AZ Guide u Medicine

ACUTE PROMYELOCYTIC LEUKEMIA

Acute promyelocytic leukemia (APL) represents 10 to 15 percent of the cases of acute myeloid leukemia in adults.
This disease is characterized by a specific cytogenetic abnormality , a chromosomal translocation that disrupt the retinoic acid receptor a gene (RAR-a ) on chromosome 17 and the promyelocytic leukemia gene (PML), which encodes a transcription factor and is located on chromosome 15.
The resulting fusion gene, PML-RAR a , encodes a chimeric protein that causes an arrest of maturation at the promyelocyte stage of myeloid cell development.

THERAPY

In the early ’90s the introduction in therapy of all-trans-retinoic acid has more than doubled the survival expected with chemotherapy alone.
All-trans-retinoic acid has provided the first proof of the principle of "differentiation therapy", in which drugs induce the terminal differentiation of malignant cells that are then incapable of further proliferation.

Two reports from China (1996 & 1997) have suggest that arsenic trioxide can induce complete remissions in patients with acute promyelocytic leukemia (APL).

Soignet SL et al. (N Engl J Med 1998; 339: 1341-1348) have evaluate arsenic trioxide in patients with APL who had relapsed.
The results show that low doses (ranging from 0.06 to 0.2 mg per kilogram of body weight per day until visible leukemic cells were eliminated from the bone marrow) of arsenic trioxide are effective and cause few serious adverse reactions.
The clinical response to arsenic trioxide is associated with the induction of "nonterminal" cytodifferentiation and the activation of cysteine proteases (caspases) that are characteristic of apoptosis.

BLEEDING in APL

Acute promyelocytic leukemia is associated with a hemorrhagic disorder that responds to treatment will all-trans-retinoic acid.

Annexin II is a phospholipid-binding protein on endothelial cells, macrophages.
It is a cell-surface receptor for both plasminogen (the inactive precursor of plasmin) and its activator, t-PA.

Annexin II has also been found on leukemic cells from patients with APL.
Overexpression of annexin II may be a mechanism for hemorrhagic diathesis of APL.
(Mennel J.S. et al. N Engl L Med 1999; 340: 994-1004).

AIDS

• EPIDEMIOLOGY

• The number of AIDS deaths in the US is decreasing.
  This decrease could be attributed mainly to the new combination drug therapies which prolong the lifespan of HIV-infected patients.
  The prevention of HIV transmission has also contributed to the decline.

• The primary targets for HIV are CD4+T cells, which express both the CD4 cell surface receptor, and one or other of the CXCR4 o CCR5 chemokine receptors needed by the virus to enter these cells.

All HIV strains require the CD4 receptor, but different strains use either the CXCR4 or CCR5 as co-receptors.

ALZHEIMER’s DISEASE

• A particular attention is focused on bleomycin hydrolase, an enzyme that could process the amyloid precursor proteins that give rise to the characteristic of Alzheimer’s disease brain plaques.
  A new gene for Alzheimer’s disease has been found.
  Individuals homozygous for the G polymorphism of the bleomycin hydrolase gene are at greater risk of developing Alzheimer’s disease than people with two copies of the A allele.

AMYOTROPHIC LATERAL SCLEROSIS (ALS)

u Riluzole

ALS is a devastating and fatal disease without an effective therapy.
Existing data indicate that Riluzole adds only three months to the lifespan of patients who have two to five years to live, with no discernible improvement in quality of life [1997].

ANOREXIA

u Fluoxetine

35 anorexics were followed for one year. 62% of the patients taking fluoxetine had no "relapse" versus 16% of those on placebo.
Before anorexics take fluoxetine, they have to achieve a body weight sufficient to allow fluoxetine to work.
Fluoxetine acts on serotonine by inhibing its re-uptake. Serotonin is produced from tryptophan, an aminoacid, only obtained in the food [1997].

