<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Lanadelumab and can you explain it in depth? [/INST] Lanadelumab (INN; trade name Takhzyro) is a human monoclonal antibody (class IgG1 kappa) that targets plasma kallikrein (pKal) in order to promote prevention of angioedema in patients with hereditary angioedema. Lanadelumab, was approved in the United States as the first monoclonal antibody indicated for prophylactic treatment to prevent hereditary angioedema (HAE) attacks. Takhzyro is the first treatment for hereditary angioedema (HEA) prevention made by using cells within a lab, not human plasma. The US Food and Drug Administration approved the use of lanadelumab on 23 August 2018 for patients that are 12 years and older and have either type I or type II hereditary angioedema (HEA). Administration of the medication is done through 1 subcutaneous injection at a dose of 300 milligrams every 2 weeks (every 4-week dosing can be considered in specific patients).In phase 1 clinical trials Lanadelumab was well tolerated and was reported to reduce cleavage of kininogen in the plasma of patients with hereditary angioedema and decrease the number of patients experiencing attacks of angioedema. Lanadelumabs approval in the United States was spearheaded by the data presented in the phase 1b, multicenter, double blind, placebo controlled, multi-ascending-dose trial. Through this trial, Lanadelumab was given Priority Review, Breakthrough Therapy, Orphan Drug designation by the FDA. The phase 3 HELP study evaluated efficacy and safety of lanadelumab. This drug was produced by Dyax Corp and currently under development by Shire.Common side effects include pain associated with injection site reactions, injection site bruising, upper respiratory infection, headache, rash, myalgia, dizziness, and diarrhea.

Medical use
In the United States, lanadelumab is indicated for patients 12 years and older for the prophylaxis of hereditary angioedema (HAE) attacks. There is no data on the efficacy or safety of lanadelumab in patients under the age of 12 years old. Lanadelumab was not studied in pregnant or breastfeeding women.

Adverse events
In a phase 3 randomized controlled trial, which examined the efficacy and safety of lanadelumab in preventing hereditary angioedema attacks, the most common adverse events noted in patients being treated were:
Injection site pain in 42.9% of patients
Viral upper respiratory tract infection in 23.8% of patients
Headache in 20.2% of patients
Injection site erythema in 95% of patients
Injection site bruising in 7.1% of patients
Dizziness in 6.0% of patients

Mechanism of action
Lanadelumab works by binding to an enzyme within the plasma, kallikrein, to inhibit its activity. Kallikrein is a protease that functions to cleave kininogen, subsequently creating kininogen and bradykinin, a potent vasodilator.Patients have hereditary angioedema (HAE) because of a deficiency or dysfunctional C1 inhibitor, which is an enzyme that regulates the activity of the kallikrein-kinin cascade. Poor regulation of the C1 inhibitor results in increased levels of kallikrein and subsequent proteolysis of kininogen. The proteolysis of the kininogen forces an upscaled production of bradykinin and kininogen within the patient </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Olopatadine and can you explain it in depth? [/INST] Olopatadine, sold under the brand name Opatanol among others, is a medication used to decrease the symptoms of allergic conjunctivitis and allergic rhinitis (hay fever). It is used as eye drops or as a nasal spray. The eye drops generally result in an improvement within half an hour.Common side effects include headache, sore throat, eye discomfort, change in taste. More significant side effects may include sleepiness. It is unclear if use during pregnancy or breastfeeding is safe. It is an antihistamine and mast cell stabilizer.Olopatadine was patented in 1986 and came into medical use in 1997. It is available as a generic medication. In 2017, it was the 270th most commonly prescribed medication in the United States, with more than one million prescriptions.

Side effects
Some known side effects include headache (7% of occurrence), eye burning and/or stinging (5%), blurred vision, dry eyes, foreign body sensation, hyperemia, keratitis, eyelid edema, pruritus, asthenia, sore throat (pharyngitis), rhinitis, sinusitis, taste perversion, and vomiting.

Chemistry
Synthesis
Pharmacology
Pharmacodynamics
Olopatadine acts as a selective antagonist of the histamine H1 receptor, thus stabilizing mast cells and inhibiting histamine release.

History
Olopatadine was patented in 1986 by Kyowa Hakko Kogyo and came into medical use in 1997.In the United States, Pataday Twice Daily Relief was first approved by the FDA in 1996, under the name Patanol as a prescription drug and was indicated for the treatment of the signs and symptoms of allergic conjunctivitis (referring to ocular redness and itching due to allergies) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Palivizumab and can you explain it in depth? [/INST] Palivizumab, sold under the brand name Synagis, is a monoclonal antibody produced by recombinant DNA technology used to prevent severe disease caused by respiratory syncytial virus (RSV) infections. It is recommended for infants at high-risk for RSV due to conditions such as prematurity or other medical problems including heart or lung diseases.The most common side effects include fever and rash.Palivizumab is a humanized monoclonal antibody (IgG) directed against an epitope in the A antigenic site of the F protein of RSV.  In two phase III clinical trials in the pediatric population, palivizumab reduced the risk of hospitalization due to RSV infection by 55% and 45%.  Palivizumab is dosed once a month via intramuscular (IM) injection, to be administered throughout the duration of the RSV season, which in based on past trends has started in Mid-September to Mid-November.Palivizumab targets the fusion protein of RSV, inhibiting its entry into the cell and thereby preventing infection. Palivizumab was approved for medical use in 1998.

Medical use
Palivizumab is indicated for the prevention of serious lower respiratory tract disease requiring hospitalization caused by the respiratory syncytial virus (RSV) in children at high risk for RSV disease:
children born at 35 weeks of gestation or less and less than six months of age at the onset of the RSV season;
children less than two years of age and requiring treatment for bronchopulmonary dysplasia within the last six months;
children less than two years of age and with hemodynamically significant congenital heart disease.The American Academy of Pediatrics has published guidelines for the use of palivizumab. The most recent updates to these recommendations are based on new information regarding RSV seasonality, palivizumab pharmacokinetics, the incidence of bronchiolitis hospitalizations, the effect of gestational age and other risk factors on RSV hospitalization rates, the mortality of children hospitalized with RSV infection, the effect of prophylaxis on wheezing, and palivizumab-resistant RSV isolates.

RSV Prophylaxis
All infants younger than one year who were born at <29 weeks (i.e. ≤28 weeks, 6 days) of gestation are recommended to use palivizumab. Infants younger than one year with bronchopulmonary dysplasia (i.e. who were born at <32 weeks gestation and required supplemental oxygen for the first 28 days after birth) and infants younger than two years with bronchopulmonary dysplasia who require medical therapy (e.g. supplemental oxygen, glucocorticoids, diuretics) within six months of the anticipated RSV season are recommended to use palivizumab as prophylaxis. A Cochrane review shows evidence that palivizumab RSV prophylaxis is effective at reducing the frequency of hospitalization in children with RSV infection.Since the risk of RSV decreases after the first year following birth, the use of palivizumab for children more than 12 months of age is generally not recommended with the exception of premature infants who need supplemental oxygen, bronchodilator therapy, or steroid therapy at the time of their second RSV season.

RSV Prophylaxis Target Groups
Infants younger than one year of age with hemodynamically significant congenital heart disease.
Infants younger than one year of age with neuromuscular disorders impairing the ability to clear secretions from the upper airways or pulmonary abnormalities.
Children younger than two years of age who are immunocompromised (e.g. those with severe combined immunodeficiency; those younger than two years of age who have undergone lung transplantation or hematopoietic stem cell transplantation) during the RSV season.
Children with Down syndrome who have additional risk factors for lower respiratory tract infections such as congenital heart disease, chronic lung disease, or premature birth.
Alaska Native and American Indian infants.Decisions regarding palivizumab prophylaxis for children in these groups should be made on a case-by-case basis.

RSV Treatment
Because palivizumab is a passive antibody, it is ineffective in the treatment of RSV infection, and its administration is not recommended for this indication. A 2019 Cochrane review found no differences in palivizumab and placebo on outcomes of mortality, length of hospital stay, and adverse events in infants and children aged up to 3 years old with RSV. Larger RCTs will be required before palivizumab can be recommended as a treatment option. If an infant has an RSV infection despite the use of palivizumab during the RSV season, monthly doses of palivizumab may be discontinued for the rest of the RSV season due to the low risk of re-hospitalization. Current studies are in progress to determine new treatments for RSV rather than solely prophylaxis.

Mechanism of Action
Palivizumab is a monoclonal antibody that targets the fusion (F) glycoprotein on the surface of RSV, and deactivates it. The F protein is a membrane protein responsible for fusing the virus with its target cell and is highly conserved among subgroups of RSV.  Deactivating the F protein prevents the virus from fusing with its targets cell membrane and prevents the virus from entering the host cell.

Pharmacodynamics
Palivizumab has demonstrated a significantly higher affinity and potency in neutralizing both A and B subtypes of RSV when compared with RSV-IGIV. Treatment with 2.5 mg/kg of palivizumab led to a serum concentration of 25-30 μg/mL in cotton rats and reduced RSV titers by 99% in their lungs.

Pharmacokinetics
Absorption
A 2008 meta-analysis found that palivizumab absorption was quicker in the pediatric population compared to adults (ka = 1.01/day vs. ka = 0.373/day). The intramuscular bioavailability of this drug is approximately 70% in healthy young adults. Current recommendation for RSV immunoprophylaxis is administration of 5 x 15 mg/kg doses of palivizumab to maintain body concentrations above 40 μg/mL.

