosage:
- Healing of Erosive Esophagitis: Initial dose – 60 mg dose once a day for 8 weeks. Maintenance dose – 30 mg orally once a day for up to 6 months.
- Healing of GERD: Oral administration of 30 mg, once a day for 4 weeks
- Pediatric dosage:
- Healing dose for Erosive Esophagitis: For 12 years and older- 60 mg orally once a day for duration of 8 weeks. Maintanance dose – 30 mg orally once a day.
- Healing dose for GERD: Oral administration of 30 mg once a day for a period of 4 weeks.
- No renal adjustment is needed for the dosage.
- Mild hepatic impairment: no adjustment needed
- Moderate hepatic impairment: recommended dosage 30mg orally once a day for up to 8 weeks
- Severe hepatic impairment: Not recommended. Safety has not been yet established in younger patients.
Dexlansoprazole can be taken without food. The capsules should be swallowed whole. If necessary, the capsules may be opened, the intact granules sprinkled on 1 tablespoon of applesauce and swallowed immediately.
What is the highest dose for Dexlansoprazole?
Till administration of 300 mg, no serious adverse effect of the drug has been reported. Beyond 300 mg adverse reactions may be seen. Thus, the use of the drug should be within limits and should not exceed beyond 300 mg.
There is no significant overdose with Dexlansoprazole. Serious hypertension has been reported in twice daily dosing of 60mg. Other adverse effects with twice daily dosing are: hot flushes, contusions, weight loss and pharyngeal pain.
Dexlansoprazole side effects
Although it is uncommon for dexlansoprazole to show any side effects, but sometimes, it does exhibit side effects listed below.
Less common side effects:
- Burning, crawling, itching, numbness, prickling, tingling feeling
- chest pain
- stomach pain
- headache, fever, joint pain
- unusual bleeding or bruising
- swelling of eyelids, face, lips, feet, hands
- difficult or labored breathing
- fast, irregular, pounding, or racing heartbeat or pulse
- incoherent speech
- joint pain, stiffness, or swelling
- light headedness, dizziness, or fainting
- swelling of the eyelids, face, lips, hands, or feet
- unusual bleeding or bruising
- watery or bloody diarrhea
- muscle pain, cramps, or weakness
- nausea or vomiting
- pain or discomfort in the arms, jaw, leg, back, or neck
- pounding in the ears
- rash or hives
- red, irritated eyes
- unusual weight gain
- Blistering, peeling, or loosening of the skin
- muscle spasms (tetany) or twitching
- red skin lesions, often with a purple center
Minor side effect
Although the drug don’t do much harm to body but, in rare cases some more side-effects can be seen which if left untreated can lead to serious damages in long run.
- Abnormal dreams
- loss of voice
- metallic taste
- passing gas
- difficult or painful urination
- ear congestion
- ear pain
From anatomy-physyology point of view dexlanoprazole side effects can be divided in:
- Dermatological – acne, dermatitis, pruritus, urticaria, rash
- Endocrine – goiter, diabetes mellitus
- GIT – nausea, vomiting, flatulence, pain.
- Hepatic – biliary colic, cholelithiasis, hepatomegaly, gallstones
- Hypersensitivity – anaphylaxis reaction
- Metabolic – total protein increase, weight gain, appetite changes, obesity, dehydration, hyperlipidemia, metabolic syndrome
- Musculocutaneous – joint strain, arthritis, swollen joints, pain, stiffness in joints
- Psychiatric – abnormal dreams, anxiety, insomnia, libido, lack of concentration, vivid dreams
- Nervous system – paresthesia, tremor, trigeminal neuralgia, restless leg syndrome, somnolence, memory impairment, convulsion
How to take Dexlansoprazole?
It comes as delayed release capsule. It is taken through oral route. It may be taken with or without food and the usually preferred dose is with an empty stomach, before meals.
- These capsules if taken early in the morning are known to provide round the clock relief.
- Do not chew the drug.
- Swallow it without crushing and if one finds it difficult to swallow then open the capsule, sprinkle the content on 1 table Spoon of apple sauce and swallow it.
Other methods for intake of the drug:
- Administration with water – Open the capsule in a container containing 20 ml of water.
Can I abrupt Dexlansoprazole therapy suddenly?
