Adalimumab

Adalimumab, trade name Humira ("human monoclonal antibody in rheumatoid arthritis") is a TNF inhibiting anti-inflammatory drugmanufactured by AbbVie. It is the world's third largest-selling drug.^{[citation needed]}

Adalimumab binds to tumor necrosis factor-alpha (TNFα). TNFα normally binds to TNFα receptors, which leads to the inflammatory response of autoimmune diseases. By binding to TNFα, adalimumab reduces this inflammatory response. Adalimumab has been approved in the United States for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, moderate to severe chronic psoriasis and juvenile idiopathic arthritis.

In rheumatoid arthritis, adalimumab has a response rate similar to methotrexate, and in combination nearly doubles the response rate of methotrexate alone.^[1]

Because TNFα is part of the immune system that protects the body from infection, treatment with adalimumab may increase the risk of infections.

It is marketed in 0.8 mL vials, preloaded 0.8 mL syringes and also in preloaded pen devices (called Humira Pen), injected subcutaneously, typically by the patient at home. It cannot be administered orally because the digestive system would destroy the drug.^{[citation needed]}

Adalimumab was the first fully human monoclonal antibody drug approved by the FDA. It was derived from phage display,^[2] and was discovered through a collaboration between BASF Bioresearch Corporation (Worcester, Massachusetts, a unit of BASF) andCambridge Antibody Technology as D2E7,^[3] then further manufactured at BASF Bioresearch Corporation and developed by BASF Knoll (BASF Pharma) and, ultimately, manufactured and marketed by Abbott Laboratories after the acquisition of BASF Pharma by Abbott. On January 1, 2013 Abbott split into two companies, one retaining the Abbott name and the other named AbbVie. Humira is now owned by AbbVie.

Humira costs approximately $1,662 per month, like the TNF-alpha inhibitor etanercept (Enbrel).

In 2012, Humira had $4.3 billion of sales in the US,^[4] and $9.3 billion worldwide.^[5]

In December 2014, Cadila Healthcare Ltd., launched in India the first biosimilar version of adalimumab, under the name Exemptia, at a price of $200 a vial. Humira's U.S. patent will expire in 2016.

Adalimumab

Adalimumab, trade name Humira ("human monoclonal antibody in rheumatoid arthritis") is a TNF inhibiting anti-inflammatory drugmanufactured by AbbVie. It is the world's third largest-selling drug.^{[citation needed]}

Adalimumab binds to tumor necrosis factor-alpha (TNFα). TNFα normally binds to TNFα receptors, which leads to the inflammatory response of autoimmune diseases. By binding to TNFα, adalimumab reduces this inflammatory response. Adalimumab has been approved in the United States for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, moderate to severe chronic psoriasis and juvenile idiopathic arthritis.

In rheumatoid arthritis, adalimumab has a response rate similar to methotrexate, and in combination nearly doubles the response rate of methotrexate alone.^[1]

Because TNFα is part of the immune system that protects the body from infection, treatment with adalimumab may increase the risk of infections.

It is marketed in 0.8 mL vials, preloaded 0.8 mL syringes and also in preloaded pen devices (called Humira Pen), injected subcutaneously, typically by the patient at home. It cannot be administered orally because the digestive system would destroy the drug.^{[citation needed]}

Adalimumab was the first fully human monoclonal antibody drug approved by the FDA. It was derived from phage display,^[2] and was discovered through a collaboration between BASF Bioresearch Corporation (Worcester, Massachusetts, a unit of BASF) andCambridge Antibody Technology as D2E7,^[3] then further manufactured at BASF Bioresearch Corporation and developed by BASF Knoll (BASF Pharma) and, ultimately, manufactured and marketed by Abbott Laboratories after the acquisition of BASF Pharma by Abbott. On January 1, 2013 Abbott split into two companies, one retaining the Abbott name and the other named AbbVie. Humira is now owned by AbbVie.

Humira costs approximately $1,662 per month, like the TNF-alpha inhibitor etanercept (Enbrel).

