Transcription

Treatment of Haemophilia

Though there is no cure for haemophilia, it can be controlled with regular infusions of the deficient clotting factor, i.e. factor VIII in haemophilia A or factor IX in haemophilia B. Some haemophiliacs develop antibodies (inhibitors) against the replacement factors given to them, so the amount of the factor has to be increased or non-human replacement products must be given, such as porcine factor VIII.

If a patient becomes refractory to replacement coagulation factor as a result of circulating inhibitors, this may be overcome with recombinant human factor VII (NovoSeven®), which is registered for this indication in many countries.

In western countries, common standards of care fall into one of two categories: prophylaxis or on-demand. Prophylaxis involves the infusion of clotting factor on a regular schedule in order to keep clotting levels sufficiently high to prevent spontaneous bleeding episodes. On-demand treatment involves treating bleeding episodes once they arise. In 2007, a clinical trial was published in the New England Journal of Medicine comparing on-demand treatment of boys (< 30 months) with Haemophilia A with prophylactic treatment (infusions of 25 IU/kg body weight of Factor VIII every other day) in respect to its effect on the prevention of joint-diseases. When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group had a normal index joint-structure on MRI. [6] Prophylactic treatment, however, resulted in average costs of $300,000 per year. The author of an editorial published in the same issue of the New England Journal of Medicine demands more clinical studies addressing the cost-effectiveness of prophylactic treatment. [7]

Armour and other pharmaceutical companies knowingly sold blood clotting products contaminated with HIV and hepatitis C to ten thousand haemophiliacs across America in the late 1970's and early mid 1980's. When the Federal Government banned their products from being sold in America, they promptly turned around and sold the HIV contaminated factor products overseas in Europe and Japan. [8]

Later criminal and civil lawsuits were brought against these manufacturers [8] and the Armour Pharmaceutical subsidiary of French chemical company Rhone-Poulenc. In Europe and Japan several high level executives received prison terms as a result of their knowingly selling HIV contaminated products to innocent haemophiliacs.

In America the pharmaceutical companies eventually paid out around 650 million dollars to compensate the haemophiliacs who were infected with HIV.

As a direct result of the contamination of the blood supply in the late 1970s and early/mid 1980s with viruses such as Hepatitis and HIV, new methods were developed in the production of clotting factor products. The initial response was to heat-treat (pasteurize) plasma-derived factor concentrate, followed by the development of monoclonal factor concentrates, which use a combination of heat treatment and affinity chromatography to inactivate any viral agents in the pooled plasma from which the factor concentrate is derived. The Lindsay Tribunal in Ireland investigated, among other things, the slow adoption of the new methods.

Since 1993 (Dr. Mary Nugent), recombinant factor products (which are typically cultured in Chinese hamster ovary (CHO) tissue culture cells and involve little, if any human plasma products) have become available and are widely used in wealthier western countries. While recombinant clotting factor products offer higher purity and safety, they are, like concentrate, extremely expensive, and not generally available in the developing world. In many cases, factor products of any sort are difficult to obtain in developing countries.

It was claimed that Rasputin was successful at treating the Tsarevich Alexei of Russia's haemophilia: however, to this day it is unclear how he accomplished this.

People affected with Hemophilia are recommended to do some specific exercises for elbow, knee, and ankles like stretching of calves, ankle circles, elbow flexion, and Quadriceps set etc. These exercises are recommended after an internal bleed occurs and on a daily basis to strengthen the muscles and joints to prevent new bleeding problems.

Causes of haemophilia

It is caused by a lack of clotting factors:

* Haemophilia A involves a lack of the clotting Factor VIII. (This represents 90% of haemophilia cases.[citation needed])
* Haemophilia B involves a lack of the clotting Factor IX.
* Haemophilia C involves a lack of the clotting Factor XI.
* Hypofibrinogenemia involves a lack of the clotting factor Factor I. Because it is so rare, about 1 or 2 cases per million births, it has no definite treatment approved by the FDA. It affects males and females equally. The blood of people with Hypofibrinogenemia neither clots nor contains sufficient amounts of Fibrinogen.

Haemophilia or hemophilia (from Greek haima "blood" and philia "to love"[1]) is the name of a family of hereditary genetic disorders that impair the body's ability to control blood clotting, or coagulation. In the most common form, haemophilia A, clotting factor VIII is absent. Hemophilia B, also known as factor IX deficiency, is the second most common type of hemophilia, but Hemophilia B is far less common than Hemophilia A. Occurring in about one in 25,000 male births.[2]

The effects of this sex-linked, X chromosome disorder are manifested almost entirely in males, although the gene for the disorder is inherited from the mother. In about 30% of cases of Hemopilia B, however, there is no family history of the disorder and the condition is the result of a spontaneous gene mutation. [3] A mother who is a carrier also has a 50% chance of giving the faulty X chromosome to her daughter. That does not give the daughter the hemophilia disease, but it does result in the daughter becoming a hemophilia carrier. Females are almost exclusively asymptomatic carriers of the disorder, and may have inherited it from either their mother or father.

These genetic deficiencies may lower blood plasma clotting factor levels of coagulation factors needed for a normal clotting process. When a blood vessel is injured, a temporary scab does form, but the missing coagulation factors prevent fibrin formation which is necessary to maintain the blood clot. Thus a haemophiliac does not bleed more intensely than a normal person, but for a much longer amount of time. In severe haemophiliacs even a minor injury could result in blood loss lasting days, weeks, or not ever healing completely. The critical risk here is with normally small bleeds which due to missing factor VIII take long times to heal. In areas such as the brain or inside joints this can be fatal or life debilitating.

The bleeding with external injury is normal, but incidence of late re-bleeding and internal bleeding is increased, especially into muscles, joints, or bleeding into closed spaces. Major complications include hemarthrosis, hemorrhage, gastrointestinal bleeding, and menorrhagia.

