Methotrexate

Methotrexate abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions.It acts by inhibiting the metabolism of folic acid. Methotrexate began to replace the more toxic antifolate aminopterin starting in the 1950s. The drug was developed by Yellapragada Subbarao.

Medical uses

Chemotherapy

Methotrexate was originally developed and continues to be used for chemotherapy either alone or in combination with other agents. It is effective for the treatment of a number of cancers including: breast, head and neck, leukemia, lymphoma, lung, osteosarcoma, bladder, and trophoblastic neoplasms.

Autoimmune disorders

It is used as a treatment for some autoimmune diseases including: rheumatoid arthritis, psoriasis, psoriatic arthritis, and Crohn's disease, to name a few. Although methotrexate was originally designed as a chemotherapy drug (in high doses), in low-doses methotrexate is a safe and well tolerated drug in the treatment of certain autoimmune diseases. Because of its efficacy and safety, low-dose methotrexate is now first-line therapy for the treatment of rheumatoid arthritis. Indeed, multiple studies and reviews showed that patients receiving methotrexate for up to 1 year had less pain, functioned better, had fewer swollen and tender joints, and had less disease activity overall as reported by themselves and their doctors. X-rays also showed that the progress of the disease slowed or stopped in many patients receiving methotrexate.

It has also been used for multiple sclerosis but is not approved by the Food and Drug Administration.

Pregnancy termination

Methotrexate is commonly used (generally in combination with misoprostol) to terminate pregnancies during the early stages (i.e., as an abortifacient). It is also used to treat ectopic pregnancies.

Administration

It can be taken orally or administered by injection (intramuscular, intravenous, subcutaneous, or intrathecal). Oral doses are taken weekly not daily. Routine monitoring of the complete blood count, liver function tests, and creatine are recommended. Measurements of creatinine are recommended at least every 2 months.

Adverse effects

The most common adverse effects include: ulcerative stomatitis, low white blood cell count and thus predisposition to infection, nausea, abdominal pain, fatigue, fever, and dizziness.

Methotrexate is a highly teratogenic drug and categorized in pregnancy category X by the FDA. Women must not take the drug during pregnancy, if there is a risk of becoming pregnant, or if they are breastfeeding. Men who are trying to get their partner pregnant must also not take the drug. To engage in any of these activities (after discontinuing the drug), women must wait until the end of a full ovulation cycle and men must wait three months.

Central nervous system reactions to methotrexate have been reported, especially when given via the intrathecal route which include myelopathies and leucoencephalopathies. It has a variety of cutaneous side effects, particularly when administered in high doses.

Generally, the more "nonspecific" action a pharmacological substance has, the more possible side effects can be expected. Methotrexate has, like all "cell toxic" substances, a broad array of possible adverse effects. Care should always be taken to read the manufacturer's original instructions for the preparation in question.

Drug interactions

Penicillins may decrease the elimination of methotrexate and thus increase the risk of toxicity. While they may be used together increased monitoring is recommended.

Mechanism of action

Methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about one thousand-fold that of folate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. Also, folate is needed for purine base synthesis, so all purine synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.

Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle. Logically, it therefore has a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and gastrointestinal and oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and proliferation of these noncancerous cells, as well as causing the side effects listed below. Facing a scarcity of dTMP, rapidly dividing cancerous cells undergo cell death via thymineless death.

For the treatment of rheumatoid arthritis, patients should supplement their diets with folate. In these cases, inhibition of DHFR is not thought to be the main mechanism, but rather the inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine, or the inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells.

Pharmacokinetics

Methotrexate is a weak dicarboxylic acid with pKa 4.8 and 5.5, and thus it is mostly ionized at physiologic pH. Oral absorption is saturatable and thus dose-dependent, with doses less than 40 mg/m² having 42% bioavailability and doses greater than 40 mg/m² only 18%. Mean oral bioavailability is 33% (13-76% range), and there is no clear benefit to subdividing an oral dose. Mean intramuscular bioavailability is 76%.

Methotrexate is metabolized by intestinal bacteria to the inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid (DAMPA), which accounts for less than 5% loss of the oral dose.

Factors that decrease absorption include food, oral nonabsorbable antibiotics (e.g. vancomycin, neomycin, and bacitracin), and more rapid transit through the gastrointestinal tract (GI) tract, such as diarrhea, while slower transit time in the GI tract from constipation will increase absorption. Methotrexate is also administered in the placenta accreta, inhibiting the blood circulation to the target site.

History

In 1947, a team of researchers led by Sidney Farber showed aminopterin, a chemical analogue of folic acid developed by Yellapragada Subbarao Lederle, could induce remission in children with acute lymphoblastic leukemia. The development of folic acid analogues had been prompted by the discovery that the administration of folic acid worsened leukemia, and that a diet deficient in folic acid could, conversely, produce improvement; the mechanism of action behind these effects was still unknown at the time. Other analogues of folic acid were in development, and by 1950, methotrexate (then known as amethopterin) was being proposed as a treatment for leukemia. Animal studies published in 1956 showed the therapeutic index of methotrexate was better than that of aminopterin, and clinical use of aminopterin was thus abandoned in favor of methotrexate. In that same year, methotrexate was found to be a curative treatment for choriocarcinoma—a solid tumor, unlike leukemia, which is a cancer of the marrow. The drug was then investigated as a treatment for many other cancers, alone or in combination with other drugs, and was studied for other, noncancer indications in the 1970s. In 1988, it was approved by the U.S. Food and Drug Administration (FDA) to treat rheumatoid arthritis. In 2002, the FDA approved methotrexate to treat Crohn's disease.