In 2012, Humira had $4.3 billion of sales in the US,^[4] and $9.3 billion worldwide.^[5]

In December 2014, Cadila Healthcare Ltd., launched in India the first biosimilar version of adalimumab, under the name Exemptia, at a price of $200 a vial. Humira's U.S. patent will expire in 2016.

Nifedipine

Nifedipine (brand names Adalat CC and Procardia, according to FDA Orange Book) is a dihydropyridine calcium channel blockerthat primarily blocks L-type calcium channels.^[1] Its main uses are as an antianginal (especially in Prinzmetal's angina) andantihypertensive, although a large number of other indications have recently been found for this agent, such as Raynaud's phenomenon, premature labor, and painful spasms of the esophagus such as in cancer and tetanus patients. It is also commonly used for the small subset of pulmonary hypertension patients whose symptoms respond to calcium channel blockers. It is on theWorld Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.

Medical uses[edit]

The approved uses for are the long-term treatment of hypertension (high blood pressure) and angina pectoris. In hypertension, recent clinical guidelines generally favour diuretics and ACE inhibitors, although calcium channel antagonists, along with thiazide diuretics, are still favoured as primary treatment for patients over 55 and African American patients.^[3]

Sublingual nifedipine has previously been used in hypertensive emergencies. It was once frequently prescribed pro re nata to patients taking MAOIs for real or perceived hypertensive crises.^[4] This was found to be dangerous, and has been abandoned. Sublingual nifedipine causes blood-pressure lowering through peripheral vasodilation. It can cause an uncontrollable decrease in blood pressure, reflex tachycardia, and a steal phenomenon in certain vascular beds. There have been multiple reports in the medical literature of serious adverse effects with sublingual nifedipine, including cerebral ischemia/infarction, myocardial infarction, complete heart block, and death. As a result of this, the FDA reviewed all data regarding the safety and efficacy of sublingual nifedipine for hypertensive emergencies in 1995, and concluded that the practice should be abandoned because it was neither safe nor efficacious.^[5][6] An exception to the avoidance of this practice is in the use of nifedipine in the treatment of hypertension associated with autonomic dysreflexia in spinal cord injury.^[7]

Other uses[edit]

Nifedipine has been used frequently as a tocolytic (agent that delays premature labor). A Cochrane review has concluded that it is comparable with magnesium sulfate and beta-agonists (such as ritodrine) with fewer side-effects.^[8] Its role vis à vis atosiban is not established.

Raynaud's phenomenon is often treated with nifedipine. A 2005 meta-analysis showed modest benefits (33% decrease in attack severity, 2.8-5 reduction in absolute number of attacks per week); it does conclude that most included studies used low doses of nifedipine.^[9]

Topical nifedipine has been shown to be as effective as topical nitrates for anal fissures.^[10]

Nifedipine is also used in high-altitude medicine to treat high altitude pulmonary edema.^[11]

Oral nifedipine has also been found to cause iron loss in the urine of small animals.^[12] A NIH NIDDK study^[13] is currently seeing if the drug can increase the removal of iron into the urine in humans as well, thus becoming a possible treatment for iron overload.

A meta-analysis in 2006 showed that Nifedipine increased frequency of kidney stone passage by 90%.^{[citation needed]} However Nifedipine is rarely used for this indication.

Side effects[edit]

Nifedipine rapidly lowers blood pressure, and patients are commonly warned they may feel dizzy or faint after taking the first few doses. Tachycardia (fast heart rate) may occur as a reaction. These problems are much less frequent in the sustained-release preparations of nifedipine (such as Adalat OROS). A more novel release system is GITS (Gastro-Intestinal Therapeutic System), which - according to Bayer - provides 24-hour continuous release through an osmotic push system. Recent trials with GITS include INSIGHT (for blood pressure)^[14] and ACTION (for angina).^[15]

Extended release formulations of nifedipine should be taken on an empty stomach, and patients are warned not to consume anything containing grapefruit or grapefruit juice, as they raise blood nifedipine levels. There are several possible mechanisms, including the lowering of CYP3A4 activity.^[16]

Overdose[edit]