Distribution
The volume of distribution is approximately 4.1 liters.

Clearance
Palivizumab has a drug clearance (CL) of approximately 198 ml/day. The half-life of this drug is approximately 20 days with three doses sustaining body concentrations that will last the entire RSV season (5 to 6 months). A 2008 meta-analysis estimated clearance in the pediatric population by considering maturation of CL and body weight which showed a significant reduction compared to adults.

Side effects
Palivizumab use may cause side effects, which include, but are not limited to:
Sore throat
Runny nose
Redness or irritation at the injection site
Vomiting
DiarrheaSome more serious side effects include:

Severe skin rash
Itching
Hives (urticaria)
Difficulty breathing

Contraindications
Contraindications for the use of palivizumab include hypersensitivity reactions upon exposure to palivizumab. Serious cases of anaphylaxis have been reported after exposure to palivizumab.  Signs of hypersensitivity include hives, shortness of breath, hypotension, and unresponsiveness. No other contraindications for palivizumab have been reported. Further studies are needed to determine if any drug-drug interactions exist as none have been conducted as of yet.

Cost
Palivizumab is a relatively expensive medication, with a 100-mg vial ranging from $904 to $1866. Multiple studies done by both the manufacturer and independent researchers to determine the cost-effectiveness of palivizumab have found conflicting results. The heterogeneity between these studies makes them difficult to compare. Given that there is no consensus about the cost-effectiveness of palivizumab, usage largely depends on the location of care and individual risk factors.A 2013 meta-analysis reported that palivizumab prophylaxis was a dominant strategy with an incremental cost-effectiveness ratio of $2,526,203 per quality-adjusted life-year (QALY). It also showed an incremental cost-effectiveness ratio for preterm infants between $5188 and $791,265 per QALY, from the payer perspective. However, as previously stated, the cost-effectiveness of palivizumab is undecided, and this meta-analysis is only one example of society can benefit from palivizumab prophylaxis.

History
The disease burden of RSV in young infants and its global prevalence have prompted attempts for vaccine development. As of 2019, there was no approved vaccine for RSV prevention. A formalin-inactivated RSV vaccine (FIRSV) was studied in the 1960s. The immunized children who were exposed to the virus in the community developed an enhanced form of RSV disease presented by wheezing, fever, and bronchopneumonia. This enhanced form of the disease led to 80% hospitalization in the recipients of FIRSV compared to 5% in the control group. Additionally, 2 fatalities occurred among the vaccine recipients upon reinfection in subsequent years. Subsequent attempts to develop an attenuated live virus vaccine with optimal immune response and minimal reactogenicity have been unsuccessful. Further research on animal subjects suggested that intravenously administered immunoglobulin with high RSV neutralizing activity can protect against RSV infection. In 1995, the U.S. Food and Drug Administration (FDA) approved the use of RespiGam (RSV-IGIV) for the prevention of serious lower respiratory tract infection caused by RSV in children younger than 24 months of age with bronchopulmonary dysplasia or a history of premature birth. The success of the RSV-IGIV demonstrated efficacy in immunoprophylaxis and prompted research into further technologies. Thus, Palivizumab was developed as an antibody that was found to be fifty times more potent than its predecessor. This antibody has been widely used for RSV since 1998 when it was approved </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Lorlatinib and can you explain it in depth? [/INST] Lorlatinib, sold under the brand name Lorbrena in the United States, Canada, and Japan, and Lorviqua in the European Union, is an anti-cancer drug developed by Pfizer. It is an orally administered inhibitor of ALK and ROS1, two enzymes that play a role in the development of cancer.

Medical uses
Lorlatinib is approved in the US and in Europe for the second- or third-line treatment of ALK-positive metastatic non-small-cell lung cancer (NSCLC). It is the only ALK inhibitor with meaningful activity against ALK G1202R mutation in lung cancer.

Contraindications
Lorlatinib must not be combined with strong inducers (i.e. activators) of the liver enzymes CYP3A4/5 if it can be avoided, as serious cases of liver toxicity have been observed under combination with the CYP3A4/5 inducer rifampicin.

Side effects
The most common side effects in studies were high blood cholesterol (84% of patients), high blood triglycerides (67%), edema (55%), peripheral neuropathy (48%), cognitive effects (29%), fatigue (28%), weight gain (26%), and mood effects (23%). Serious side effects led to dose reduction in 23% of patients and in termination of lorlatinib treatment in 3% of patients.

Interactions
Lorlatinib is metabolized by the enzymes CYP3A4/5. Therefore, CYP3A4/5 inducers such as rifampicin, carbamazepine or St Johns wort decrease its concentrations in the blood plasma and can reduce its effectiveness. Additionally, the combination of lorlatinib with rifampicin showed liver toxicity in studies. Inhibitors of these enzymes such as ketoconazole or grapefruit juice increase lorlatinib plasma concentrations, leading to higher toxicity. Lorlatinib is also a (moderate) CYP3A4/5 inducer, so that  drugs that are metabolized by these enzymes are broken down more quickly when combined with lorlatinib. Examples include midazolam and ciclosporin.Interactions via other enzymes have only been studied in vitro. According to these findings, lorlatinib may inhibit CYP2C9, UGT1A1 and several transport proteins, induce CYP2B6, and has probably no relevant effect on CYP1A2.

Pharmacology
Mechanism of action
Lorlatinib is a small molecule kinase inhibitor of ALK and ROS1 as well as a number of other kinases. It is active in vitro against many mutated forms of ALK.

Pharmacokinetics
The drug is swallowed in the form of tablets. It reaches highest blood plasma concentrations 1.2 hours after a single dose, or 2 hours after ingestion when taken regularly. Its absolute bioavailability is 80.8%. Intake with fatty food increases its availability by 5%, which is not considered clinically significant. When in the bloodstream, 66% of the substance are bound to plasma proteins. Lorlatinib is able to cross the blood-brain barrier.Lorlatinib is inactivated by oxidation, mainly through CYP3A4, and by glucuronidation, mainly through UGT1A4. Other CYPs and UGTs play a minor role. Lorlatinib and its metabolites are excreted with a half-life of 23.6 hours after a single dose; 47.7% into the urine (of which less than 1% in unchanged form), and 40.9% into the faeces (9.1% unchanged).

Chemistry
Lorlatinib is a white to off-white powder </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Tiopronin and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Botulinum toxin and can you explain it in depth? [/INST] Botulinum toxin, often shortened to BoNT, is a neurotoxic protein produced by the bacterium Clostridium botulinum and related species. It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromuscular junction, thus causing flaccid paralysis. The toxin causes the disease botulism. The toxin is also used commercially for medical and cosmetic purposes.
The seven main types of botulinum toxin are named types A to G (A, B, C1, C2, D, E, F and G). New types are occasionally found. Types A and B are capable of causing disease in humans, and are also used commercially and medically. Types C–G are less common; types E and F can cause disease in humans, while the other types cause disease in other animals. Botulinum toxin types A and B are used in medicine to treat various muscle spasms.
Botulinum toxins are among the most potent toxins known. Intoxication can occur naturally as a result of either wound or intestinal infection or by ingesting formed toxin in food. The estimated human lethal dose of type A toxin is 1.3–2.1 ng/kg intravenously or intramuscularly, 10–13 ng/kg when inhaled, or 1000 ng/kg when taken by mouth. Commercial forms are marketed under the brand names Botox (onabotulinumtoxinA), Dysport/Azzalure (abobotulinumtoxinA), Xeomin/Bocouture (incobotulinumtoxinA), and Jeuveau (prabotulinumtoxinA).

Medical uses
Botulinum toxin is used to treat a number of therapeutic indications, many of which are not part of the approved drug label.

Muscle spasticity
Botulinum toxin is used to treat a number of disorders characterized by overactive muscle movement, including cerebral palsy, post-stroke spasticity, post-spinal cord injury spasticity, spasms of the head and neck, eyelid, vagina, limbs, jaw, and vocal cords. Similarly, botulinum toxin is used to relax the clenching of muscles, including those of the esophagus, jaw, lower urinary tract and bladder, or clenching of the anus which can exacerbate anal fissure. Botulinum toxin appears to be effective for refractory overactive bladder.

Other muscle disorders
Strabismus, otherwise known as improper eye alignment, is caused by imbalances in the actions of muscles that rotate the eyes. This condition can sometimes be relieved by weakening a muscle that pulls too strongly, or pulls against one that has been weakened by disease or trauma. Muscles weakened by toxin injection recover from paralysis after several months, so injection might seem to need to be repeated, but muscles adapt to the lengths at which they are chronically held, so that if a paralyzed muscle is stretched by its antagonist, it grows longer, while the antagonist shortens, yielding a permanent effect. If binocular vision is good, the brain mechanism of motor fusion, which aligns the eyes on a target visible to both, can stabilize the corrected alignment.In January 2014, botulinum toxin was approved by UKs Medicines and Healthcare products Regulatory Agency for treatment of restricted ankle motion due to lower-limb spasticity associated with stroke in adults.On 29 July 2016, the U.S. Food and Drug Administration (FDA) approved abobotulinumtoxinA for injection for the treatment of lower-limb spasticity in pediatric patients two years of age and older. AbobotulinumtoxinA is the first and only FDA-approved botulinum toxin for the treatment of pediatric lower limb spasticity. In the U.S., the FDA approves the text of the labels of prescription medicines and for which medical conditions the drug manufacturer may sell the drug. However, prescribers may freely prescribe them for any condition they wish, also known as off-label use. Botulinum toxins have been used off-label for several pediatric conditions, including infantile esotropia.