Malaria

Malaria is a serious disease caused by a parasite. Infected mosquitoes spread it. Malaria is a major cause of death worldwide, but it is almost wiped out in the United States. The disease is mostly a problem in developing countries with warm climates. If you travel to these countries, you are at risk. There are four different types of malaria caused by four related parasites. The most deadly type occurs in Africa south of the Sahara Desert.

Malaria symptoms include chills, flu-like symptoms, fever, vomiting, diarrhea and jaundice. The disease can be life-threatening. However, you can treat malaria with medicines. The type of medicine depends on which kind of malaria you have and where you were infected.

Malaria can be prevented. When traveling to malaria-prone regions

• See your doctor for medicines that protect you
• Wear insect repellent with DEET
• Cover up
• Sleep under mosquito netting

AIDS

Also called: HIV

AIDS stands for acquired immunodeficiency syndrome. It is the most advanced stages of infection with the human immunodeficiency virus (HIV). HIV is a virus that kills or damages cells of the body's immune system.

HIV most often spreads through unprotected sex with an infected person. AIDS may also spread by sharing drug needles or through contact with the blood of an infected person. Women can give it to their babies during pregnancy or childbirth.

The first signs of HIV infection may be swollen glands and flu-like symptoms. These may come and go a month or two after infection. Severe symptoms may not appear until months or years later.

A blood test can tell if you have HIV infection. Your health care provider can perform the test, or call the National AIDS hotline for a referral at (800) 342-AIDS (1-800-342-2437). There is no cure, but there are many medicines to fight both HIV infection and the infections and cancers that come with it. People can live with the disease for many years.

Lung Cancer

Also called: Bronchogenic carcinoma

Lung cancer is one of the most common cancers in the world. It is a leading cause of cancer death in men and women in the United States. Cigarette smoking causes most lung cancers. The more cigarettes you smoke per day and the earlier you started smoking, the greater your risk of lung cancer. High levels of pollution, radiation and asbestos exposure may also increase risk.

Common symptoms of lung cancer include

• A cough that doesn't go away and gets worse over time
• Constant chest pain
• Coughing up blood
• Shortness of breath, wheezing, or hoarseness
• Repeated problems with pneumonia or bronchitis
• Swelling of the neck and face
• Loss of appetite or weight loss
• Fatigue

There are many types of lung cancer. Each type of lung cancer grows and spreads in different ways and is treated differently. Treatment also depends on the stage, or how advanced it is. Treatment may include chemotherapy, radiation and surgery.

National Cancer Institute

Signs and symptoms Of Diabetes Mellitus

The classical triad of diabetes symptoms is polyuria, polydipsia and polyphagia, which are, respectively, frequent urination; increased thirst and consequent increased fluid intake; and increased appetite. Symptoms may develop quite rapidly (weeks or months) in type 1 diabetes, particularly in children. However, in type 2 diabetes the symptoms develop much more slowly and may be subtle or completely absent. Type 1 diabetes may also cause weight loss (despite normal or increased eating) and irreducible fatigue. These symptoms can also manifest in type 2 diabetes in patients whose diabetes is poorly controlled.

When the glucose concentration in the blood is raised beyond the renal threshold, reabsorption of glucose in the proximal renal tubuli is incomplete, and part of the glucose remains in the urine (glycosuria). This increases the osmotic pressure of the urine and inhibits the reabsorption of water by the kidney, resulting in increased urine production (polyuria) and increased fluid loss. Lost blood volume will be replaced osmotically from water held in body cells, causing dehydration and increased thirst.

Prolonged high blood glucose causes glucose absorption, which leads to changes in the shape of the lenses of the eyes, resulting in vision changes. Blurred vision is a common complaint leading to a diabetes diagnosis; type 1 should always be suspected in cases of rapid vision change whereas type 2 is generally more gradual, but should still be suspected.

Patients (usually with type 1 diabetes) may also present with diabetic ketoacidosis (DKA), an extreme state of metabolic dysregulation characterized by the smell of acetone on the patient's breath; a rapid, deep breathing known as Kussmaul breathing; polyuria; nausea; vomiting and abdominal pain; and any of many altered states of consciousness or arousal (such as hostility and mania or, equally, confusion and lethargy). In severe DKA, coma may follow, progressing to death. Diabetic ketoacidosis is a medical emergency and requires hospital admission.

A rarer but equally severe possibility is hyperosmolar nonketotic state, which is more common in type 2 diabetes and is mainly the result of dehydration due to loss of body water. Often, the patient has been drinking extreme amounts of sugar-containing drinks, leading to a vicious circle in regard to the water loss.

Diabetes mellitus

Diabetes mellitus (IPA: /ˌdaɪəˈbiːtiːz/ or /ˌdaɪəˈbiːtəs/, /məˈlaɪtəs/ or /ˈmɛlətəs/), often simply diabetes (Greek: διαβήτης), is a syndrome characterized by disordered metabolism and inappropriately high blood sugar (hyperglycaemia) resulting from either low levels of the hormone insulin or from abnormal resistance to insulin's effects coupled with inadequate levels of insulin secretion to compensate.^[2] The characteristic symptoms are excessive urine production (polyuria), excessive thirst and increased fluid intake (polydipsia), and blurred vision; these symptoms are likely absent if the blood sugar is only mildly elevated.

The World Health Organization recognizes three main forms of diabetes mellitus: type 1, type 2, and gestational diabetes (occurring during pregnancy),^[3] which have different causes and population distributions. While, ultimately, all forms are due to the beta cells of the pancreas being unable to produce sufficient insulin to prevent hyperglycemia, the causes are different.^[4] Type 1 diabetes is usually due to autoimmune destruction of the pancreatic beta cells. Type 2 diabetes is characterized by insulin resistance in target tissues, this causes a need for abnormally high amounts of insulin and diabetes develops when the beta cells cannot meet this demand. Gestational diabetes is similar to type 2 diabetes in that it involves insulin resistance; the hormones of pregnancy can cause insulin resistance in women genetically predisposed to developing this condition.