Abrupt stoppage of Dexlansoprazole medication is strictly not recommended. Diarrhea is the most immediate and common effect of sudden discontinuation. One should not discontinue the therapy without prior consultation from a doctor else other withdrawal side effects may also occur.
How long does it take for Dexlansoprazole to work?
It takes 1 hour for its release as it is a delayed release capsule. It reaches its peak concentration in 4-5 hours during which the patient feels relived of stomach pain. Although, the stomach pain should stop by administration of capsule, if relief is not observed, immediate visit to a doctor is recommended.
Can Dexlansoprazole cause withdrawal effects?
Since the drug is not addictive and no long run use of this drug is usually recommended in medication, therefore, withdrawal effects are rarely seen, if any. In fact, no withdrawal effects have been reported yet. Plus, one thing one should always keep in mind with the use of this drug is it is strictly prohibited for any use in younger children and pregnant women.
What are the addictions related to Dexlansoprazole?
No such addictions reported due to the Declansoprazole administration therapy.
What precautions and warning should be considered while using Dexlansoprazole?
Dexlansoprazole usage is always accompanied by some warnings and limitations of its safety administration. General precautions and warnings during dexlansoprazole use are:
- Presence of gastric malignancy
- Acute interstitial nephritis – this has been observed in patients taking Dexlansoprazole.
- Daily treatment with any acid – suppressing medications may lead to malabsorption of Vitamin B12
- Clostridium difficele associated diarrhea
- Increased risk of osteoporosis
- Hypomagnesemia have been reported.
- Megaloblastic anemia
- Acute interstitial nephritis
Apart from this, you should not use the drug if:
- You are allergic to dexlansoprazole or any of its ingredients
- You are taking a medicine that contains rilpivirine (Complera, Edurant) used in the treatment of HIV-1.
A few medical conditions may interact with dexlansoprazole. Discuss with your doctor if you are suffering from the following medical conditions to avoid any future damage to your body:
- if you have allergies to medicines, foods, or other substances
- if you are pregnant, planning to become pregnant, or are breast-feeding
- if you are taking any prescription or non prescription medicine, herbal preparation, or dietary supplement
- if you have low blood potassium or magnesium levels, low blood vitamin B12 levels or vitamin B12 deficiency, liver problems, or stomach or bowel cancer
- if you have osteoporosis (weak bones), a family history of osteoporosis, or other risk factors of osteoporosis (eg, smoking, poor nutrition)
Also, tell your doctor if you are on following medication schedule:
- Anticoagulants (eg, warfarin), digoxin, methotrexate, saquinavir, or tacrolimus because the risk of their side effects may be increased by dexlansoprazole delayed-release capsules
- Diuretics (eg, hydrochlorothiazide, furosemide) as these may increase the risk of low blood magnesium levels
- Ampicillin, atazanavir, bosutinib, clopidogrel, dasatinib, erlotinib, indinavir, iron, itraconazole, ketoconazole, mycophenolate, nelfinavir, nilotinib, posaconazole, rilpivirine, or sorafenib because their effectiveness may be decreased by dexlansoprazole delayed-release capsules
Discuss any other medication schedule, if any because not every interaction with the drug is known yet. It’s better to take precaution than to start another treatment for side effects.
How long does Dexlansoprazole stay in your system, urine, blood, saliva?
As it is slow release tablet it stays longer than other proton pump inhibitors. And hence, one time dosing will suffice there is no need of additional intake as plateau concentration is reached at later hours.
Is it safe to use Dexlansoprazole during pregnancy?
Dexlansoprazole is listed in FDA pregnancy category B which means that: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.
There were no sode fetal effects in animal reproduction studies of dexlansoprazole in rabbits. A reproduction study conducted in rabbits at oral dexlansoprazole doses up to about 9 times of the maximum recommended human dose (60 mg per day) revealed no evidence of impaired fertility or harm to the fetus due to dexlansoprazole.
Moreover, reproduction studies performed in pregnant rats with oral lansoprazole (which is chemically most similar to dexlansoprazole) at doses up to about 40 times than the recommended human lansoprazole dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human lansoprazole dose revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole
Because animal reproduction studies are not always predictive of human response, dexlansoprazole should be used during pregnancy only if clearly needed with doctor recommendations.