Excessive sweating
AbobotulinumtoxinA (BTX-A) has been approved for the treatment of excessive underarm sweating of unknown cause, which cannot be managed by topical agents.

Migraine
In 2010, the FDA approved intramuscular botulinum toxin injections for prophylactic treatment of chronic migraine headache.

Cosmetic Indications
In cosmetic applications, botulinum toxin is considered relatively safe and effective for reduction of facial wrinkles, especially in the uppermost third of the face. Commercial forms are marketed under the brand names Botox Cosmetic/Vistabel from Allergan, Dysport/Azzalure from Galderma and Ipsen, Xeomin/Bocouture from Merz, Jeuveau/Nuceiva from Evolus, manufactured by Daewoong in South Korea. DaxibotulinumtoxinA (Daxxify) was approved for medical use in the United States. In Europe, Letybo is also available, marketed by Croma and manufactured by Hugel in South Korea, along with the first liquid formulated botulinum toxin in Europe, Alluzience, from Galderma and Ipsen. The effects of current botulinum toxin injections for glabellar lines (11s lines between the eyes) typically last two to four months and in some cases, product-dependent, with some patients experiencing a longer duration of effect of up to 6 months or longer. Injection of botulinum toxin into the muscles under facial wrinkles causes relaxation of those muscles, resulting in the smoothing of the overlying skin. Smoothing of wrinkles is usually visible three to five days after injection, with maximum effect typically a week following injection. Muscles can be treated repeatedly to maintain the smoothed appearance.

Other
Botulinum toxin is also used to treat disorders of hyperactive nerves including excessive sweating, neuropathic pain, and some allergy symptoms. In addition to these uses, botulinum toxin is being evaluated for use in treating chronic pain. Studies show that botulinum toxin may be injected into arthritic shoulder joints to reduce chronic pain and improve range of motion. The use of botulinum toxin A in children with cerebral palsy is safe in the upper and lower limb muscles.

Side effects
While botulinum toxin is generally considered safe in a clinical setting, serious side effects from its use can occur. Most commonly, botulinum toxin can be injected into the wrong muscle group or with time spread from the injection site, causing temporary paralysis of unintended muscles.Side effects from cosmetic use generally result from unintended paralysis of facial muscles. These include partial facial paralysis, muscle weakness, and trouble swallowing. Side effects are not limited to direct paralysis, however, and can also include headaches, flu-like symptoms, and allergic reactions. Just as cosmetic treatments only last a number of months, paralysis side effects can have the same durations. At least in some cases, these effects are reported to dissipate in the weeks after treatment. Bruising at the site of injection is not a side effect of the toxin, but rather of the mode of administration, and is reported as preventable if the clinician applies pressure to the injection site; when it occurs, it is reported in specific cases to last 7–11 days. When injecting the masseter muscle of the jaw, loss of muscle function can result in a loss or reduction of power to chew solid foods. With continued high doses, the muscles can atrophy or lose strength; research has shown that those muscles rebuild after a break from Botox.Side effects from therapeutic use can be much more varied depending on the location of injection and the dose of toxin injected. In general, side effects from therapeutic use can be more serious than those that arise during cosmetic use. These can arise from paralysis of critical muscle groups and can include arrhythmia, heart attack, and in some cases, seizures, respiratory arrest, and death. Additionally, side effects common in cosmetic use are also common in therapeutic use, including trouble swallowing, muscle weakness, allergic reactions, and flu-like syndromes.In response to the occurrence of these side effects, in 2008, the FDA notified the public of the potential dangers of the botulinum toxin as a therapeutic. Namely, the toxin can spread to areas distant from the site of injection and paralyze unintended muscle groups, especially when used for treating muscle spasticity in children treated for cerebral palsy. In 2009, the FDA announced that boxed warnings would be added to available botulinum toxin products, warning of their ability to spread from the injection site. However, the clinical use of botulinum toxin A in cerebral palsy children has been proven to be safe with minimal side effects. Additionally, the FDA announced name changes to several botulinum toxin products, to emphasize that the products are not interchangeable and require different doses for proper use. Botox and Botox Cosmetic were given the INN of onabotulinumtoxinA, Myobloc as rimabotulinumtoxinB, and Dysport retained its INN of abobotulinumtoxinA. In conjunction with this, the FDA issued a communication to health care professionals reiterating the new drug names and the approved uses for each. A similar warning was issued by Health Canada in 2009, warning that botulinum toxin products can spread to other parts of the body.

Role in disease
Botulinum toxin produced by Clostridium botulinum is the cause of botulism. Humans most commonly ingest the toxin from eating improperly canned foods in which C. botulinum has grown. However, the toxin can also be introduced through an infected wound. In infants, the bacteria can sometimes grow in the intestines and produce botulinum toxin within the intestine and can cause a condition known as floppy baby syndrome. In all cases, the toxin can then spread, blocking nerves and muscle function. In severe cases, the toxin can block nerves controlling the respiratory system or heart, resulting in death.
Botulism can be difficult to diagnose, as it may appear similar to diseases such as Guillain–Barré syndrome, myasthenia gravis, and stroke. Other tests, such as brain scan and spinal fluid examination, may help to rule out other causes. If the symptoms of botulism are diagnosed early, various treatments can be administered. In an effort to remove contaminated food that remains in the gut, enemas or induced vomiting may be used. For wound infections, infected material may be removed surgically. Botulinum antitoxin is available and may be used to prevent the worsening of symptoms, though it will not reverse existing nerve damage. In severe cases, mechanical respiration may be used to support patients with respiratory failure. The nerve damage heals over time, generally over weeks to months. With proper treatment, the case fatality rate for botulinum poisoning can be greatly reduced.Two preparations of botulinum antitoxins are available for treatment of botulism. Trivalent (serotypes A, B, E) botulinum antitoxin is derived from equine sources using whole antibodies. The second antitoxin is heptavalent botulinum antitoxin (serotypes A, B, C, D, E, F, G), which is derived from equine antibodies that have been altered to make them less immunogenic. This antitoxin is effective against all main strains of botulism.

Mechanism of action
Botulinum toxin exerts its effect by cleaving key proteins required for nerve activation. First, the toxin binds specifically to nerves that use the neurotransmitter acetylcholine. Once bound to the nerve terminal, the neuron takes up the toxin into a vesicle by receptor-mediated endocytosis. As the vesicle moves farther into the cell, it acidifies, activating a portion of the toxin that triggers it to push across the vesicle membrane and into the cell cytoplasm. BoNTs recognize distinct classes of receptors simultaneously (gangliosides, synaptotagmin and SV2). Once inside the cytoplasm, the toxin cleaves SNARE proteins (proteins that mediate vesicle fusion, with their target membrane bound compartments) meaning that the acetylcholine vesicles cannot bind to the intracellular cell membrane, preventing the cell from releasing vesicles of neurotransmitter. This stops nerve signaling, leading to paralysis.The toxin itself is released from the bacterium as a single chain, then becomes activated when cleaved by its own proteases. The active form consists of a two-chain protein composed of a 100-kDa heavy chain polypeptide joined via disulfide bond to a 50-kDa light chain polypeptide. The heavy chain contains domains with several functions; it has the domain responsible for binding specifically to presynaptic nerve terminals, as well as the domain responsible for mediating translocation of the light chain into the cell cytoplasm as the vacuole acidifies. The light chain is a M27-family zinc metalloprotease and is the active part of the toxin. It is translocated into the host cell cytoplasm where it cleaves the host protein SNAP-25, a member of the SNARE protein family, which is responsible for fusion. The cleaved SNAP-25 cannot mediate fusion of vesicles with the host cell membrane, thus preventing the release of the neurotransmitter acetylcholine from axon endings. This blockage is slowly reversed as the toxin loses activity and the SNARE proteins are slowly regenerated by the affected cell.The seven toxin serotypes (A–G) are traditionally separated by their antigenicity. They have different tertiary structures and sequence differences. While the different toxin types all target members of the SNARE family, different toxin types target different SNARE family members. The A, B, and E serotypes cause human botulism, with the activities of types A and B enduring longest in vivo (from several weeks to months). Existing toxin types can recombine to create "hybrid" (mosaic, chimeric) types. Examples include BoNT/CD, BoNT/DC, and BoNT/FA, with the first letter indicating the light chain type and the latter indicating the heavy chain type. BoNT/FA received considerable attention under the name "BoNT/H", as it was mistakenly thought it could not be neutralized by any existing antitoxin.Botulinum toxins are closely related to tetanus toxin; the two are collectively known as Clostridium neurotoxins and the light chain is classified by MEROPS as family M27. Nonclassical types include BoNT/X (P0DPK1), which is toxic in mice and possibly in humans; a BoNT/J (A0A242DI27) found in cow Enterococcus; and a BoNT/Wo (A0A069CUU9) found in the rice-colonizing Weissella oryzae.