Gestational diabetes typically resolves with delivery of the child, however types 1 and 2 diabetes are chronic conditions.^[2] All types have been treatable since insulin became medically available in 1921. Type 1 diabetes, in which insulin is not secreted by the pancreas, is directly treatable only with injected or inhaled insulin, although dietary and other lifestyle adjustments are part of management. Type 2 may be managed with a combination of dietary treatment, tablets and injections and, frequently, insulin supplementation. While insulin was originally produced from natural sources such as porcine pancreas, most insulin used today is produced through genetic engineering, either as a direct copy of human insulin, or human insulin with modified molecules that provide different onset and duration of action. Insulin can also be delivered continuously by a specialized pump which subcutaneously provides insulin through a changeable catheter.

Diabetes can cause many complications.


Acute complications (hypoglycemia, ketoacidosis or nonketotic hyperosmolar coma) may occur if the disease is not adequately controlled. Serious long-term complications include cardiovascular disease (doubled risk), chronic renal failure, retinal damage (which can lead to blindness), nerve damage (of several kinds), and microvascular damage, which may cause impotence and poor healing. Poor healing of wounds, particularly of the feet, can lead to gangrene, which may require amputation. Adequate treatment of diabetes, as well as increased emphasis on blood pressure control and lifestyle factors (such as not smoking and keeping a healthy body weight), may improve the risk profile of most aforementioned complications. In the developed world, diabetes is the most significant cause of adult blindness in the non-elderly, the leading cause of non-traumatic amputation in adults, and diabetic nephropathy is the main illness requiring renal dialysis in the United States.^[5]

Tuberculosis treatment

Active tuberculosis will kill about two of every three people affected if left untreated. Treated tuberculosis has a mortality rate of less than 5% (or less in developed countries where intensive supportive measures are available).

The standard "short" course treatment for tuberculosis (TB), if it is active, is isoniazid, rifampicin, pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin alone for a further four months. The patient is considered cured at six months (although there is still a relapse rate of 2 to 3%). For latent tuberculosis, the standard treatment is six to nine months of isoniazid alone.

If the organism is known to be fully sensitive, then treatment is with isoniazid, rifampicin, and pyrazinamide for two months, followed by isoniazid and rifampicin for four months. Ethambutol need not be used.

Drugs

First line tuberculosis drugs
3-letter	1-letter	Drug
EMB	E	ethambutol
INH	H	isoniazid
PZA	Z	pyrazinamide
RMP	R	rifampicin
STM	S	streptomycin
Second line tuberculosis drugs
CIP	(none)	ciprofloxacin
MXF	(none)	moxifloxacin
PAS	P	p-aminosalicylic acid

All first-line anti-tuberculous drug names have a standard three-letter and a single-letter abbreviation:

• streptomycin is STM or S,
• isoniazid is INH or H,
• rifampicin is RMP or R,
• ethambutol is EMB or E,
• pyrazinamide is PZA or Z.

The US commonly uses abbreviations and names that are not internationally recognised: rifampicin is called rifampin and abbreviated RIF; streptomycin is commonly abbreviated SM.

Drug regimens are similarly abbreviated in a standardised manner. The drugs are listed using their single letter abbreviations (in the order given above, which is roughly the order of introduction into clinical practice). A prefix denotes the number of months the treatment should be given for; a subscript denotes intermittent dosing (so ₃ means three times a week) and no subscript means daily dosing. Most regimens have an initial high-intensity phase, followed by a continuation phase (also called a consolidation phase or eradication phase): the high-intensity phase is given first, then the continuation phase, the two phases divided by a slash.

So,

2HREZ/4HR₃

means isoniazid, rifampicin, ethambutol, pyrazinamide daily for two months, followed by four months of isoniazid and rifampicin given three times a week.

These standard abbreviations are used in the rest of this article.

There are six classes of second-line drugs (SLDs) used for the treatment of TB. A drug may be classed as second-line instead of first-line for one of two possible reasons: it may be less effective than the first-line drugs (e.g., p-aminosalicylic acid); or, it may have toxic side-effects (e.g., cycloserine); or it may be unavailable in many developing countries (e.g., fluoroquinolones):

• aminoglycosides: e.g., amikacin (AK), kanamycin;
• polypeptides: e.g., capreomycin, viomycin, enviomycin;
• fluoroquinolones: e.g., ciprofloxacin (CIP), moxifloxacin (MXF);
• thioamides: e.g. ethionamide, prothionamide
• cycloserine (the only antibiotic in its class);
• p-aminosalicylic acid (PAS or P).

Other drugs that may be useful, but are not on the WHO list of SLDs:

• rifabutin
• macrolides: e.g., clarithromycin (CLR);
• linezolid (LZD);
• thioacetazone (T);
• thioridazine;
• arginine;
• vitamin D;
• R207910.

These drugs may be considered "third-line drugs" and are listed here either because they are not very effective (e.g., clarithromycin) or because their efficacy has not been proven (e.g., linezolid, R207910). Rifabutin is effective, but is not included on the WHO list because for most developing countries, it is impractically expensive.

The standard regimen

Rationale and evidence for the standard regimen

Tuberculosis has been treated with combination therapy for over fifty years. Drugs are not used singly (except in latent TB or chemoprophylaxis), and regimens that use only single drugs result in the rapid development of resistance and treatment failure.^[1][2] The rationale for using multiple drugs to treat TB are based on simple probability. The frequency of spontaneous mutations that confer resistance to an individual drug are well known: 1 in 10⁷ for EMB, 1 in 10⁸ for STM and INH, and 1 in 10¹⁰ for RMP.^[3]

A patient with extensive pulmonary TB has approximately 10¹² bacteria in his body, and therefore will probably be harboring approximately 10⁵ EMB-resistant bacteria, 10⁴ STM-resistant bacteria, 10⁴ INH-resistant bacteria and 10² RMP-resistant bacteria. Resistance mutations appear spontaneously and independently, so the chances of him harbouring a bacterium that is spontaneously resistant to both INH and RMP is 1 in 10⁶, and the chances of him harbouring a bacterium that is spontaneously resistant to all four drugs is 1 in 10¹¹. This is, of course, an oversimplification, but it is a useful way of explaining combination therapy.

