Brentuximab vedotin is an antibody-drug conjugate approved to treat anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma. The drug was approved in August by FDA.

Antibody drug conjugate consists of an antibody linked to a payload drug. This kind of mechanism helps to deliver the drug to targeted cells like cancer cells.

The US Food and Drug Administration (FDA) has issued a warning about the lymphoma drug brentuximab (Adcetris, Seattle Genetics).

This warning comes after two new cases of progressive multifocal leukoencephalopathy a rare but serious brain infection.

A new Boxed Warning highlighting this risk has been added to the drug label.

In addition, a new Contraindication warning was added against use of Adcetris with the cancer drug bleomycin due to increased risk of lung toxicity.

Brentuximab was approved by the FDA in August 2011 for the treatment of Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma.

Healthcare professionals should suspend brentuximab dosing if PML is suspected, and discontinue the drug therapy if a diagnosis of PML is confirmed, according to the FDA.

Source: FDA site

Natalizumab is a humanized monoclonal antibody against the cellular adhesion molecule α4-integrin used in the treatment of multiple sclerosis and Crohn’s disease.

Natalizumab is administered by intravenous infusion every 28 days. The drug is believed to work by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood-brain barrier.

Natalizumab has been found to be effective in treating the symptoms in both Crohn’s disease and multiple sclerosis. In multiple sclerosis, it also is effective in preventing relapse, vision loss, cognitive decline and significantly improving quality of life in people.

It is effective in increasing rates of remission and preventing relapse in Crohn’s disease.

Mechanism of Action

Natalizumab is a humanized monoclonal antibody against alpha-4 (α4) integrin, which is required for white blood cells to move into organs. Thus natalizumab’s mechanism of action is believed to be the inhibition these immune cells from crossing blood vessel walls to reach affected organs.

Multiple Sclerosis

In multiple sclerosis, symptoms are believed to be caused when inflammatory cells such as T-lymphocytes pass through the blood-brain barrier through interaction with receptors on the endothelial cells.

Natalizumab appears to reduce the transmission of immune cells by interfering with the α4β1-integrin receptor molecules on the surfaces of cells.

The effect appears to occur on endothelial cells expressing the VCAM-1 gene, and in parenchymal cells expressing the osteopontin gene. I

Crohn’s disease

The interaction of the α4β7 integrin and the addressin  endothelial cell receptor is believed to contribute to the chronic bowel inflammation that causes Crohn’s disease. Addressin is primarily expressed in the endothelium of venules in the small intestine and are critical in guiding T-lymphocytes to lymphatic tissues in Peyer’s patches.

Patients with Croh’s disease have increased expression of addressin. Natalizumab is thought to block interaction between the α4β7 integrin and addressin at sites of inflammation.

Adverse Effects

• Fatigue
• Allergic reactions
• Exacerbation of Crohn’s disease in a minority of patients
• Liver injury
• Progressive ultifocal leukoencephalopathy [an opportunistic infection caused by the JC virus]

  Interactions

Drug has only been linked to Progressive ultifocal leukoencephalopathy when combined with other immune-modulating drugs.

New long-acting nonopioid anesthetic/analgesic for postsurgical pain by US Food and Drug Administration. The drug is bupivacaine extended-release liposome injection (Exparel, Pacira Pharmaceuticals).

Exparel consists of bupivacaine encapsulated in the multivesicular liposome DepoFoam [Pacira Pharmaceutical's extended drug-delivery technology].

The new product is designed to extend the duration of analgesia provided by bupivacaine. Exparel provides continuous and extended postsurgical analgesia for up to 72 hours compared with bupivacaine’s analgesic time of 7 hours.

The new drug is expected to reduce the dependence on opioid use in the postoperative setting.

New-generation anti-inflammatory drug natalizumab  in multiple sclerosis, published online October 5, show the drug reduces relapses and disability at 2 years, a Cochrane review findings suggest.

This new review is based on 3 key natalizumab trials involving 2223 patients.

Natalizumab is a monoclonal antibody that inhibits leukocyte migration across the blood–brain barrier. It is said to reduce inflammation in the central nervous system and has been approved worldwide for the treatment of relapsing-remitting multiple sclerosis.

The studies involved more than a single infusion of natalizumab at least 3 mg/kg infused intravenously every 4 weeks.

Natalizumab reduced the risk of experiencing a new exacerbation at 2 years by about 40%. Treatment lowered the risk for progression by approximately 25% compared with the control group.

Common adverse events included infusion reactions, anxiety, sinus congestion, lower limb swelling, rigors, vaginitis, and menstrual disorders.

The drug was found to be well tolerated during a follow-up period of 2 years.

The finndings of review become important because of  Progressive Multifocal Leukoencephalopathy cases associated with use of this drug.

In the trials included in this review, there were 2 cases of PML. One patient had received 29 doses of natalizumab, and a second case was fatal after 37 doses.

The authors pointed at various factors which seem to increase the risk of developing PML

• Natalizumab infusions a person receives
• Any previous immunosuppressive treatment
• Antibodies against John Cunningham virus

The authors pointed that the protocol for this review was insufficient to evaluate PML risk.