History
Initial descriptions and discovery of Clostridium botulinum
One of the earliest recorded outbreaks of foodborne botulism occurred in 1793 in the village of Wildbad in what is now Baden-Württemberg, Germany. Thirteen people became sick and six died after eating pork stomach filled with blood sausage, a local delicacy. Additional cases of fatal food poisoning in Württemberg led the authorities to issue a public warning against consuming smoked blood sausages in 1802 and to collect case reports of "sausage poisoning". Between 1817 and 1822, the German physician Justinus Kerner published the first complete description of the symptoms of botulism, based on extensive clinical observations and animal experiments. He concluded that the toxin develops in bad sausages under anaerobic conditions, is a biological substance, acts on the nervous system, and is lethal even in small amounts. Kerner hypothesized that this "sausage toxin" could be used to treat a variety of diseases caused by an overactive nervous system, making him the first to suggest that it could be used therapeutically. In 1870, the German physician Müller coined the term "botulism" to describe the disease caused by sausage poisoning, from the Latin word botulus, meaning "sausage".In 1895 Émile van Ermengem, a Belgian microbiologist, discovered what is now called Clostridium botulinum and confirmed that a toxin produced by the bacteria causes botulism. On 14 December 1895, there was a large outbreak of botulism in the Belgian village of Ellezelles that occurred at a funeral where people ate pickled and smoked ham; three of them died. By examining the contaminated ham and performing autopsies on the people who died after eating it, van Ermengem isolated an anaerobic microorganism that he called Bacillus botulinus. He also performed experiments on animals with ham extracts, isolated bacterial cultures, and toxins extracts from the bacteria. From these he concluded that the bacteria themselves do not cause foodborne botulism, but rather produce a toxin that causes the disease after it is ingested. As a result of Kerners and van Ermengems research, it was thought that only contaminated meat or fish could cause botulism. This idea was refuted in 1904 when a botulism outbreak occurred in Darmstadt, Germany, because of canned white beans. In 1910, the German microbiologist J. Leuchs published a paper showing that the outbreaks in Ellezelles and Darmstadt were caused by different strains of Bacillus botulinus and that the toxins were serologically distinct. In 1917, Bacillus botulinus was renamed Clostridium botulinum, as it was decided that term Bacillus should only refer to a group of aerobic microorganisms, while Clostridium would be only used to describe a group of anaerobic microorganisms. In 1919, Georgina Burke used toxin-antitoxin reactions to identify two strains of Clostridium botulinum, which she designated A and B.

Food canning
Over the next three decades, 1895–1925, as food canning was approaching a billion-dollar-a-year industry, botulism was becoming a public health hazard. Karl Friedrich Meyer, a Swiss-American veterinary scientist, created a center at the Hooper Foundation in San Francisco, where he developed techniques for growing the organism and extracting the toxin, and conversely, for preventing organism growth and toxin production, and inactivating the toxin by heating. The California canning industry was thereby preserved.

World War II
With the outbreak of World War II, weaponization of botulinum toxin was investigated at Fort Detrick in Maryland. Carl Lamanna and James Duff developed the concentration and crystallization techniques that Edward J. Schantz used to create the first clinical product. When the Armys Chemical Corps was disbanded, Schantz moved to the Food Research Institute in Wisconsin, where he manufactured toxin for experimental use and provided it to the academic community.
The mechanism of botulinum toxin action – blocking the release of the neurotransmitter acetylcholine from nerve endings – was elucidated in the mid-20th century, and remains an important research topic. Nearly all toxin treatments are based on this effect in various body tissues.

Strabismus
Ophthalmologists specializing in eye muscle disorders (strabismus) had developed the method of EMG-guided injection (using the electromyogram, the electrical signal from an activated muscle, to guide injection) of local anesthetics as a diagnostic technique for evaluating an individual muscles contribution to an eye movement. Because strabismus surgery frequently needed repeating, a search was undertaken for non-surgical, injection treatments using various anesthetics, alcohols, enzymes, enzyme blockers, and snake neurotoxins. Finally, inspired by Daniel B. Drachmans work with chicks at Johns Hopkins, Alan B. Scott and colleagues injected botulinum toxin into monkey extraocular muscles. The result was remarkable; a few picograms induced paralysis that was confined to the target muscle, long in duration, and without side effects.
After working out techniques for freeze-drying, buffering with albumin, and assuring sterility, potency, and safety, Scott applied to the FDA for investigational drug use, and began manufacturing botulinum type A neurotoxin in his San Francisco lab. He injected the first strabismus patients in 1977, reported its clinical utility in 1980, and had soon trained hundreds of ophthalmologists in EMG-guided injection of the drug he named Oculinum ("eye aligner").
In 1986, Oculinum Inc, Scotts micromanufacturer and distributor of botulinum toxin, was unable to obtain product liability insurance, and could no longer supply the drug. As supplies became exhausted, patients who had come to rely on periodic injections became desperate. For four months, as liability issues were resolved, American blepharospasm patients traveled to Canadian eye centers for their injections.Based on data from thousands of patients collected by 240 investigators, Oculinum Inc (which was soon acquired by Allergan) received FDA approval in 1989 to market Oculinum for clinical use in the United States to treat adult strabismus and blepharospasm. Allergan then began using the trademark Botox. This original approval was granted under the 1983 US Orphan Drug Act.

Cosmetics
The effect of BTX-A on reducing and eliminating forehead wrinkles was first described and published by Richard Clark, MD, a plastic surgeon from Sacramento, California. In 1987 Clark was challenged with eliminating the disfigurement caused by only the right side of the forehead muscles functioning after the left side of the forehead was paralyzed during a facelift procedure. This patient had desired to look better from her facelift, but was experiencing bizarre unilateral right forehead eyebrow elevation while the left eyebrow drooped, and she constantly demonstrated deep expressive right forehead wrinkles while the left side was perfectly smooth due to the paralysis. Clark was aware that Botulinum toxin was safely being used to treat babies with strabismus and he requested and was granted FDA approval to experiment with Botulinum toxin to paralyze the moving and wrinkling normal functioning right forehead muscles to make both sides of the forehead appear the same. This study and case report of the cosmetic use of Botulinum toxin to treat a cosmetic complication of a cosmetic surgery was the first report on the specific treatment of wrinkles and was published in the journal Plastic and Reconstructive Surgery in 1989. Editors of the journal of the American Society of Plastic Surgeons have clearly stated "the first described use of the toxin in aesthetic circumstances was by Clark and Berris in 1989."Jean and Alastair Carruthers observed that blepharospasm patients who received injections around the eyes and upper face also enjoyed diminished facial glabellar lines ("frown lines" between the eyebrows). Alastair Carruthers reported that others at the time also noticed these effects and discussed the cosmetic potential of botulinum toxin. Unlike other investigators, the Carruthers did more than just talk about the possibility of using botulinum toxin cosmetically. They conducted a clinical study on otherwise normal individuals whose only concern was their eyebrow furrow. They performed their study during 1987-1989 and presented their results at the 1990 annual meeting of the American Society for Dermatologic Surgery. Their findings were subsequently published in 1992.

Chronic pain
William J. Binder reported in 2000, that patients who had cosmetic injections around the face reported relief from chronic headache. This was initially thought to be an indirect effect of reduced muscle tension, but the toxin is now known to inhibit release of peripheral nociceptive neurotransmitters, suppressing the central pain processing systems responsible for migraine headache.

Society and culture
Economics
As of 2018, botulinum toxin injections are the most common cosmetic operation, with 7.4 million procedures in the United States, according to the American Society of Plastic Surgeons. Qualifications for Botox injectors vary by county, state, and country. Botox cosmetic providers include dermatologists, plastic surgeons, aesthetic spa physicians, dentists, nurse practitioners, nurses, and physician assistants.The global market for botulinum toxin products, driven by their cosmetic applications, was forecast to reach $2.9 billion by 2018. The facial aesthetics market, of which they are a component, was forecast to reach $4.7 billion ($2 billion in the U.S.) in the same timeframe.
Global Market
In 2019, 6,271,488 Botulinum Toxin procedures were administered worldwide. The Global Botulinum Toxin market size was US$4.83 billion in 2019 and is projected to reach US$7.71 billion by 2027.US Market
In 2020, 4,401,536 Botulinum Toxin Type A procedures were administered. In 2019 the botulinum Toxin market made US$3.19 billion.Botox cost
Botox cost is generally determined by the number of units administered (avg. $10.00 - $30.00 per unit) or by the area ($200–1000) and depends on expertise of a physician, clinic location, number of units, and treatment complexity.Insurance
Botox for medical purposes is usually covered by insurance if deemed medically necessary by your doctor and covers a plethora of medical problems including overactive bladder (OAB), urinary incontinence due to neurologic conditions, headaches and migraines, TMJ, spasticity in adult patients, cervical dystonia in adult patients, severe axillary hyperhidrosis (or other areas of the body), blepharospasm, upper or lower limb spasticity.Migraines
For migraine induced headaches the FDA-recommended dosage is 155 units and costs between $300 to $600 per treatment out of pocket when covered by insurance.Hyperhidrosis
Botox for excessive sweating is FDA approved.Cosmetic
Standard areas for aesthetics botox injections include facial and other areas that can form fine lines and wrinkles due to every day muscle contractions and/or facial expressions such as smiling, frowning, squinting, and raising eyebrows. These areas include the glabellar region between the eyebrows, horizontal lines on the forehead, crows feet around the eyes, and even circular bands that form around the neck secondary to platysmal hyperactivity.