There are other theoretical reasons for supporting combination therapy. The different drugs in the regimen have different modes of action: INH and EMB are bacteriostatic (they stop the bacteria replicating, but do not kill them); RMP is bacteriocidal (it actually kills bacteria).

All TB regimens in use were 18 months or longer until the appearance of rifampicin. In 1953, the standard UK regimen was 3SPH/15PH or 3SPH/15SH₂. Between 1965 and 1970, EMB replaced PAS. RMP began to be used to treat TB in 1968 and the BTS study in the 1970s showed that 2HRE/7HR was efficacious. In 1984, a BTS study showed that 2HRZ/4HR was efficacious,^[4] with a relapse rate of less than 3% after two years.^[5] In 1995, with the recognition that INH resistance was increasing, the BTS recommended adding EMB or STM to the regimen: 2HREZ/4HR or 2SHRZ/4HR, which are the regimens currently recommended. The WHO also recommend a six month continuation phase of HR if the patient is still culture positive after 2 months of treatment (approximately 15% of patients with fully-sensitive TB) and for those patients who have extensive bilateral cavitation at the start of treatment.

Monitoring and DOTS

DOTS stands for "Directly Observed Therapy, Short-course" and is a major plank in the WHO global TB eradication programme. The WHO advises that all TB patients should have at least the first two months of their therapy observed (and preferably the whole of it observed): this means an independent observer watching tuberculosis patients swallow their anti-TB therapy. The independent observer is often not a healthcare worker and may be a shopkeeper or a tribal elder or similar senior person within that society. DOTS is used with intermittent dosing (thrice weekly or 2HREZ/4HR₃). Twice weekly dosing is effective^[6] but not recommended by the WHO, because there is no margin for error (accidentally omitting one dose per week results in once weekly dosing, which is ineffective).

Treatment with properly implemented DOTS has a success rate exceeding 95% and prevents the emergence of further multi-drug resistant strains of tuberculosis.

Some people recommend monthly surveillance until cultures convert to negative; this does not form any part of the UK or WHO recommendations for TB. If cultures are positive or symptoms do not resolve after three months of treatment, it is necessary to re-evaluate the patient for drug-resistant disease or nonadherence to drug regimen. If cultures do not convert to negative despite three months of therapy, consider initiating directly observed therapy.

Extra-pulmonary tuberculosis

Tuberculosis not affecting the lungs is called extra-pulmonary tuberculosis. Disease of the central nervous system is specifically excluded from this classification.

The UK and WHO recommendation is 2HREZ/4HR; the US recommendation is 2HREZ/7HR. There is good evidence from randomised-controlled trials to say that in tuberculous lymphadenitis^[7] and in TB of the spine,^[8][9][10] the six month regimen is equivalent to the nine month regimen; the US recommendation is therefore not supported by the evidence.

Up to 25% of patients with TB of the lymph nodes (TB lymphadenitis) will get worse on treatment before they get better and this usually happens in the first few months of treatment. A few weeks after starting treatment, lymph nodes often start to enlarge, and previously solid lymph nodes may become fluctuant. This should not be interpreted as failure of therapy and is a common reason for patients (and their physicians) to panic unnecessarily. With patience, two to three months into treatment the lymph nodes start to shrink again and re-aspiration or re-biopsy of the lymph nodes is unnecessary: if repeat microbiological studies are ordered, they will show the continued presence of viable bacteria with the same sensitivity pattern, which further adds to the confusion: physicians inexperienced in the treatment of TB will then often add second-line drugs in the belief that the treatment is not working. In these situations, all that is required is re-assurance. Steroids may be useful in resolving the swelling, especially if it is painful, but they are unnecessary. Additional antibiotics are unnecessary and the treatment regimen does not need to be lengthened.

Tuberculosis of the central nervous system

Tuberculosis may affect the central nervous system (meninges, brain or spinal cord) in which case it is called TB meningitis, TB cerebritis, and TB myelitis respectively; the standard treatment is 12 months of drugs (2HREZ/10HR) and steroid are mandatory. Diagnosis is difficult as CSF culture is positive in less than half of cases, and therefore a large proportion of cases are treated on the basis of clinical suspicion alone. PCR of CSF does not significantly improve the microbiology yield; culture remains the most sensitive method and a minimum of 5 ml (preferably 20 ml) of CSF should be sent for analysis. TB cerebritis (or TB of the brain) may require brain biopsy in order to make the diagnosis, because the CSF is commonly normal: this is not always available and even when it is, some clinicians would debate whether it is justified putting a patient through such an invasive and potentially dangerous procedure when a trial of anti-TB therapy may yield the same answer; probably the only justification for brain biopsy is when drug-resistant TB is suspected. It is possible that shorter durations of therapy (e.g. six months) may be sufficient to treat TB meningitis, but no clinical trial has addressed this issue. The CSF of patients with treated TB meningitis is commonly abnormal even at 12 months;^[11] the rate of resolution of the abnormality bears no correlation with clinical progress or outcome,^[12] and is not an indication for extending or repeating treatment; repeated sampling of CSF by lumbar puncture to monitor treatment progress should therefore not be done.

Although TB meningitis and TB cerebritis are classified together, the experience of many clinicians is that their progression and response to treatment is not the same. TB meningitis usually responds well to treatment, but TB cerebritis may require prolonged treatment (up to two years) and the steroid course needed is often also prolonged (up to six months). Unlike TB meningitis, TB cerebritis often required repeated CT or MRI imaging of the brain to monitor progress.