This study was supported by Cochrane Vaccines and the Multiple Sclerosis Association in Italy

Cochrane Database Syst Rev. Published online October 5, 2011.

A case control study published online September 6 in the Canadian Medical Association Journal says that nonaspirin nonsteroidal anti-inflammatory drugs use in early pregnancy is linked to twice the risk for miscarriage

The authors conducted the study with an aim to quantify the association between having a spontaneous abortion and types and dosages of nonaspirin NSAIDs in a cohort of pregnant women.”

The study consisted of 4705 women who were identified from the Quebec Pregnancy Registry and who had a spontaneous abortion.

For each case patient, 10 matched control participants were randomly selected. Case patients and control participants were compared in use of nonaspirin NSAIDs. The investigators analyzed associations between different types and dosages of nonaspirin NSAIDs and spontaneous abortion

Of the 4705 patients with spontaneous abortion, 352  had NSAID exposure [7.5%]  whereas in control only 12.6% had abortion.

The authors concluded that the use of nonaspirin NSAIDs during pregnancy was significantly associated with the risk for spontaneous abortion, after adjustment for potential confounders.

“Gestational exposure to any type or dosage of nonaspirin NSAIDs may increase the risk of spontaneous abortion,” the study authors write.

Limitations of Study

• Lack of data on exposure to over-the-counter formulations of nonaspirin NSAIDs during pregnancy
• Lack of information on the indications for which nonaspirin NSAIDs were used
• Covariables such as smoking and body mass index.
• The study population covered only 36% of pregnant women in Quebec.

THe authors have cautioned over the use of nonaspirin NSAIDs during early pregnancy.

CMAJ. Published online September 6, 2011.

A large systematic review confirms that rofecoxib is associated with a significantly increased risk of cardiovascular events and also suggests thatt diclofenac also poses an equivalent risk to patients.

Ibuprofen and naproxen are the least likely to increase the risk of MI and coronary heart disease death.

The study has been published by Patricia McGettigan  and David Henry on  September 27, 2011 in the open-access journal PLoS Medicine.

The systemic review included 31 case-control studies with 184 946 cardiovascular events and 21 cohort studies that include outcomes in more than 2.7 million individuals exposed to the drugs.

The new review confirms the increased risk of cardiovascular events with rofecoxib, as well as an increased risk with diclofenac.  The risk between the two drugs is nearly identical.

The authors recommended that clinicians should  not use diclofenac in certain patients.

The observation does not  matter in people at very low risk of a hea

Diclofenac has been found to increase the risk by about 40%.

[Note: Rofecoxib has already been withdrawn from market]

Naproxen and ibuprofen have been found safe drugs in cardiovascular patients  even at high doses.

The researchers also observed a significantly increased risk of cardiovascular events in patients treated with indomethacin.

PLOS Medicine, September Issue

Eplerenone  is an aldosterone antagonist, spironolactone.

Indications

Eplerenone is  indicated for the reduction of risk of cardiovascular death in patients with heart failure and left ventricular dysfunction within 3–14 days of an acute myocardial infarction, in combination with standard therapies and as treatment against hypertension.

Contraindications

• Hyperkalaemia
• Severe renal failure(creatinine clearance less than 30 ml/min)
• Severe hepatic impairment
• Concomitant treatment with ketoconazole, itraconazole
• Should not be prescribed with other potassium-sparing diuretics.

Adverse Effects

• Hyperkalaemia
• Hypotension
• Dizziness
• Altered renal function
• Increased creatinine concentration

Drug Interactions

Eplerenone is primarily metabolised by the cytochrome P450 enzyme CYP3A4.

The drugs that induce or inhibit  CYP3A4 produce interactions with the drug.

Potent inhibitors of CYP3A4 like ketoconazole and itraconazole are contraindicated as concomitant therapy.  Other CYP3A4 inhibitors including erythromycin, saquinavir, and verapamil should be used with caution.

The drugs that increase potassium concentrations may increase the risk of hyperkalaemia associated with eplerenone therapy, including salt substitutes,  potassium supplements and other potassium-sparing diuretics.

Routine checks on the individual’s potassium level to screen for hyperkalemia should be done.

In a randomized prospective crossover study published recently in Archives of Internal Medicine, it has been found that taking levothyroxine on an empty stomach at bedtime, instead of in the morning before breakfast results in significant improvements in thyroid hormone levels.

The study that included 90 patients who completed the study.

The author suggested that night time tablet is more convenient also

However, bedtime dosing, relative to morning dosing, had no significant impact on measures of quality of life (including fatigue, anxiety and depression), creatinine or lipid levels, blood pressure, body mass index or heart rate.

Arch Intern Med. 2010;170(22):1996-2003. doi:10.1001/archinternmed.2010.436

A recent publication in European Respiratory Journal has reported that inhaled corticosteroids  can slow the deterioration of  lung function in young children with cystic fibrosis.

The present study was led by Dr. De Boeck and colleagues who evaluated the effect of inhalational corticosteroids use on the evolution of lung function, growth, and insulin use in a retrospective analysis of data obtained from the Belgian Cystic Fibrosis Registry for the years 1998 to 2007. .

Eur Respir J. Posted November 11, 2010. Abstract