Bioterrorism
Botulinum toxin has been recognized as a potential agent for use in bioterrorism. It can be absorbed through the eyes, mucous membranes, respiratory tract, and non-intact skin.
The effects of botulinum toxin are different from those of nerve agents involved insofar in that botulism symptoms develop relatively slowly (over several days), while nerve agent effects are generally much more rapid. Evidence suggests that nerve exposure (simulated by injection of atropine and pralidoxime) will increase mortality by enhancing botulinum toxins mechanism of toxicity.
With regard to detection, protocols using NBC detection equipment (such as M-8 paper or the ICAM) will not indicate a "positive" when samples containing botulinum toxin are tested. To confirm a diagnosis of botulinum toxin poisoning, therapeutically or to provide evidence in death investigations, botulinum toxin may be quantitated by immunoassay of human biological fluids; serum levels of 12–24 mouse LD50 units per milliliter have been detected in poisoned patients.Japanese doomsday cult Aum Shinrikyo produced botulinum toxin and spread it as an aerosol in downtown Tokyo during the 1990s, but the attacks caused no fatalities.During the early 1980s, German and French newspapers reported that the police had raided a Baader-Meinhof gang safe house in Paris and had found a makeshift laboratory that contained flasks full of Clostridium botulinum, which makes botulinum toxin. Their reports were later found to be incorrect; no such lab was ever found.

Brand names
Botulinum toxin A is sold under the brand names Jeuveau, Botox, and Xeomin. Botulinum toxin B is sold under the brand name Myobloc.In the United States, botulinum toxin products are manufactured by a variety of companies, for both therapeutic and cosmetic use. A U.S. supplier reported in its company materials in 2011 that it could "supply the worlds requirements for 25 indications approved by Government agencies around the world" with less than one gram of raw botulinum toxin. Myobloc or Neurobloc, a botulinum toxin type B product, is produced by Solstice Neurosciences, a subsidiary of US WorldMeds. AbobotulinumtoxinA), a therapeutic formulation of the type A toxin manufactured by Galderma in the United Kingdom, is licensed for the treatment of focal dystonias and certain cosmetic uses in the U.S. and other countries.Besides the three primary U.S. manufacturers, numerous other botulinum toxin producers are known. Xeomin, manufactured in Germany by Merz, is also available for both therapeutic and cosmetic use in the U.S. Lanzhou Institute of Biological Products in China manufactures a BTX-A product; as of 2014, it was the only BTX-A approved in China. BTX-A is also sold as Lantox and Prosigne on the global market. Neuronox, a BTX-A product, was introduced by Medy-Tox Inc. of South Korea in 2009.

Toxin production
Botulism toxins are produced by bacteria of the genus Clostridium, namely C. botulinum, C. butyricum, C. baratii and C. argentinense, which are widely distributed, including in soil and dust. Also, the bacteria can be found inside homes on floors, carpet, and countertops even after cleaning.
Food-borne botulism results, indirectly, from ingestion of food contaminated with Clostridium spores, where exposure to an anaerobic environment allows the spores to germinate, after which the bacteria can multiply and produce toxin. Critically, ingestion of toxin rather than spores or vegetative bacteria causes botulism. Botulism is nevertheless known to be transmitted through canned foods not cooked correctly before canning or after can opening, so is preventable. Infant botulism arising from consumption of honey or any other food that can carry these spores can be prevented by eliminating these foods from diets of children less than 12 months old.

Organism and toxin susceptibilities
Proper refrigeration at temperatures below 3 °C (38 °F) slows the growth of C. botulinum. The organism is also susceptible to high salt, high oxygen, and low pH levels. The toxin itself is rapidly destroyed by heat, such as in thorough cooking. The spores that produce the toxin are heat-tolerant and will survive boiling water for an extended period of time.The botulinum toxin is denatured and thus deactivated at temperatures greater than 85 °C (185 °F) for five minutes. As a zinc metalloprotease (see below), the toxins activity is also susceptible, post-exposure, to inhibition by protease inhibitors, e.g., zinc-coordinating hydroxamates.

Research
Blepharospasm and strabismus
University-based ophthalmologists in the US and Canada further refined the use of botulinum toxin as a therapeutic agent. By 1985, a scientific protocol of injection sites and dosage had been empirically determined for treatment of blepharospasm and strabismus. Side effects in treatment of this condition were deemed to be rare, mild and treatable. The beneficial effects of the injection lasted only 4–6 months. Thus, blepharospasm patients required re-injection two or three times a year.In 1986, Scotts micromanufacturer and distributor of Botox was no longer able to supply the drug because of an inability to obtain product liability insurance. Patients became desperate, as supplies of Botox were gradually consumed, forcing him to abandon patients who would have been due for their next injection. For a period of four months, American blepharospasm patients had to arrange to have their injections performed by participating doctors at Canadian eye centers until the liability issues could be resolved.In December 1989, Botox was approved by the U.S. FDA for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients over 12 years old.Botox has not been approved for any pediatric use. It has, however, been used off-label by physicians for several conditions, including spastic conditions in pediatric patients with cerebral palsy, a therapeutic course that has resulted in patient deaths. In the case of treatment of infantile esotropia in patients younger than 12 years of age, several studies have yielded differing results.

Cosmetic
The effect of BTX-A on reducing and eliminating forehead wrinkles was first described and published by Richard Clark, MD a plastic surgeon from Sacramento, California. In 1987 Clark was challenged with eliminating the disfigurement caused by only the right side of the forehead muscles functioning after the left side of the forehead was paralyzed during a facelift procedure. This patient had desired to look better from her facelift, but was experiencing bizarre unilateral right forehead eyebrow elevation while the left eyebrow drooped and she emoted with deep expressive right forehead wrinkles while the left side was perfectly smooth due to the paralysis. Clark was aware that Botulinum toxin was safely being used to treat babies with strabismus and he requested and was granted FDA approval to experiment with Botulinum toxin to paralyze the moving and wrinkling normal functioning right forehead muscles to make both sides of the forehead appear the same. This study and case report of the Cosmetic use of Botulinum toxin to treat a Cosmetic complication of a Cosmetic surgery was the first report on the specific treatment of wrinkles and was published in the journal Plastic and Reconstructive Surgery in 1989. Editors of the journal of the American Society of Plastic Surgeons have clearly stated "the first described use of the toxin in aesthetic circumstances was by Clark and Berris in 1989."JD and JA Carruthers also studied and reported in 1992 the use of BTX-A as a cosmetic treatment.[78] They conducted a study of patients whose only concern was their glabellar forehead wrinkle or furrow. Study participants were otherwise normal. Sixteen of seventeen patients available for follow-up demonstrated a cosmetic improvement. This study was reported at a meeting in 1991. The study for the treatment of glabellar frown lines was published in 1992. This result was subsequently confirmed by other groups (Brin, and the Columbia University group under Monte Keen). The FDA announced regulatory approval of botulinum toxin type A (Botox Cosmetic) to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines) in 2002 after extensive clinical trials. Well before this, the cosmetic use of botulinum toxin type A became widespread. The results of Botox Cosmetic can last up to four months and may vary with each patient. The U.S. Food and Drug Administration (FDA) approved an alternative product-safety testing method in response to increasing public concern that LD50 testing was required for each batch sold in the market.BTX-A has also been used in the treatment of gummy smiles, the material is injected into the hyperactive muscles of upper lip, which causes a reduction in the upward movement of lip thus resulting in a smile with a less exposure of gingiva. Botox is usually injected in the three lip elevator muscles that converge on the lateral side of the ala of the nose; the levator labii superioris (LLS), the levator labii superioris alaeque nasi muscle (LLSAN), and the zygomaticus minor (ZMi).

Upper motor neuron syndrome
BTX-A is now a common treatment for muscles affected by the upper motor neuron syndrome (UMNS), such as cerebral palsy, for muscles with an impaired ability to effectively lengthen. Muscles affected by UMNS frequently are limited by weakness, loss of reciprocal inhibition, decreased movement control, and hypertonicity (including spasticity). In January 2014, Botulinum toxin was approved by UKs Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of ankle disability due to lower limb spasticity associated with stroke in adults. Joint motion may be restricted by severe muscle imbalance related to the syndrome, when some muscles are markedly hypertonic, and lack effective active lengthening. Injecting an overactive muscle to decrease its level of contraction can allow improved reciprocal motion, so improved ability to move and exercise.

Sialorrhea
Sialorrhea is a condition where oral secretions are unable to be eliminated, causing pooling of saliva in the mouth. This condition can be caused by various neurological syndromes such as Bells_palsy, intellectual disability, and cerebral palsy. Injection of BTX-A into salivary glands is useful in reducing the secretions.

Cervical dystonia
BTX-A is commonly used to treat cervical dystonia, but it can become ineffective after a time. Botulinum toxin type B (BTX-B) received FDA approval for treatment of cervical dystonia on 21 December 2000. Brand names for BTX-B are Myobloc in the United States, and Neurobloc in the European Union.

Chronic migraine
Onabotulinumtoxin A (trade name Botox) received FDA approval for treatment of chronic migraines on 15 October 2010. The toxin is injected into the head and neck to treat these chronic headaches. Approval followed evidence presented to the agency from two studies funded by Allergan showing a very slight improvement in incidence of chronic migraines for those with migraines undergoing the Botox treatment.Since then, several randomized control trials have shown botulinum toxin type A to improve headache symptoms and quality of life when used prophylactically for patients with chronic migraine who exhibit headache characteristics consistent with: pressure perceived from outside source, shorter total duration of chronic migraines (<30 years), "detoxification" of patients with coexisting chronic daily headache due to medication overuse, and no current history of other preventive headache medications.

Depression
A few small trials have found benefits in people with depression. Research is based on the facial feedback hypothesis.

Premature ejaculation
The drug for the treatment of premature ejaculation has been under development since 7 August 2013, and is in Phase II of the FDA trials.