CNS TB may be secondary to blood-borne spread: therefore some experts advocate the routine sampling of CSF in patients with miliary TB.^[13]

The anti-TB drugs that are most useful for the treatment of CNS TB are:

• INH (CSF penetration 100%)
• RMP (10–20%)
• EMB (25–50% inflamed meninges only)
• PZA (100%)
• STM (20% inflamed meninges only)
• LZD (20%)
• Cycloserine (80–100%)
• Ethionamide (100%)
• PAS (10–50%) (inflamed meninges only)

The use of steroids is routine in TB meningitis (see section below).

Steroids

The usefulness of corticosteroids (e.g., prednisolone or dexamethasone) in the treatment of TB is proven for TB meningitis and TB pericarditis. The dose for TB meningitis is dexamethasone 8 to 12mg daily tapered off over six weeks (for those who prefer more precise dosing, please see Thwaites, 2004^[14]). The dose for pericarditis is prednisolone 60mg daily tapered off over four to eight weeks.

Steroids may be of temporary benefit in pleurisy, extremely advanced TB, and TB in children:

• Pleurisy: prednisolone 20 to 40mg daily tapered off over 4 to 8 weeks
• Extremely advanced TB: 40 to 60mg daily tapered off over 4 to 8 weeks
• TB in children: 2 to 5mg/kg/day for one week, 1mg/kg/day the next week, then tapered off over 5 weeks

Steroids may be of benefit in peritonitis, miliary disease, laryngeal TB, lymphadenitis and genitourinary disease, but the evidence is scant and the routine use of steroids cannot be recommended. Steroid treatment in these patients should be considered on a case by case basis by the attending physician.

Thalidomide may be of benefit in TB meningitis and has been used in cases where patients have failed to respond to steroid treatment.^[15]

Non-compliance

Patients who take their TB treatment in an irregular and unreliable way are at greatly increased risk of treatment failure, relapse and the development of drug-resistant TB strains.

There are variety of reasons why patients fail to take their medication. The symptoms of TB commonly resolve within a few weeks of starting TB treatment and many patients then lose motivation to continue taking their medication. Regular follow-up is important to check on compliance and to identify any problems patients are having problems with their medication. Patients need to be told of the importance of taking their tablets regularly, and the importance of completing treatment, because of the risk of relapse or drug-resistance developing otherwise.

One of the main complaints is the bulkiness of the tablets. The main offender is PZA (the tablets being the size of horse tablets). PZA syrup may be offered as a substitute, or if the size of the tablets is truly an issue and liquid preparations are not available, then PZA can be omitted altogether. If PZA is omitted, the patient should be warned that this results in a significant increase in the duration of treatment (details of regimens omitting PZA are given below).

The other complaint is that the medicines must be taken on an empty stomach to facilitate absorption. This can be difficult for patients to follow (for example, shift workers who take their meals at irregular times) and may mean the patient waking up an hour earlier than usual everyday just to take medication. The rules are actually less stringent than many physicians and pharmacists realise: the issue is that the absorption of RMP is reduced if taken with fat, but is unaffected by carbohydrate, protein,^[16] or antacids.^[17] So the patient can in fact have his or her medication with food as long as the meal does not contain fat or oils (e.g., a cup of black coffee or toast with jam and no butter).^[18] Taking the medicines with food also helps ease the nausea that many patients feel when taking the medicines on an empty stomach. The effect of food on the absorption of INH is not clear: two studies have shown reduced absorption with food^[19][20] but one study showed no difference.^[21] There is a small effect of food on the absorption of PZA and of EMB that is probably not clinically important.^[22][23]

It is possible to test urine for isoniazid and rifampicin levels in order to check for compliance. The interpretation of urine analysis is based on the fact that isoniazid has a longer half-life than rifampicin:

• urine positive for isoniazid and rifampicin patient probably fully compliant
• urine positive for isoniazid only patient has taken his medication in the last few days preceding the clinic appointment, but had not yet taken a dose that day.
• urine positive for rifampicin only patient has omitted to take his medication the preceding few days, but did take it just before coming to clinic.
• urine negative for both isoniazid and rifampicin patient has not taken either medicine for a number of days

In countries where doctors are unable to compel patients to take their treatment (e.g., the UK), some say that urine testing only results in unhelpful confrontations with patients and does not help increase compliance. In countries where legal measures can be taken to force patients to take their medication (e.g., the US), then urine testing can be a useful adjunct in assuring compliance.

RMP colours the urine and all bodily secretions (tears, sweat, etc.) an orange-pink colour and this can be a useful proxy if urine testing is not available (although this colour fades approximately six to eight hours after each dose).

Adverse effects

For information on adverse effects of individual anti-TB drugs, please refer to the individual articles for each drug.

The relative incidence of major adverse effects has been carefully described:^[24]

• INH 0.49 per hundred patient months
• RMP 0.43
• EMB 0.07
• PZA 1.48
• All drugs 2.47

This works out to an 8.6% risk that any one patient will need to have his drug therapy changed during the course of standard short-course therapy (2HREZ/4HR). The people identified to be most at risk of major adverse side effects in this study were:

• age >60,
• females,
• HIV positive patients, and
• Asians.

It can be extremely difficult identifying which drug is responsible for which side effect, but the relative frequency of each is known.^[25] The offending drugs are given in decreasing order of frequency:

• Thrombocytopaenia: RMP
• Neuropathy: INH
• Vertigo: STM
• Hepatitis: PZA, RMP, INH
• Rash: PZA, RMP, EMB

Thrombocytopaenia is only caused by RMP and no test dosing need be done. Regimens omitting RMP are discussed below. Please refer to the entry on rifampicin for further details.