A number of persons have developed toxicity due to acute overdosage with nifedipine, either accidentally or intentionally, and via either oral or parenteral administration. The adverse effects include lethargy, bradycardia, marked hypotension and loss of consciousness. The drug may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients or to assist in a medicolegal death investigation. Analytical methods usually involve gas or liquid chromatography and specimen concentrations are usually in the 100-1000 μg/L range.^[17][18]

History[edit]

Nifedipine (initially BAY a1040) was developed by the German pharmaceutical company Bayer, with most initial studies being performed in the early 1970s.^[19]

The use of nifedipine and related calcium channel antagonists was much reduced in response to 1995 trials that mortality was increased in patients with coronary artery diseasewho took nifedipine.^[20] This study was a meta-analysis, and demonstrated harm mainly in short-acting forms of nifedipine (that could cause large fluctations in blood pressure) and at high doses of 80 mg a day and more.

Adenosine deaminase

Adenosine deaminase (also known as adenosine aminhydrolase, or ADA) is an enzyme (EC 3.5.4.4) involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues.

Present in virtually all mammalian cells, its primary function in humans is the development and maintenance of the immune system.^[1] However, the full physiological role of ADA is not yet completely understood.

Structure[edit]

ADA exists in both small form (as a monomer) and large form (as a dimer-complex).^[2] In the monomer form, the enzyme is a polypeptide chain,^[3] folded into eight strands of parallel α/β barrels, which surround a central deep pocket that is the active site.^[1] In addition to the eight central β-barrels and eight peripheral α-helices, ADA also contains five additional helices: residues 19-76 fold into three helices, located between β1 and α1 folds; and two antiparallel carboxy-terminal helices are located across the amino-terminal of the β-barrel.

The ADA active site contains a zinc ion, which is located in the deepest recess of the active site and coordinated by five atoms from His15, His17, His214, Asp295, and the substrate.^[1] Zinc is the only cofactor necessary for activity.

The substrate, adenosine, is stabilized and bound to the active site by nine hydrogen bonds.^[1] The carboxyl group of Glu217, roughly coplanar with the substrate purine ring, is in position to form a hydrogen bond with N1 of the substrate. The carboxyl group of Asp296, also coplanar with the substrate purine ring, forms hydrogen bond with N7 of the substrate. The NH group of Gly184 is in position to form a hydrogen bond with N3 of the substrate. Asp296 forms bonds both with the Zn²⁺ ion as well as with 6-OH of the substrate. His238 also hydrogen bonds to substrate 6-OH. The 3'-OH of the substrate ribose forms a hydrogen bond with Asp19, while the 5'-OH forms a hydrogen bond with His17. Two further hydrogen bonds are formed to water molecules, at the opening of the active site, by the 2'-OH and 3'-OH of the substrate.

Due to the recessing of the active inside the enzyme, the substrate once bound is almost completely sequestered from solvent.^[1] The surface exposure of the substrate to solvent when bound is 0.5% the surface exposure of the substrate in the free state.

Reactions[edit]

ADA irreversibly deaminates adenosine, converting it to the related nucleoside inosine by the substitution of the aminogroup for a hydroxyl group.

Inosine can then be deribosylated (removed from ribose) by another enzyme called purine nucleoside phosphorylase(PNP), converting it to hypoxanthine.

Mechanism[edit]

Two proposed mechanisms exist for ADA-catalyzed deamination: 1) stereospecific addition-elimination via tetrahedral intermediate or 2) an S_N2 reaction.^[2][4] By either mechanism, Zn²⁺ as a strong electrophile activates a water molecule, which is deprotonated by the basic Asp295 to form the attacking hydroxide.^[1] His238 orients the water molecule and stabilizes the charge of the attacking hydroxide. Glu217 is protonated to donate a proton to N1 of the substrate.

The reaction is stereospecific due to the location of the zinc, Asp295, and His238 residues, which all face the B-side of the purine ring of the substrate.^[1]

Competitive inhibition has been observed for ADA, where the product inosine acts at the competitive inhibitor to enzymatic activity.^[5]

Biological Function[edit]

ADA is considered one of the key enzymes of purine metabolism.^[4] The enzyme has been found in bacteria, plants, invertebrates, vertebrates, and mammals, with high conservation of amino acid sequence.^[2] The high degree of amino acid sequence conservation suggests the crucial nature of ADA in the purine salvage pathway.