References
External links
BotDB: extensive resources on BoNT structures, inhibitors, kinetics, and literature
Overview of all the structural information available in the PDB for UniProt: P0DPI1 (Botulinum neurotoxin type A) at the PDBe-KB.
Overview of all the structural information available in the PDB for UniProt: P10844 (Botulinum neurotoxin type B) at the PDBe-KB.
Overview of all the structural information available in the PDB for UniProt: A0A0X1KH89 (Bontoxilysin A) at the PDBe-KB.
"OnabotulinumtoxinA". Drug Information Portal. U.S. National Library of Medicine.
"RimabotulinumtoxinB". Drug Information Portal </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Belumosudil and can you explain it in depth? [/INST] Belumosudil, sold under the brand name Rezurock among others, is a medication used for the treatment of chronic graft versus host disease (cGvHD).It is in the class of drugs known as  serine/threonine kinase inhibitors. Specifically, it is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2; ROCK-II).  Belumosudil binds to and inhibits the  serine/threonine kinase activity of ROCK2. This inhibits ROCK2-mediated signaling pathways which play major roles in pro- and anti-inflammatory immune cell responses.  A genomic study in human primary cells demonstrated that the drug also has effects on oxidative phosphorylation, WNT signaling, angiogenesis, and KRAS signaling.The most common side effects include infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma glutamyl transferase increased, lymphocytes decreased, and hypertension.Belumosudil was approved for medical use in the United States in July 2021.

Medical uses
Belumosudil is indicated for the treatment of people aged 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.

History
Originally developed by Surface Logix, Inc, belumosudil was later acquired by Kadmon Corporation. By July 2020, the drug completed Phase II clinical studies for cGvHD, IPF, and psoriasis.cGvHD is a complication that can follow  allogeneic stem cell or hematopoietic stem cell transplantation  where the transplanted cells (graft) attack healthy cells (host) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Pertuzumab/trastuzumab/hyaluronidase and can you explain it in depth? [/INST] Pertuzumab/trastuzumab/hyaluronidase, sold under the brand name Phesgo, is a fixed-dose combination medication to treat adults with HER2-positive breast cancer that has spread to other parts of the body, and for treatment of adults with early HER2-positive breast cancer. It contains pertuzumab, trastuzumab, and hyaluronidase–zzxf. It is injected under the skin via subcutaneous injection in the thigh. In the European Union, Phesgo contains the active ingredients pertuzumab and trastuzumab along with the enzyme vorhyaluronidase alfa.The most common side effects include alopecia (hair loss), nausea, diarrhea, anemia (reduced number of red blood cells) and asthenia (lack of energy). It can cause worsening of chemotherapy induced neutropenia (low level of white blood cells). It may cause harm to a developing fetus or a newborn baby.HER2-positive breast cancer, which makes up approximately one-fifth of breast cancers, has too much of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. Pertuzumab and trastuzumab bind to sites on HER2 and disrupt signaling to stop cancer cell growth.

Medical uses
The fixed-dose combination is indicated for the treatment of early breast cancer (EBC):

Use in combination with chemotherapy for:the neoadjuvant treatment of adults with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than two cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer;
the adjuvant treatment of adults with HER2-positive early breast cancer at high risk of recurrence.and for the treatment of metastatic breast cancer (MBC):

Use in combination with docetaxel for the treatment of adults with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Adverse effects
The FDA label includes a boxed warning about the risk of potential heart failure, fetal harm, and lung toxicity.

History
The fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase was approved for medical use in the United States in June 2020.The FDAs approval was based on the results of a non-inferiority study in participants with HER2-positive early breast cancer, which demonstrated the fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase had comparable efficacy and safety as IV pertuzumab and IV trastuzumab, except for administration-related reactions, which were higher with the fixed-dose combination due to the subcutaneous route of administration.Efficacy was investigated in FeDeriCa (NCT03493854), an open-label, multicenter, randomized trial enrolling 500 participants with operable or locally advanced HER2-positive breast cancer. Participants were randomized to receive neoadjuvant chemotherapy with concurrent administration of either the fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase or intravenous pertuzumab and intravenous trastuzumab during the neoadjuvant and adjuvant therapies.The primary endpoint of FeDeriCa was non-inferiority of cycle 7 pertuzumab serum trough concentration comparing the fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase to intravenous pertuzumab. Secondary endpoints included cycle 7 trastuzumab serum trough concentration, pathological complete response (pCR), and safety. The fixed-dose combination showed non-inferior pertuzumab and trastuzumab serum trough concentrations compared to intravenous pertuzumab and trastuzumab. The pCR rate was 59.7% (95% CI: 53.3, 65.8) in the pertuzumab/trastuzumab/hyaluronidase arm and 59.5% (95% CI: 53.2, 65.6) in the intravenous pertuzumab and intravenous trastuzumab arm. The safety profile of the fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase is comparable to intravenous pertuzumab and trastuzumab, except for increased administration-related reactions.The FDA granted approval of Phesgo to Genentech Inc.

Society and culture
Legal status
On 12 November 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Phesgo, intended for the treatment of early and metastatic breast cancer. The applicant for this medicinal product is Roche Registration GmbH. Phesgo was approved for medical use in the European Union in December 2020.

References
Further reading
"AusPAR: Pertuzumab/trastuzumab". Therapeutic Goods Administration (TGA) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Tretinoin/benzoyl peroxide and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Omeprazole/amoxicillin/rifabutin and can you explain it in depth? [/INST] Omeprazole/amoxicillin/rifabutin, sold under the brand name Talicia, is a fixed-dose combination medication used for the treatment of Helicobacter pylori infection </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Piroxicam and can you explain it in depth? [/INST] Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class used to relieve the symptoms of painful inflammatory conditions like arthritis. Piroxicam works by preventing the production of endogenous prostaglandins which are involved in the mediation of pain, stiffness, tenderness and swelling. The medicine is available as capsules, tablets and (not in all countries) as a prescription-free gel 0.5%. It is also available in a betadex formulation, which allows a more rapid absorption of piroxicam from the digestive tract. Piroxicam is one of the few NSAIDs that can be given parenteral routes.It was patented in 1968 by Pfizer and approved for medical use in 1979. It became generic in 1992, and is marketed worldwide under many brandnames.

Medical uses
It is used in the treatment of certain inflammatory conditions like rheumatoid and osteoarthritis, primary dysmenorrhoea, postoperative pain; and act as an analgesic, especially where there is an inflammatory component. The European Medicines Agency issued a review of its use in 2007 and recommended that its use be limited to the treatment of chronic inflammatory conditions, as it is only in these circumstances that its risk-benefit ratio proves to be favourable.

Adverse effects
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As with other NSAIDs the principal side effects include: digestive complaints like nausea, discomfort, diarrhoea and bleeds or ulceration of the stomach, as well as headache, dizziness, nervousness, depression, drowsiness, insomnia, vertigo, hearing disturbances (such as tinnitus), high blood pressure, oedema, light sensitivity, skin reactions (including, albeit rarely, Stevens–Johnson syndrome and toxic epidermal necrolysis) and rarely, kidney failure, pancreatitis, liver damage, visual disturbances, pulmonary eosinophilia and fibrosing alveolitis. Compared to other NSAIDs it is more prone to causing gastrointestinal disturbances and serious skin reactions.In October 2020, the U.S </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Vortioxetine and can you explain it in depth? [/INST] Vortioxetine, sold under the brand names Trintellix and Brintellix among others, is a medication used to treat major depressive disorder. Effectiveness is viewed as similar to that of other antidepressants. In the United Kingdom, it is only recommended in people who have not improved sufficiently on two other antidepressants. It is taken by mouth.Common side effects include nausea, vomiting, constipation, and sexual dysfunction. Serious side effects may include suicide in those under the age of 25, serotonin syndrome, bleeding, mania, and SIADH. A withdrawal syndrome may occur if the medication is abruptly stopped or the dose is decreased. Use during pregnancy and breastfeeding is not generally recommended. It is classified as a serotonin modulator and stimulator. How it works is not entirely clear but is believed to be related to increasing serotonin levels and possibly interacting with certain receptors for serotonin.It was approved for medical use in the United States in 2013. In 2017, it was the 312th most commonly prescribed medication in the United States, with more than one million prescriptions.

Medical uses
Vortioxetine is used as a treatment for major depressive disorder. Effectiveness appears to be similar to other antidepressants and in terms of effect size has been described as modest. Vortioxetine may be used when other treatments have failed. A 2017 Cochrane review on vortioxetine determined that the place for it in the treatment of severe depression is unclear due to low-quality evidence and that more study is needed comparing vortioxetine to selective serotonin reuptake inhibitors (SSRIs) which are typical first-line treatments.Vortioxetine is also used off-label for anxiety. A 2016 review found it was not useful in generalized anxiety disorder at 2.5, 5, and 10 mg doses (15 and 20 mg doses were not tested). A 2019 meta-analysis found that vortioxetine didnt produce statistically significant results over placebo in the symptoms, quality of life and remission rates of generalized anxiety disorder, but it was well-tolerated. However, a 2018 meta-analysis supported use and efficacy of vortioxetine for generalized anxiety disorder, though stated that more research was necessary to strengthen the evidence. A 2021 systematic review and meta-analysis concluded that there was uncertainty about the effectiveness of vortioxetine for anxiety due to existing evidence being very low-quality. In a 2020 network meta-analysis of randomized controlled trials, vortioxetine was associated with among the lowest remission rates for generalized anxiety disorder of the included medications (odds ratio = 1.30 for vortioxetine, range of odds ratios for other agents = 1.13–2.70).