The most frequent cause of neuropathy is INH. The peripheral neuropathy of INH is always a pure sensory neuropathy and finding a motor component to the peripheral neuropathy should always prompt a search for an alternative cause. Once a peripheral neuropathy has occurred, INH must be stopped and pyridoxine should be given at a dose of 50mg thrice daily. Simply adding high dose pyridoxine to the regimen once neuropathy has occurred will not stop the neuropathy from progressing. Patients at risk of peripheral neuropathy from other causes (diabetes mellitus, alcoholism, renal failure, malnutrition, pregnancy, etc.) should all be given pyridoxine] 10mg daily at the start of treatment. Please refer to the entry on isoniazid for details on other neurological side effects of INH.

Rashes are most frequently due to PZA, but can occur with any of the TB drugs. Test dosing using the same regimen as detailed below for hepatitis may be necessary to determine which drug is responsible.

Itching RMP commonly causes itching without a rash in the first two weeks of treatment: treatment should not be stopped and the patient should be advised that the itch usually resolves on its own. Short courses of sedative antihistamines such as chlorpheniramine may be useful in alleviating the itch.

Fever during treatment can be due to a number of causes. It can occur as a natural effect of tuberculosis (in which case it should resolve within three weeks of starting treatment). Fever can be a result of drug resistance (but in that case the organism must be resistant to two or more of the drugs). Fever may be due to a superadded infection or additional diagnosis (patients with TB are not exempt from getting influenza and other illnesses during the course of treatment). In a few patients, the fever is due to drug allergy. The clinician must also consider the possibility that the diagnosis of TB is wrong. If the patient has been on treatment for more than two weeks and if the fever had initially settled and then come back, it is reasonable to stop all TB medication for 72 hours. If the fever persists despite stopping all TB medication, then the fever is not due to the drugs. If the fever disappears off treatment, then the drugs need to be tested individually to determine the cause. The same scheme as is used for test dosing for drug-induced hepatitis (described below) may be used. The drug most frequently implicated as causing a drug fever is RMP: details are given in the entry on rifampicin.

Drug-induced hepatitis

The single biggest problem with TB treatment is drug-induced hepatitis, which has a mortality rate of around 5%.^[26] Three drugs can induce hepatitis: PZA, INH and RMP (in decreasing order of frequency).^[1][27] It is not possible to distinguish between these three causes based purely on signs and symptoms. Test dosing must be carried out to determine which drug is responsible (this is discussed in detail below).

Liver function tests (LFTs) should be checked at the start of treatment, but, if normal, need not be checked again; the patient need only be warned of the symptoms of hepatitis. Some clinicians insist on regular monitoring of LFT's while on treatment, and in this instance, tests need only be done two weeks after starting treatment and then every two months thereafter, unless any problems are detected.

Elevations in bilirubin must be expected with RMP treatment (RMP blocks bilirubin excretion) and usually resolve after 10 days (liver enzyme production increases to compensate). Isolated elevations in bilirubin can be safely ignored.

Elevations in liver transaminases (ALT and AST) are common in the first three weeks of treatment. If the patient is asymptomatic and the elevation is not excessive then no action need be taken; some experts suggest a cut-off of four times the upper limit of normal, but there is no evidence to support this particular number over and above any other number. Some experts consider that treatment should only be stopped if jaundice becomes clinically evident.

If clinically significant hepatitis occurs while on TB treatment, then all the drugs should be stopped until the liver transaminases return to normal. If the patient is so ill that TB treatment cannot be stopped, then STM and EMB should be given until the liver transaminases return to normal (these two drugs are not associated with hepatitis).

Fulminant hepatitis can occur in the course of TB treatment, but is fortunately rare; emergency liver transplantation may be necessary and deaths do occur.

Test dosing for drug-induced hepatitis

Drugs should be re-introduced individually. This cannot be done in an outpatient setting, and must be done under close observation. A nurse must be present to take patient's pulse and blood pressure at 15 minute intervals for a minimum of four hours after each test dose is given (most problems will occur within six hours of test dosing, if they are going to occur). Patients can become very suddenly unwell and access to intensive care facilities must be available. The drugs should be given in this order:

• Day 1: INH at 1/3 or 1/4 dose
• Day 2: INH at 1/2 dose
• Day 3: INH at full dose
• Day 4: RMP at 1/3 or 1/4 dose
• Day 5: RMP at 1/2 dose
• Day 6: RMP at full dose
• Day 7: EMB at 1/3 or 1/4 dose
• Day 8: EMB at 1/2 dose
• Day 9: EMB at full dose

No more than one test dose per day should be given, and all other drugs should be stopped while test dosing is being done. So on day 4, for example, the patient only receives RMP and no other drugs are given. If the patient completes the nine days of test dosing, then it is reasonable to assume that PZA has caused the hepatitis and no PZA test dosing need be done.

The reason for using the order for testing drugs is because the two most important drugs for treating TB are INH and RMP, so these are tested first: PZA is the most likely drug to cause hepatitis and is also the drug that can be most easily omitted. EMB is useful when the sensitivity pattern of the TB organism are not known and can be omitted if the organism is known to be sensitive to INH. Regimens omitting each of the standard drugs are listed below.

The order in which the drugs are tested can be varied according to the following considerations:

1. The most useful drugs (INH and RMP) should be tested first, because the absence of these drugs from a treatment regimen severely impairs its efficacy.
2. The drugs most likely to be causing the reaction should be tested as late as possible (and possibly need not be tested at all). This avoids rechallenging patients with a drug to which they have already had a (possibly) dangerous adverse reaction.

A similar scheme may be used for other adverse effects (such as fever and rash), using similar principles.

Mesothelioma: Improved survival rates with chemotherapy

A leading expert on asbestos related diseases has suggested that survival rates for some mesothelioma sufferers may not be as poor as many believe.

Dr Gunnar Hillerdal, an expert on asbestos diseases from the Department of Pulmonary Medicine, Karolinska University Hospital, Stockholm, Sweden reported his findings at the International Association for the Study of Lung Cancer, 12th World Conference on Lung Cancer in Seoul, South Korea.