Is it safe to use Dexlansoprazole during breastfeeding?
The safety during breastfeeding is not known. But, no sign of any harm from Dexlansoprazole use has been reported in infants. Also, studies have shown that it do not pass in to infants during breastfeed. So it is unlikely that the drug will cause harm during breastfeeding.
Can I use dexlansoprazole if I have liver disease?
Dexlansoprazole is mainly metabolized by the liver. The drug interaction with patients suffering from liver disease is has moderate effect. Sage dose can be administered on the patient. However, no any dosage adjustment is required for patients with mild hepatic impairment (Child Pugh Class A).
A dose of 30 mg should be given to patients with moderate hepatic impairment (Child Pugh Class B). For severe hepatic impairment, no studies or research have been conducted yet and the effects are not known.
Can I use dexlansoprazole if I have bone fracture?
Various published observational studies have been reported that PPI therapy might be associated with an increased risk for osteoporosis related fractures of the wrist, hip or spine. The risk factor increased in patients who received high doses (multiple daily doses), and long term treatment (a year or longer).
Patients are recommended to use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Caution has to be taken in patients at risk for osteoporosis related fractures and should be precisely monitored and managed according to established treatment guidelines.
Dexlansoprasole and Clostridium Difficile Associated Diarrhea
Observational studies have been showen that PPI drugs like dexlanoprazole may be related with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered in patients with diarrhea that does not improve. Patients should use the lowest dose and shortest duration of PPI therapy appropriate for approved indication.
Can I use dexlansoprazole if I have hypomagnesemia?
Hypomagnesemia – Symptomatic and asymptomatic hypomagnesemia has been rarely reported in patients treated with PPIs for at least 3 months, in most cases after a year of therapy. Serious adverse events can include arrhythmias, seizures and tetany.
Caution should be used in patients prone to magnesium imbalances such as patients taking other medications that can cause hypomagnesemia (e.g., diuretics). Regular monitoring is recommended.
Can I use dexlansoprazole if I have cardiovascular problems?
There is a contraindication for dexlansoprazole use in patients with heart issues such as bradycardia, chest pain, edema, myocardial infarction, angina, palpitation, arrhythmia, tachycardia, deep vein thrombosis, hypertension and hot flush.
Dexlansoprazole absorption, metabolism and elimination
After oral administration of drug mean Cmax increases with the dose. Its half life is 1-2 hours. Fat delays the absorption of food.
- Metabolism – it is metabolized in liver by oxidation, reduction, and glucuronidation and glutathione metabolism to inactive metabolites.
- Excretion – no unchanged Dexlansoprazole is excreted in urine.
- Sex differences – female has higher systemic exposure than males.
- Age differences – elimination half life of Dexlansoprazole is increased in older age than in younger age.
No dose adjustment is needed in renal failure.
Can I drink alcohol while taking Dexlansoprazole?
Alcohol may aggravate the acid secretion and thus worsen the ulcers and hence alcohol antagonizes the action of Dexlansoprazole. Thus, a person on the drug therapy should quit drinking.
Dexlansoprazole Drug Interactions
Following drug interactions have been observed during concomitant use of dexlansoprazole with following drugs:
- Antiretroviral agents – Dexlansoprazole decreases antiviral effect and promote resistance.
- Methotrexate – concomitant use of PPI with methotrexate increases plasma concentration of methotrexate
- Tacrolimus – concentration of tacrolimus increases when used with Dexlansoprazole
- Absorption of drugs like ketoconazole, iron salts, mycophenolate mofetil as these require acidic ph for absorption thus orange juice must be given before ketoconazole is given for increasing the absorption.
- Sucralfate should not be given as it polymerizes at pH 4.
- Rifampicin – avoid concomitant use with dexlansoprazole
- Monitor digoxin levels when used with dexlansoprazole
Can I take Dexlansoprazole with Aspirin?
Aspirin being a NSAID inhibit prostaglandin, which are necessary for secretion of bicarbonate in stomach and are cytoprotective thus inhibition of PG release may aggaravate the ulcers. Thus aspirin increases the risk of ulcers and antagonise the action of dexlansoprazole
Can I take Dexlansoprazole with Cymbalta?
There exist minor interactions according to FDA thus drug should be avoided.