Dosage
The recommended starting dosage of vortioxetine is 10 mg/day. The dosage should then be increased as tolerated to 20 mg/day. For individuals who dont tolerate higher doses, 5 mg/day may be considered. The maximum recommended dose of vortioxetine in known CYP2D6 poor metabolizers is 10 mg/day. Similarly, the dose should be reduced by half in those taking strong CYP2D6 inhibitors. Vortioxetine can be discontinued abruptly without tapering, but it is recommended that at doses of 15 to 20 mg/day it be tapered first to 10 mg/day one week prior to full discontinuation if possible.

Available forms
Vortioxetine is available in the form of 5, 10, and 20 mg immediate-release, film-coated oral tablets.

Contraindications
Vortioxetine is contraindicated in those with hypersensitivity to vortioxetine or to any other components of vortioxetine tablets. It is also contraindicated in those taking monoamine oxidase inhibitors (MAOIs) due to the possibility of serotonin syndrome.

Adverse effects
The most common side effects reported with vortioxetine are nausea, vomiting, constipation, and sexual dysfunction, among others. With the exceptions of nausea and sexual dysfunction, these side effects were reported by less than or equal to 10% of study participants given vortioxetine. Significant percentages of placebo-treated participants also report these side effects. Discontinuation of treatment due to adverse effects in clinical trials was 8% with vortioxetine versus 3% with placebo.Sexual dysfunction, such as decreased libido, abnormal orgasm, delayed ejaculation, and erectile dysfunction, are well-known side effects of SSRIs and serotonin–norepinephrine reuptake inhibitors (SNRIs). In clinical trials, sexual dysfunction occurred more often with vortioxetine than with placebo and appeared to be dose-dependent. The specific incidences of treatment-emergent sexual dysfunction as measured with the Arizona Sexual Experience Scale (ASEX) were 14 to 20% for placebo and 16 to 34% for vortioxetine over a dosage range of 5 to 20 mg/day. The incidence of sexual dysfunction with vortioxetine was similar to that with the SNRI duloxetine, which had an incidence of 26 to 28% at the used dosage of 60 mg/day. However, treatment-emergent sexual dysfunction caused by a prior SSRI was better improved by switching to vortioxetine than by switching to the SSRI escitalopram. In another study, vortioxetine at a dosage of 10 mg/day though not at 20 mg/day produced less sexual dysfunction than the SSRI paroxetine. These findings suggest that although vortioxetine can still cause sexual dysfunction itself, it may cause somewhat less sexual dysfunction than SSRIs and might be a useful alternative option for people experiencing sexual dysfunction with these medications. The rates of voluntarily or spontaneously reported sexual dysfunction with vortioxetine are much lower than with the ASEX, ranging from <1 to 5% for vortioxetine versus <1 to 2% for placebo in clinical trials.
Significant changes in body weight (gain or loss) were not observed with vortioxetine in clinical trials. Vortioxetine might cause less emotional blunting than SSRIs and SNRIs based on a couple of preliminary clinical studies.If vortioxetine is used in combination with other serotonergic drugs like MAOIs or SSRIs, this may result in serotonin syndrome.

Interactions
Vortioxetine is metabolized primarily by the cytochrome P450 enzyme CYP2D6. Inhibitors and inducers of CYP2D6 may modify the pharmacokinetics of vortioxetine and necessitate dosage adjustments.Bupropion, a strong CYP2D6 inhibitor, has been found to increase peak levels of vortioxetine by 2.1-fold and total vortioxetine levels by 2.3-fold (bupropion dosed at 300 mg/day and vortioxetine dosed at 10 mg/day). The incidence of side effects with vortioxetine, like nausea, headache, vomiting, and insomnia, was correspondingly increased with the combination. Other strong CYP2D6 inhibitors, like fluoxetine, paroxetine, and quinidine, may have similar influences on the pharmacokinetics of vortioxetine, and it is recommended that the dosage of vortioxetine be reduced by half when it is administered in combination with such medications. Lesser interactions have additionally been identified for vortioxetine with the cytochrome P450 inhibitors ketoconazole and fluconazole.Rifampicin, a strong and broad cytochrome P450 inducer (though notably not of CYP2D6), has been found to decrease peak levels of vortioxetine by 51% and total levels of vortioxetine by 72% (rifampicin dosed at 600 mg/day and vortioxetine at 20 mg/day). Similar influences on vortioxetine pharmacokinetics may also occur with other strong cytochrome P450 inducers like carbamazepine and phenytoin. As such, it is recommended that increasing vortioxetine dosage be considered when it is given in combination with strong cytochrome P450 inducers. The maximum recommended dose should not exceed three times the original vortioxetine dose.Vortioxetine and its metabolites show no meaningful interactions with a variety of assessed cytochrome P450 enzymes and transporters (e.g., P-glycoprotein) and hence vortioxetine is not expected to importantly influence the pharmacokinetics of other medications.The combination of vortioxetine with MAOIs, including other MAOIs like linezolid and intravenous methylene blue, may cause serotonin syndrome and is contraindicated. The risk of serotonin syndrome may also be increased when vortioxetine is combined with other serotonergic drugs, like SSRIs, SNRIs, tricyclic antidepressants (TCAs), triptans, tramadol, tryptophan, buspirone, St Johns wort, fentanyl, and lithium, among others. However, vortioxetine is not considered to be contraindicated with serotonergic medications besides MAOIs.

Pharmacology
Pharmacodynamics
Vortioxetine increases serotonin concentrations in the brain by inhibiting its reuptake in the synapse, and also modulates (activates or blocks) certain serotonin receptors. This puts it in the class of serotonin modulators and stimulators, which also includes vilazodone. More specifically, vortioxetine is a serotonin reuptake inhibitor, agonist of the serotonin 5-HT1A receptor, partial agonist of the 5-HT1B receptor, and antagonist of the serotonin 5-HT1D, 5-HT3, and 5-HT7 receptors, as well as an apparent ligand of the β1-adrenergic receptor. In terms of functional activity however, vortioxetine appears to be much more potent on serotonin reuptake inhibition and 5-HT3 receptor antagonism than for its interactions with the other serotonin receptors. Whereas vortioxetine has IC50 or EC50 values of 5.4 nM for the SERT and 12 nM for the 5-HT3 receptor, its values are 120 to 450 nM for the 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT7 receptors. This translates to about 22- to 83-fold selectivity for SERT inhibition and 10- to 38-fold selectivity for 5-HT3 antagonism over activities at the other serotonin receptors.It has been claimed that the serotonin transporter (SERT) and 5-HT3 receptor may be primarily occupied at lower clinical doses of vortioxetine and that the 5-HT1B, 5-HT1A, and 5-HT7 receptors may additionally be occupied at higher doses. Occupancy of the serotonin transporter with vortioxetine in young men was found to be highest in the raphe nucleus with median occupancies of 25%, 53%, and 98% after 9 days of administration with 2.5, 10, and 60 mg/day vortioxetine. In another study, serotonin transporter occupancy in men was 50%, 65%, and ≥80% for 5, 10, and 20 mg/day vortioxetine.Based on its clinical efficacy (e.g., at 5 mg/day), it appears that vortioxetine may produce antidepressant effects at SERT occupancy as low as 50%. This is in apparent contrast to SSRIs and SNRIs, which appear to require a minimum of 70 to 80% occupancy for antidepressant efficacy. These findings are suggestive that the antidepressant effects of vortioxetine may be mediated by serotonin receptor interactions in addition to serotonin reuptake inhibition. A study found no significant occupancy of the 5-HT1A receptor with vortioxetine at 30 mg/day for 9 days, which suggests that at least this specific serotonin receptor may not be involved in the clinical pharmacology of vortioxetine. However, methodological concerns were noted that may limit the interpretability of this result. Occupancy of other serotonin receptors like 5-HT3 and 5-HT7 by vortioxetine in humans does not seem to have been studied. In relation to the preceding, the contribution of serotonin receptor interactions to the antidepressant effects of vortioxetine is unknown and remains to be established. Uncertainties remain about whether vortioxetine is indeed a clinically multimodal antidepressant or whether it is effectively "[just] another selective serotonin reuptake inhibitor".Antagonism of the 5-HT3 receptor has been found to enhance the increase in brain serotonin levels produced by serotonin reuptake inhibition in animal studies. Whether or not the 5-HT3 receptor antagonism of vortioxetine likewise does this in humans or contributes to its clinical antidepressant efficacy is unclear. SSRIs and 5-HT1A receptor agonists often produce nausea as a side effect, whereas 5-HT3 receptor antagonists like ondansetron are antiemetics and have been found to be effective in treating SSRI-induced nausea. It was thought that the 5-HT3 receptor antagonism of vortioxetine would reduce the incidence of nausea relative to SSRIs. However, clinical trials found significant and dose-dependent rates of nausea with vortioxetine that appeared to be comparable to those found with the SNRI duloxetine.