The findings of the Scandinavian study contrast with studies in other countries such as the USA. A US based trial of cisplatin with or without pemetrexed demonstrated survival of 12 months compared to cisplatin alone. Dr Hillerdal commented that: “…the experience of the Nordic Mesothelioma Group is different.”

Dr Hillerdal also stated that surgery was used sparingly to treat mesothelioma in Scandinavia, whilst in some other countries; patients with favourable characteristics (like less advanced disease or good performance status) are indicated for surgery, leaving patients who have the worst prognosis for treatment with chemotherapy.

The report assessed 147 mesothelioma sufferers treated with chemotherapy alone. All the patients were given doxorubicin, carboplatin and gemcitabine. The results demonstrated that the most favourable outlook was for patients with the epithelial subtype of mesothelioma. Please click here for further information about the study.

Dr Hillerdal commented that: “The key message from this study is that survival of mesothelioma is not so bad as many believe. With proper patient selection survival with chemotherapy can be just as good as with surgery or even better. The important thing to remember is patient selection. Subtype is more important than stage, and that should be kept in mind when evaluating results of surgical series.”

In England and Wales the National institute of Clinical Excellence (NICE) recently reversed their earlier decision to refuse public funding for Alimta (pemetrexed disodium), on the ground that it was not cost effective. Click here for further information about this decision.

Kevin Johnson, a solicitor who specialises in mesothelioma and other asbestos disease claims, from specialist claimant law firm, John Pickering and Partners LLP said: “Studies like this show that chemotherapy can have positive effects for some mesothelioma sufferers and vindicates the efforts of asbestos campaigners, asbestos victim support groups and others to lobby NICE to reverse their decision to refuse to fund Alimta.”

A note on Mesothalmia

Asbestos Cancer Law-Information KAZAN, MCCLAIN, ABRAMS, FERNANDEZ, LYONS, FARRISE & GREENWOOD, A Professional Law Corporation (KazanLaw) is a nationally recognized plaintiffs' asbestos law firm located in Oakland, CA.

Our particular expertise is as mesothelioma lawyers in California - experienced attorneys fighting for victims of mesothelioma cancer, a disease that is a result of exposure to airborne asbestos fibers. We built our reputation on asbestos litigation, representing people diagnosed with mesothelioma, lung cancer, asbestosis and other asbestos-related diseases. KazanLaw.com contains information about asbestos diseases (such as mesothelioma), asbestos litigation and asbestos products, as well as our other practice areas not related to asbestos / mesothelioma.There are sections about occupational safety and health (OSH), a profile of Kazan, McClain, Abrams, Fernandez, Lyons, Farrise & Greenwood law firm, significant trial verdicts and appellate decisions, biographies of our attorneys, employment opportunities, and news / feature articles. If you need information about asbestos exposure or disease, or have questions about filing an asbestos lawsuit, please take a look at the FAQs (frequently-asked questions), or contact us directly. You might also want to read some of the feedback that we've received about our work and web site. KazanLaw.com changes frequently, so please come back and visit it soon. Lancet, England's premier medical journal and one of the world's leading sources for current medical information in a 7.30 review article on mesothelioma praises our website and says asbestos lawyers Kazan Law 'provide useful info for patients and relatives'. ASBESTOS CANCER...CotdMesothelioma cancer law is really personal injury law applied to people who have contracted mesothelioma cancer as a result of exposure to asbestos. Mesothelioma is an otherwise very rare form of cancer which invades the mesothelial cells in the membranes in the chest and abdominal cavity.mesothelioma abestos cancer Because asbestos is highly carcinogenic, and easily inhaled, asbestos exposure is a leading cause of mesothelioma, which in turn has given rise to the mesothelioma law practice.The American Cancer Institute explains that "The main risk factor for mesothelioma is contact with asbestos. In the past, asbestos was used for insulation because it does not conduct heat well and doesn't easily melt or burn. It was also used in other products such as floor tiles, door gaskets, roofing, and patching compounds. Since asbestos is a naturally occurring mineral, it can also be found in dust and rocks in certain parts of the United States.If asbestos fibers are breathed in, they travel to the ends of the small air passages and...[Continue reading Mesothelioma Cancer Law]mesotheliomaMesothelioma is a form of cancer that is almost always caused by exposure to asbestos. Visit Baron & Budd's Web site devoted to this issue at www.mesotheliomanews.com to learn more about the symptoms, treatment options, resources for dealing with this disease, and information about your legal rights. As a service to our clients and other mesothelioma victims who contact us, Baron & Budd has prepared a helpful packet of information about mesothelioma, including treatment options for the disease. This informative resource will provide you with information on: Mainstream and Experimental Therapies Alternative Therapies and Treatments Specialists and Support Organizations Articles and Abstracts from Medical Publications and Journals Glossary of Medical Terms

What Are the Risk Factors for Malignant Mesothelioma?

A risk factor is anything that increases your chance of getting a disease such as cancer. Different cancers have different risk factors. For example, exposing skin to strong sunlight is a risk factor for skin cancer. Smoking is a risk factor for cancers of the lung, mouth, larynx, bladder, kidney, and several other organs. Individuals exposed to asbestos should be encouraged to avoid tobacco exposure because together the risk for lung cancer is significantly higher than from smoking without a history of asbestos exposure. But having a risk factor, or even several, does not mean that you will get the disease.

Asbestos

The main risk factor for developing mesothelioma is exposure to asbestos. Asbestos refers to a family of fibrous minerals made of silicate. Asbestos was once used in many products such as insulation, floor tiles, door gaskets, soundproofing, roofing, patching compounds, fireproof gloves and ironing board covers, and even brake pads. As the link between asbestos and mesothelioma has become well known, the use of this material has almost stopped. Most use stopped after 1989, but it is still used in some products. Experts have linked this drop in asbestos use to the fact that the rate of development of mesothelioma is no longer increasing.

Still, up to 8 million Americans may already have been exposed to asbestos. Exposure to asbestos particles suspended in air and building materials is much less hazardous except when they are being removed.