Primarily, ADA in humans is involved in the development and maintenance of the immune system. However, ADA association has also been observed with epithelial cell differentiation, neurotransmission, and gestation maintenance.^[6] It has also been proposed that ADA, in addition to adenosine breakdown, stimulates release of excitatory amino acids and is necessary to the coupling of A1 adenosine receptors and heterotrimeric G proteins.^[2]

Pathology[edit]

Some mutations in the gene for adenosine deaminase cause it not to be expressed. The resulting deficiency is one cause of severe combined immunodeficiency (SCID).^[7] Deficient levels of ADA have also been associated with pulmonary inflammation, thymic cell death, and defective T-cell receptor signaling.^[8][9]

Conversely, mutations causing this enzyme to be overexpressed are one cause of hemolytic anemia .^[10]

There is some evidence that a different allele (ADA2) may lead to autism.^[11]

Elevated levels of ADA has also been associated with AIDS.^[8][12]

Isoforms[edit]

There are 2 isoforms of ADA: ADA1 and ADA2.

• ADA1 is found in most body cells, particularly lymphocytes and macrophages, where it is present not only in the cytosol and nucleus but also as the ecto- form on the cell membrane attached to dipeptidyl peptidase-4 (aka, CD26). ADA1 is involved mostly in intracellular activity, and exists both in small form (monomer) and large form (dimer).^[2] The interconversion of small to large forms is regulated by a 'conversion factor' in the lung.^[13]

• ADA2 was first identified in human spleen.^[14] It was subsequently found in other tissues including the macrophage where it co-exists with ADA1. The two isoforms regulate the ratio of adenosine to deoxyadenosine potentiating the killing of parasites. ADA2 is found predominantly in the human plasma and serum, and exists solely as a homodimer.^[15]

Clinical significance[edit]

ADA2 is the predominant form present in human blood plasma and is increased in many diseases, particularly those associated with the immune system: for example rheumatoid arthritis, psoriasis, and sarcoidosis. The plasma ADA2 isoform is also increased in most cancers. ADA2 is not ubiquitous but co-exists with ADA1 only in monocytes-macrophages.^{[citation needed]}

Total plasma ADA can be measured using high performance liquid chromatography or enzymatic or colorimetric techniques. Perhaps the simplest system is the measurement of the ammonia released from adenosine when broken down to inosine. After incubation of plasma with a buffered solution of adenosine the ammonia is reacted with a Berthelot reagent to form a blue colour which is proportionate to the amount of enzyme activity. To measure ADA2, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) is added prior to incubation so as to inhibit the enzymatic activity of ADA1.^[14] It is the absence of ADA1 that causes SCID.

ADA can also be used in the workup of lymphocytic pleural effusions or peritoneal ascites, in that such specimens with low ADA levels essentially excludes tuberculosis from consideration.^[16]

Tuberculosis pleural effusions can now be diagnosed accurately by increased levels of pleural fluid adenosine deaminase, above 40 U per liter.^[17]

Cladribine is an anti-neoplastic agent used in the treatment of hairy cell leukemia; its mechanism of action is inhibition of adenosine deaminase.

Ketorolac

Ketorolac or ketorolac tromethamine is a non-steroidal anti-inflammatory drug (NSAID) in the family of heterocyclic acetic acidderivatives, used as an analgesic. Ketorolac was developed in 1989 by Syntex Corp. (now Roche Bioscience, which is a wholly owned subsidiary of Roche holding Ltd., the parent company of Roche).^[1] It was approved by FDA on 30 November 1989 and introduced as Toradol by Syntex.^[2] The ophthalmic (i.e., eye-drop) form was approved by FDA on 9 November 1992 and was introduced as Acular eye drops by Allergan under license from Syntex.^[3] An intranasal formulation of ketorolac tromethamine was approved by FDA on 14 May 2010 and introduced as Sprix Nasal Spray by Daiichi Sankyo^[4] for short-term management of moderate to moderately severe pain requiring analgesia at the opioid level. In India it is available as Ketanov by Ranbaxy, which is owned by Daiichi Sankyo.