Pharmacokinetics
Vortioxetine is well-absorbed when taken orally and has an oral bioavailability of 75%. It is systemically detectable after a single oral dose by 0.781 hours. Peak levels of vortioxetine are reached within 7 to 11 hours post-dose with single or multiple doses. Steady-state levels of vortioxetine are generally reached within 2 weeks of administration, with 90% of individuals reaching 90% of steady state after 12 days of administration. Steady-state peak levels of vortioxetine with doses of 5, 10, and 20 mg/day were 9, 18, and 33 ng/mL, respectively. The accumulation index of vortioxetine (area-under-the-curve levels after a single dose versus at steady state) is 5 to 6. A loading dose given intravenously has been found to achieve steady-state levels more rapidly with oral vortioxetine therapy. The pharmacokinetics of vortioxetine are known to be linear and dose proportional over a range of 2.5 to 75 mg for single doses and 2.5 to 60 mg for multiple doses. Food has no influence on the pharmacokinetics of vortioxetine.The apparent volume of distribution of vortioxetine is large and ranges from 2,500 to 3,400 L after single or multiple doses of 5 to 20 mg vortioxetine, with extensive extravascular distribution. The plasma protein binding of vortioxetine is approximately 98 or 99%, with about 1.25 ± 0.48% free or unbound.Vortioxetine is extensively metabolized by oxidation via cytochrome P450 enzymes and subsequent glucuronidation via UDP-glucuronosyltransferase. CYP2D6 is the primary enzyme involved in the metabolism of vortioxetine, but others including CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 are also involved. It is also metabolized by alcohol dehydrogenase, aldehyde dehydrogenase, and aldehyde oxidase. Six metabolites of vortioxetine have been identified. The major metabolite of vortioxetine (Lu AA34443) is inactive and its minor active metabolite (Lu AA39835) is not thought to cross the blood–brain barrier. The remaining metabolites are glucuronide conjugates. Hence, vortioxetine itself is thought to be primarily responsible for its pharmacological activity.The estimated total clearance of vortioxetine ranges from 30 to 41 L/h. The elimination half-life of vortioxetine is 66 hours, with a range of 59 to 69 hours after single or multiple doses. Elimination of vortioxetine is almost entirely via the liver (99%) rather than the kidneys (<1%). Approximately 85% of vortioxetine was recovered in a single-dose excretion study after 15 days, with 59% in urine and 26% in feces.

Pharmacogenomics
Genetic variations in cytochrome P450 enzymes can influence exposure to vortioxetine. CYP2D6 extensive metabolizers have approximately 2-fold higher clearance of vortioxetine than CYP2D6 poor metabolizers. The estimated clearance rates were 52.9, 34.1, 26.6, and 18.1 L/h for CYP2D6 ultra-rapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers. Area-under-the-curve levels of vortioxetine were 35.5% lower in CYP2D6 ultra-rapid metabolizers than in extensive metabolizers, though with significant overlap due to interindividual variability. Dosage adjustment for CYP2D6 ultra-rapid metabolizers is considered to not be necessary. Vortioxetine exposure in CYP2D6 poor metabolizers is expected to be approximately twice as high as in extensive metabolizers. Depending on the individual response, dosage adjustment may be considered for CYP2D6 poor metabolizers, with a maximum recommended dosage of 10 mg/day for known such individuals. In addition to CYP2D6, CYP2C19 extensive metabolizers have 1.4-fold higher clearance of vortioxetine than poor metabolizers. However, this is not considered to be clinically important and dose adjustment is not considered to be necessary based on CYP2C19 status.

Chemistry
Vortioxetine (1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine) is a bis-aryl-sulfanyl amine as well as piperazine derivative. The acid dissociation constant (pKa) values for vortioxetine hydrobromide were determined to be 9.1 (± 0.1) and 3.0 (± 0.2) according to an Australian Public Assessment Report.

History
Vortioxetine was discovered by scientists at Lundbeck who reported the rationale and synthesis for the drug (then called Lu AA21004) in a 2011 paper.In 2007, the compound was in Phase II clinical trials, and Lundbeck and Takeda entered into a partnership in which Takeda paid Lundbeck $40 million up-front, with promises of up to $345 million in milestone payments, and Takeda agreed to pay most of the remaining cost of developing the drug.  The companies agreed to co-promote the drug in the US and Japan, and that Lundbeck would receive a royalty on all such sales.  The deal included another drug candidate, tedatioxetine (Lu AA24530), and could be expanded to include two other Lundbeck compounds.Vortioxetine was approved by the U.S </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Fexofenadine and can you explain it in depth? [/INST] Fexofenadine, sold under the brand name Allegra among others, is an antihistamine pharmaceutical drug used in the treatment of allergy symptoms, such as hay fever and urticaria.Therapeutically, fexofenadine is a selective peripheral H1 blocker. It is classified as a second-generation antihistamine because it is less able to pass the blood–brain barrier and cause sedation, compared to first-generation antihistamines.It was patented in 1979 and came into medical use in 1996. It is on the World Health Organizations List of Essential Medicines. Fexofenadine has been manufactured in generic form since 2011. In 2019, it was the 283rd most commonly prescribed medication in the United States, with more than 1 million prescriptions.

Medical uses
Fexofenadine is used for relief from physical symptoms associated with seasonal allergic rhinitis and for treatment of chronic urticaria. It does not cure, but rather prevents the aggravation of allergic rhinitis and chronic idiopathic urticaria, and reduces the severity of the symptoms associated with those conditions, providing relief from repeated sneezing, runny nose, itchy eyes or skin, and general body fatigue. In a 2018 review, fexofenadine, along with levocetirizine, desloratadine, and cetirizine, was cited to be a safe to use for individuals with inherited long QT syndrome.

Efficacy
For the treatment of allergic rhinitis, fexofenadine is similarly effective to cetirizine, but is associated with less drowsiness than cetirizine. Fexofenadine was also shown to inhibit histamine-induced wheal and flare to a significantly greater degree than loratadine or desloratadine, but was slightly less effective than levocetirizine.Fexofenadine at doses above 120 mg a day does not appear to provide additional efficacy in the treatment of allergic rhinitis.

Side effects
The most common side effects include headache, back and muscle pain, miosis or pinpoint pupils, nausea, drowsiness, and menstrual cramps. Anxiety and insomnia have also been rarely reported. The most common side effects demonstrated during clinical trials were cough, upper respiratory tract infection, fever, and otitis media for children ages 6 to 11 and fatigue for children ages 6 months to 5 years.

Overdose
The safety profile of fexofenadine is quite favorable, as no cardiovascular or sedative effects have been shown to occur even when taking 10 times the recommended dose. Research on humans ranges from a single 800-mg dose, to a twice-daily, 690-mg dose for a month, with no clinically significant adverse effects, when compared to a placebo. No deaths occurred in testing on mice, at 5000 mg/kg body weight, which is 110 times the maximum recommended dose for an adult human. If overdose were to occur, supportive measures are recommended. Theoretically, an overdose could present as dizziness, dry mouth, and/or drowsiness, consistent with an exaggeration of the usual side effects. Hemodialysis does not appear to be an effective means of removing fexofenadine from the blood.

Pharmacology
Pharmacodynamics
Fexofenadine is a selective peripheral H1 receptor antagonist. Blockage prevents the activation of the H1 receptors by histamine, preventing the symptoms associated with allergies from occurring. Fexofenadine does not readily cross the blood–brain barrier, so is less likely to cause drowsiness in comparison to other antihistamines that readily cross that barrier (i.e., first-generation antihistamines such as diphenhydramine). In general, fexofenadine takes about an hour to take effect, though this may be affected by the choice of dosage form and the presence of certain foods.Fexofenadine also exhibits no anticholinergic, antidopaminergic, alpha 1-adrenergic, or beta-adrenergic receptor-blocking effects.

Pharmacokinetics
Absorption: After oral application, maximum plasma concentrations are reached after 2–3 hours. Fexofenadine should not be taken with a high-fat meal, as mean concentrations of fexofenadine in the bloodstream are seen to be reduced from 20 to 60% depending on form of medication (tablet, ODT, or suspension).
Distribution: Fexofenadine is 60–70% bound to plasma proteins, mostly albumin.
Metabolism: Fexofenadine is a substrate of CYP3A4, but only about 5% is metabolized by the liver, indicating that hepatic metabolism is relatively minor in clearance from the body.
Elimination: Most of the substance is eliminated unchanged via the feces (80%) and urine (11–12%).

Interactions
Taking erythromycin or ketoconazole while taking fexofenadine does increase the plasma levels of fexofenadine, but this increase does not influence the QT interval. The reason for this effect is likely due to transport-related effects, specifically involving p-glycoprotein (p-gp). Both erythromycin and ketoconazole are inhibitors of p-gp, a transporter protein involved in preventing the intestinal absorption of fexofenadine. When p-gp is inhibited, fexofenadine may be better absorbed by the body, increasing its plasma concentration by more than intended.Fexofenadine is not to be taken with apple, orange, or grapefruit juice because they could decrease absorption of the drug. Therefore, it should be taken with water. Grapefruit juice can significantly reduce the plasma concentration of fexofenadine.Antacids containing aluminum or magnesium should not be taken within 15 minutes of fexofenadine, as they reduce its absorption by almost 50%. This is not thought to be due to a change in pH (in fact, absorption can actually increase under increasingly alkaline pH), but rather due to the formation of metal complexes with charged/polar moieties on fexofenadine. As suggested by Shehnaza et al (2014), various sites of the molecule are thought to be responsible for this interaction, including the piperidine nitrogen, the carboxylic acid (-COOH) group, and both hydroxyl (-OH) groups.

History
The older antihistaminic agent terfenadine was found to metabolize into the related carboxylic acid, fexofenadine. Fexofenadine was found to retain all of the biological activity of its parent, while giving fewer adverse reactions in patients, so terfenadine was replaced in the market by its metabolite. Fexofenadine was originally synthesized in 1993 by Massachusetts-based biotechnology company Sepracor, which then sold the development rights to Hoechst Marion Roussel (now part of Sanofi-Aventis), and was later approved by the U.S. Food and Drug Administration (FDA) in 1996 </s>