Since asbestos is a naturally occurring mineral, it can also be found in dust and rocks in certain parts of the United States as well as the world.

According to the U.S. Environmental Protection Agency, as many as 733,000 schools and public buildings in the country today contain asbestos insulation. As many as 10% to 15% of schools in the United States may contain asbestos insulation. People who may be at risk for occupational asbestos exposure include some miners, factory workers, insulation manufacturers, railroad workers, ship builders, gas mask manufacturers, and construction workers, particularly those involved with installing insulation. Several studies have shown that family members of people exposed to asbestos at work have an increased risk of developing mesothelioma, because asbestos fibers are carried home on the clothes of the workers.

The incidence rate for mesothelioma in men is dropping, probably because they are no longer being exposed directly to asbestos in their work. But the incidence rate for mesothelioma in women is steady, which suggests that they are being exposed in a way that is not directly tied to work, but more to their environment either at home or work. One example would be asbestos in buildings where they work or live. A study from California also links mesothelioma to naturally occurring asbestos deposits in mountains.

Another important point about asbestos and mesothelioma is that the risk of mesothelioma does not drop with time after exposure to asbestos. The risk appears to be lifelong and undiminished.

There are 2 main forms of asbestos -- serpentine and amphiboles.

Serpentine fibers are curly and pliable. Chrysotile is the only type of serpentine fiber and it is the most widely used form of asbestos.

Amphiboles are thin, rod-like fibers. There are 5 main types — crocidolite, amosite, anthrophylite, tremolite, and actinolyte. Amphiboles (particularly crocidolite) are considered to be the most carcinogenic (cancer-causing).

However, even the more commonly used chrysotile fibers are associated with malignant (cancerous) mesotheliomas and should be considered dangerous as well.

When asbestos fibers are inhaled, most are cleared in the nose, throat, trachea (windpipe), or bronchi (large breathing tubes of the lungs). Fibers are cleared by sticking to mucus inside the air passages and being coughed up or swallowed. The long, thin, fibers are less readily cleared, and they may reach the ends of the small airways and penetrate into the pleural lining of the lung and chest wall. These fibers may then directly injure mesothelial cells of the pleura, and eventually cause mesothelioma.

Asbestos fibers can also damage cells of the lung and result in asbestosis (formation of scar tissue in the lung), and/or lung cancer. The risk of lung cancer among people exposed to asbestos is increased by 7 times, compared with the general population. Indeed, asbestosis, mesothelioma, and lung cancer are the 3 most frequent causes of death and disease among people with heavy asbestos exposure. Peritoneal mesothelioma, which forms in the abdomen, may result from coughing up and swallowing inhaled asbestos fibers. Cancers of the larynx, pancreas, esophagus, colon, and kidney may also come from asbestos exposure, but the increased risk is small.

The risk of developing a mesothelioma is related to how much asbestos a person was exposed to and how long this exposure lasted. People exposed at an early age, for a long period of time, and at higher levels are most likely to develop this cancer. Mesotheliomas take a long time to develop. The time between first exposure to asbestos and diagnosis of mesothelioma is usually between 20 and 50 years.

Radiation

There have been a few published reports of pleural and peritoneal mesotheliomas that developed following exposure to thorium dioxide (Thorotrast). This material was used in the past by doctors for certain x-ray tests. Because Thorotrast was found to cause cancers, it has not been used for many years.

Zeolite

This is a silicate mineral, chemically related to asbestos, common in the soil of the Anatoli region of Turkey. Many cases of mesothelioma have been described in this region and may have been caused by this mineral.

Tobacco

Although tobacco smoking has not been associated with developing mesothelioma, the combination of smoking and asbestos exposure greatly increases the risk of lung cancer. Asbestos workers who also smoke have a lung cancer risk 50 to 90 times greater than that of the general population. More asbestos workers die of lung cancer than of mesothelioma.

SV40 Virus

Some recent studies have raised the possibility that infection with simian virus 40 (SV40) might increase the risk of developing mesothelioma. Some injectable polio vaccines prepared between 1955 and 1963 were contaminated with SV40. About 10 to 30 million people were probably exposed to the virus.

Intentional infection with SV40 of some laboratory animals, such as hamsters, causes mesotheliomas to develop. Researchers also have noticed that SV40 can cause mouse cells grown in dishes to become cancerous, and that asbestos increases the cancer-causing effect of SV40 on these cells. Other researchers have studied biopsy specimens of human mesotheliomas and detected SV40 DNA. However, similar fragments of SV40 DNA can also be found in noncancerous human tissues and some researchers think the SV40 viruses found are contaminants.

Another study did find SV40 virus in tissues from mesothelioma patients that did not appear to be contaminants. In this study, which also looked at tissue from healthy people, the SV40 virus wasn’t linked to mesothelioma unless the person was also exposed to asbestos. The researchers in this study thought the SV40 infection was not caused by the polio immunization, but occurred naturally as do other viral infections.

So far, the largest studies addressing this issue in humans have not found any increased risk for mesothelioma or other cancers among people who received the contaminated vaccines as children. But, the peak age range for diagnosis of mesothelioma is 50 to 70 years. Some researchers have pointed out that this issue may remain unresolved until more of the people accidentally exposed to SV40 between 1955 and 1963 reach that age range. Research into this important topic is still underway.

A recent study by the Institute of Medicine concluded that we still don’t know whether SV40 is responsible for some mesotheliomas and more research needs to be done.

Mesothelioma

Also called: Malignant mesothelioma

The tissue that lines your lungs, stomach, heart and other organs is called mesothelium. Mesothelioma is cancer of that tissue. It is a rare but serious type of cancer. It usually starts in the lungs, but can also start in the abdomen or other organs. Most people who develop mesothelioma have worked on jobs where they inhaled asbestos particles. It can take a long time - 30 to 50 years - between being around asbestos and getting the disease. Treatment includes surgery, radiation, chemotherapy or all three.