Sleep apnea

What is sleep apnea?

If you have sleep apnea, there are times during the night when you stop breathing for 10 seconds or longer.

Sleep apnea can make you feel tired during the day.

You may wake up with a snorting, choking, or gasping sound. You start breathing again and go back to sleep. This can happen several times an hour, all night, so you can't stay in a deep sleep.

You may not even be aware that you woke up briefly. But if your sleep is upset throughout the night, you'll feel sleepy during the day.

The most common type of sleep apnea is called obstructive sleep apnea. It happens because the muscles in your throat relax, blocking the flow of air to your lungs. Your airway might be completely blocked or only partly blocked. When you stop breathing, the amount of oxygen in your blood drops. Your brain recognizes this and makes your body start breathing again.

Doctors call this type of disturbed sleep and daytime sleepiness obstructive sleep apnea/hypopnea syndrome (OSAHS).

There are also two other kinds of sleep apnea: central sleep apnea and complex sleep apnea.

To find out if you have sleep apnea, and how bad it is, your doctor will need to find out more about how well you breathe while you're asleep. He or she will also ask about how sleepy you are during the day.

Breathing during sleep

Your doctors needs to know how often there is a pause in your breathing. This helps them decide how severe your problem is. You might be asked to stay overnight in a sleep laboratory. Or your doctor might ask you to have your breathing measured at home.

Here's one guide that doctors use:

• If your breathing is affected between five and 20 times an hour, you have mild sleep apnea
• If your breathing is affected between 20 and 35 times an hour, you have moderate sleep apnea
• If your breathing is affected more than 35 times an hour, you have severe sleep apnea.

Daytime sleepiness

You may be asked to fill in a questionnaire called the Epworth Sleepiness Scale.

• If you feel drowsy or fall asleep when you're doing things that don't need much attention, like watching TV, you have mild sleep apnea. It only affects your life a little.
• If you feel drowsy or fall asleep doing things that require some attention, such as during a meeting or concert, you have moderate sleep apnea.
• If you feel drowsy or fall asleep doing things like eating, walking, or driving, you have severe sleep apnea. It affects your life a lot.

You are more likely to get sleep apnea if you are:

• Obese. This means you are very overweight. The extra fat around your neck makes it harder for you to keep your throat open when you sleep
• Older. The risk increases as you get older
• A man. Sleep apnea is twice as common among men as it is among women
• Someone who has large tonsils or adenoids
• A recreational user of ecstasy. One small study found a higher risk of sleep apnea for young people who had taken this illegal drug.

Sources for the information on this page:

1. American Academy of Sleep Medicine Task Force.Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research.
2. Young TB, Peppard P.Epidemiology of obstructive sleep apnea.In: McNicholas WT, Phillipson EA (editors). Breathing disorders in sleep. WB Saunders, London, UK; 2002: 31-43.
3. McCann UD, Sgambati FP, Schwartz AR, et al.Sleep apnea in young abstinent recreational MDMA ("ecstasy") consumers.

Obesity

What is obesity?

If you're obese, it means you weigh much more than is healthy for you. It happens because you eat more calories than your body uses. The extra calories are stored as fat.

Obesity is more than being just a few pounds overweight. It can cause serious health problems.

Being obese is more than being just a few pounds overweight. Obesity can cause health problems such as diabetes, high blood pressure, arthritis, and heart disease. And it makes some people feel bad about themselves.

Losing weight isn't easy. You'll need to change the way you eat and the amount of exercise you get. But if you make these changes, you'll be healthier.

Key points about obesity

• Obesity is a serious medical condition.
• Losing even a small amount of weight can lower the risk to your health.
• Cutting down on calories, getting more exercise, and learning good eating habits can help you lose weight.
• Medical treatments might also help.
• You're more likely to lose weight if you get help from a health professional.
• If you're very obese, surgery can help you lose a lot of weight. But there are risks with surgery, so doctors usually recommend it only if your weight is a danger to your health.

What's a healthy weight?

When doctors talk about a "healthy" or "ideal" weight, they mean a weight that lowers your risk of getting serious health problems, such as heart disease or high blood pressure. It's not based on how thin you would like to look. ¹

Most doctors use the body mass index (BMI for short) to figure out whether you're at a healthy weight. Your BMI is a single number that's worked out from your height and weight.

This table shows what the different BMI scores mean.

BMI	What it means
Less than 18.5	Underweight
18.5 to 24.9	Healthy weight
25 to 29.9	Overweight
30 or greater	Obese

You might have read that there are problems with using someone's BMI to find out if they're overweight. For example, an athlete who's very muscular might have a BMI that suggests they're overweight, even though they're healthy. That's because muscle is heavier than fat. However, for most people, working out their BMI is a quick and simple way of finding whether their weight is healthy.