Ketorolac acts by inhibiting the bodily synthesis of prostaglandins. Ketorolac in its oral (tablet or capsule) and intramuscular (injected) preparations is a racemic mixture of both (S)-(−)-ketorolac, the active isomer, and (R)-(+)-ketorolac. An ophthalmic solution of ketorolac is available and is used to treat eye pain and to relieve the itchiness and burning of seasonal allergies.

Medical uses[edit]

Ketorolac is indicated for short-term management of moderate to severe pain.^[5] Concerns about the high incidence of reported side effects led to restriction in its dosage and maximum duration of use. In the UK, treatment should be initiated only in a hospital. Maximum duration of treatment should not exceed five days for tablets (per package insert), or two days for continuous daily dosing with intravenous or intramuscular formulations.^[6] The ophthalmic formulation can be used instead of steroidal anti inflammatories in cases where a raised intraocular pressure (glaucoma) is to be avoided.

Chemistry[edit]

Although its name does not suggest similarity with propionic acid derivatives (e.g. ketoprofen, flurbiprofen, naproxen, ibuprofen,carprofen etc.), ketorolac is an isostere of ketoprofen.^{[citation needed]} More precisely, it is a dihydropyrrolizine carboxylic acid derivative structurally related to indomethacin.^[7] NSAIDs (non-steroidal anti-inflammatory drug) are not recommended for use with other NSAIDs because of the potential for additive side effects. The protein-binding effect of most non-aspirin NSAIDs are inhibited by the presence of aspirin in the blood.

Mechanism of action[edit]

The primary mechanism of action responsible for ketorolac's anti-inflammatory, antipyretic and analgesic effects is the inhibition of prostaglandin synthesis by competitive blocking of the enzyme cyclooxygenase (COX). Ketorolac is a non-selective COX inhibitor.^[8]

Adverse effects[edit]

Concerns over the high incidence of reported side effects with ketorolac trometamol has led to its withdrawal (apart from the ophthalmic formulation) in several countries, while in others its permitted dosage and maximum duration of treatment have been reduced. From 1990 to 1993, 97 reactions with a fatal outcome were reported worldwide.^[9]

A postmarketing surveillance study^[10] indicated a dose-response relationship with average daily dose for both gastrointestinal bleeding and operative site bleeding, and an association between gastrointestinal bleeding and therapy for more than five days.

Contraindications[edit]

Ketorolac is contraindicated in patients with a previously demonstrated hypersensitivity to ketorolac, and in patients with the complete or partial syndrome of nasal polyps, angioedema, bronchospastic reactivity or other allergic manifestations to aspirin or other non-steroidal anti-inflammatory drugs (due to possibility of severe anaphylaxis). As with all NSAIDs, ketorolac should be avoided in patients with renal (kidney) dysfunction. (Prostaglandins are needed to dilate the afferent arteriole; NSAIDs effectively reverse this.) The patients at highest risk, especially in the elderly, are those with fluid imbalances or with compromised renal function (e.g., heart failure, diuretic use, cirrhosis, dehydration, and renal insufficiency).^{[medical citation needed]}

Patent controversy[edit]

The Syntex company, of Palo Alto, California developed the ophthalmic solution Acular, and holds the registered trademark on that name, as well as on the name Toradol. The actual product using this brand name is manufactured and distributed by Allergan under license from Syntex.^[11]

Apotex, a Canadian manufacturer, offers generic Ketorolac tromethamine as a 0.5% ophthalmic solution and as 10 mg tablets under the name "Apo-Ketorolac",^[12] in Canada and some other countries. Syntex and Allergan sued Apotex for patent infringement of US 5110493, over the generic ketorolac tomethamine product. In May, 2005, the United States Court of Appeals for the Federal Circuit handed Apotex a victory, ruling that a lower court upholding the Syntex patent misapplied the rules for judging whether an invention was obvious. Allergan had claimed that the patent was valid until 2009.