Can I take Dexlansoprazole with Warfarin?
Co-administration of dexlansoprazole in dose of 90 mg and warfarin 25 mg did not affect the warfarin pharmacokinetics or INR values. However, there have been some reports of increased INR and prothrombin time in patients receiving other PPIs drugs and warfarin concomitantly.
Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with dexlansoporazole and warfarin together should be monitored for increases in INR and prothrombin time.
Dexlansoprazole use with drugs with pH-dependent absorption pharmacokinetics
Dexlansoprazole works by inhibiting gastric acid secretion. It is likely to substantially decrease plasma concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance.
Dexlansoprazole may also interfere with the absorption of other drugs which absorption is pH dependent such as: ampicillin, digoxin, iron salts, ketoconazole.
Can I take Dexlansoprazole with Clopidogrel (Plavix)?
Theoretically, dexlansoprazole may have an impact on clopidogrel metabolism and it seems that this effect is dose-related. Clopidogrel is a pro-drug substance that is converted into active metabolite by 2 major metabolic pathways. One of those pathways utilizes following liver enzymes: CYP2C19, CYP3A, CYP2B6, and CYP1A2.
By inhibiting this pathway, PPIs such as dexlansoprazole, may decrease conversion of clopidogrel to its active metabolite reducing the effects of clopidogrel to prevent acute myocardial events. Because of that the use of PPIs with clopidogrel without clear indication should be avoided. The use of H-2 receptor antagonists in patients who require acid-lowering therapy should be considered in such cases.
However, there are some studies showed that concomitant use of dexlansoprazole and clopidogrel didn’t show important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition.
This may be because of dexlansoprazole’s pure nature (it is not racemic mixture like other PPIs) and better pharmacokinetic profile. Thus, no dose adjustment of clopidogrel (Plavix) is needed when administered with labeled doses dexlansoprasole.
Can I take Dexlansoprazole with Ampicillin?
Ampicillin and dexlansoprazole should not be used together. By reducing stomach acid, dexlansoprazole can lower the absorption and blood levels of ampicillin and make the medication less effective against infections.
Can I take Dexlansoprazole with Digoxin?
These two drugs should not be used together. Proton pump inhibitors drugs such as dexlansoprazole may increase the bioavailability of digoxin. The mechanism may involve a pH-dependent increase in gastrointestinal absorption of digoxin and/or inhibition by PPIs of the P-glycoprotein-mediated intestinal transport of digoxin.
Dexlansoprazole can infrequently cause an increase in the blood levels of digoxin. You should seek immediate medical attention if you experience signs and symptoms that may indicate excessive effects of digoxin, such as nausea, vomiting, visual disturbances (blurred vision; light halos around objects; green or yellow vision), diarrhea, loss of appetite or an abnormally fast or slow or uneven heartbeat.
Can I take Dexlansoprazole with vitamin B12?
Yes it decreases the risk of B12 deficiency which usually occurs when a person is taking PPI. Thus it is advices to supplement intake of vitamin B 12 to prevent megaloblastic anemia at later stages.
Can I take Dexlansoprazole with food?
Dexlansoprazole may be taken with or without food, but some patients may benefit more from pre-meal dosing if symptoms don’t resolve with post-meal dosing.
The absence of a pharmacokinetic interaction between dexlansoprazole and food was determined in a study which showed that, even though the percentage of time intragastric pH exceeded 4 over a 24-hour dosing interval decreased 7 %points with dexlansoprazole DDR given after a meal relative to fasting (57% versus 64%, respectively), there was no statistically significant difference in mean gastric pH between preprandial and postprandial conditions.
Can Dexlansoprazole get you high?
No, dexlansoprazole can never make you high. Human body do not adapt to the drug use in long term medication. Therefore, it does not have potential to cause addictions.
Does Dexlansoprazole lead to weight gain?
No, it does not cause significant weight gain. No such case has been reported yet.
Does Dexlansoprazole lead to hair loss?
No, case of hair loss has been reported so far.
- Nexium vs Prevacid
- Prevacid vs Prilosec
- Can I take omeprazole with levothyroxine
- Can Omeprazole be taken with Amoxicillin
- Lansoprazole : Drug class, mechanism of action, uses, dosage, side effects and interactions