How your body uses food

Food gives you energy. The amount of energy in food is measured in calories (short for kilocalories, or kcal).

Your body needs energy all the time, especially for moving and keeping warm. Different people need different amounts of energy. The amount of energy you need depends on your metabolic rate. And the more active you are, the more energy you use.

Your brain helps you stay a healthy weight. It helps to balance how much you eat with how much energy you burn. Your brain sends out "hungry" or "full" signals that make you want to eat or stop eating.

What happens in obesity?

Being obese is not the same as being a few pounds overweight. Doctors say someone is obese if their BMI is 30 or higher (see the table above). For most people, having a BMI greater than 30 means they're at least 30 pounds overweight.

If you're obese, it means you're eating more calories than your body is using up as energy. Your body stores the extra calories as fat.

Doctors aren't sure why some people eat more food than they need. There are probably lots of reasons.

One theory is that early humans probably had to go for long periods without food, so our bodies needed to be able to store fat easily in order to survive. But nowadays we can get food easily. Some scientists think that our bodies haven't had enough time to evolve and adapt to a plentiful supply of food.So, our bodies still work as if we might have to face a famine.

And for some people who are obese, their "full" and "hungry" signals may not work properly.

For some people, this happens because of a medical condition, or because of side effects of medications. Medical conditions that can cause obesity include having an underactive thyroid. Medicines that can make you put on weight include some antidepressants and corticosteroids.

"It must be my glands"

Like many people who are overweight, you might feel that you don't eat a lot. You might think that your weight problems must be due to something else, such as a "slow metabolism" or your "glands." ⁵

Some medical conditions can make you more likely to put on weight. But you can only become obese by eating more calories than your body uses.

Medical conditions such as hypothyroidism and medications such as steroids make it more likely that you'll put on weight. Some conditions make you feel more hungry. Other conditions slow down your metabolic rate, so you use fewer calories. And some of these conditions affect your glands.

If you have one of these conditions, you might find it more difficult to keep your weight down. It's important to get medical help.

"But I don't eat that much"

The bad news is that you only have to eat slightly more calories than you use for the weight to add up.

• The average American over age 25 takes in only 0.3 percent more energy than they use each day. This about 150 calories, which is the number of calories in a small soda.
• Over time, this extra energy adds up. It's stored as fat.
• By the age of 55, that average American has gained 20 pounds.

If the amount of fat in your body increases gradually, your body doesn't seem to notice that you're putting on weight. Your appetite might stay the same.

Obesity and our lifestyle

There are two things about our Western lifestyle that are linked to more and more people becoming obese:

• Modern fast-food culture
• Lack of physical activity.

Because we're less active than people were in the past, and because fatty and sugary foods are so widely available, it's very easy to gain weight. Some doctors think it would make a difference if unhealthy foods were more clearly labeled. Others think that fast-food ads aimed at children should be banned. These things might make it easier for people to eat a healthy diet and avoid being overweight. But you'd still need to make sure you didn't eat more calories than you needed.

Obesity: why me?

Anybody can become obese if they eat more calories than they use. But there are certain things that make this more likely. These are called risk factors. Some of these you can control, others you can't.

Here are some of the things that make it more likely that you'll become obese. It's probably a combination of these factors that lead to obesity in most people.

Your parents and your genes

You're at risk of obesity if one or both of your parents is overweight or obese. This might be because you share the same genes as your parents. Or it could be because family members tend to eat the same things and have a similar lifestyle.

The ob gene

Genes are in every cell in your body. They tell cells how to grow and what to do. The ob gene tells the cells in your body that store fat to make a chemical called leptin. Leptin tells the brain how hungry or how full you feel. It also helps your body burn the food you eat to keep you warm.

Researchers think that some people who are obese might have a faulty ob gene. So these people don't make enough leptin. This makes it harder for them to control how much they eat because they don't sense when they feel hungry or full. This makes them more likely to be obese. ¹¹

But this problem is rare. Most people with obesity don't have this problem.

Comfort eating

You might eat too much as a way of dealing with painful or difficult emotions. Perhaps you eat when you feel unhappy or bored, even if you don't feel hungry. This is often called comfort eating. It can be hard to break this habit.

You might also eat too much if you have a mental health condition, such as depression or anxiety disorder, or if you feel bad about yourself (have low self-esteem).

Other risk factors

Many things make it more likely that you'll gain too much weight. If you're overweight, there's a risk you might become obese.

• Your sex: Women are slightly more likely to be overweight than men are.
• Your ethnic group: Women who are Mexican-American or African-American are particularly at risk.
• Age: Men and women are most likely to gain weight between the ages of 20 and 40.
• Menopause: The changes in levels of hormones during menopause can make it easier to gain weight.
• Drinking too much alcohol: Alcoholic beverages are high in calories.
• Quitting smoking: Quitting smoking is good for your health, but you might gain weight afterward.
• Being married: Married people are more likely to be overweight than those who stay single.
• Having children: Women are likely to gain about 2 pounds each time they have a baby.
• Poor education: People who do less well at school are more likely to get obese later in life.