ASTHMA

• Bronchial asthma is believed an inflammatory disorder, involving a variety of cell types and mediators.
• Corticosteroids have assumed a dominant role in asthma therapy.
  The development of inhaled corticosteroids has made such treatment attractive, since this mode of delivery is not accompanied by the toxicity associated with oral administration.
• Systemically administered corticosteroids are reserved for acute exacerbations.
• A small subset of patients gain little benefit from corticosteroids while remaining responsive to beta-adrenergic agonists.
• Steroids resistance
  The precise mechanisms underlying steroid resistance are unknown.
  Corticosteroids are transported into the nucleus bound to receptors and there they attach to DNA sites that code for cytokine production.
  Corticosteroid resistance has been related to

• defects in DNA binding
• a decrease in the number of corticosteroid receptors
• decreased ligand-receptor affinity.

• The corticosteroid resistance and the toxicity associated with systemic corticosteroid administration has prompted the evaluation of other anti-inflammatory agents for the treatment of asthma.
• The value of NSAID (non-steroidal anti-inflammatory drugs) for steroid-resistant asthma is unknown.
  The National Institutes of Health are supporting (1998) cooperative trials of alternative asthma therapies.

Axillary lymph nodes are important prognostic in patients with breast cancer.
However a high number of women presents:
postoperative complications
psychological distress.

A potential alternative to axillary lymphadenectomy is sentinel-node resection.
In 1977, Canabas proposed to remove sentinel lymph nodes (the first nodes that receive drainage from tumors) by limited surgery and to examine their ………… to determine whether more extensive lymphadenectomy should be performed.
443 patients with breast cancer were enrolled.
Before surgery, 1 mCi (37 M Bq) of technetium – 99m sulfur colloid was injected into the breast tissue surrounding the primary tumor or biopsy cavity.
The accuracy of the sentinel nodes was 97%; the specificity of the method was 100 percent, the negative predictive value was 96% and the sensitivity was 89%.
The multicenter Validation Study conclused saying that "the biopsy of sentinel nodes can be technically challenging and the success rate varies according to the surgeon and the characteristics of the patients.

[Krag D. et al, E Engl J Med 1998; 339: 941-946].

CHRONIC HEPATITIS C

• Mortality associated with chronic hepatitis C results mainly from the development of liver fibrosis and the subsequent occurrence of cirrhosis, with complications such as hepatocellular carcinoma.
• Ageing, alcohol consumption and male sex have a stronger association with fibrosis progression than virological factors in HCV infection (Poynard T. et al, Lancet 1997; 349: 825-832).

CHRONIC LYMPHOCYTIC LEUKEMIA

The treatment of early-stage chronic lymphocytic leukemia (CLL) with alkylating agents not only is ineffective but also may adversely affect survival.

[Dighiero G et al. N Engl J Med 1998; 338: 1506-1514]

CHRONIC PANCREATITIS

Chronic pancreatitis is a potentially life-threatening disease.
The most common types are alcohol related and idiopathic.
Alcoholism is a major etiologic factor, exposure to cigarette smoke and occupational exposure to volatile hydrocarbons independently increase the risk, duct-obstructing lesions initiate a few cases, and there may also be an underlying metabolic or autoimmune disorder.
The cause of the rare hereditary form has been identified as a mutation in the cationic trypsinogen gene locus 7q35.
The disease is idiopathic in up to 40 percent of affected patients.

A study (Sharper N. et al N Engl J Med 1998; 339: 645-652) has demonstrated that mutations of the CFTR gene and the 5T genotype are associated with chronic pancreatitis

CYSTIC FIBROSIS

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
More than 750 putative mutations of the CFTR gene have been identified.
The most common disease-causing mutation, D F508, accounts for approximately 70% of all mutant CFTR chromosomes.
CFTR protein works as a cyclic AMP-regulated chloride channel.
Mutations may cause severe or mild pancreatic abnormalities.
Patients with pancreatic insufficiency generally have two alleles associated with severe abnormalities, whereas patients with pancreatic sufficiency have one allele associated with mild disease.

Cystic fibrosis is the most common inherited disease of the exocrine pancreas. In cystic fibrosis, mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene lead to dysfunction of the lung, sweat glands, vas deferens, and pancreas.
Lung disease accounts for most of the complications and deaths related to cystic fibrosis.
In persons with normal lung function, CFTR mutations cause one type of male infertility, congenital (bilateral) absence of the vas deferens.

DIABETES (type 1)
(insulin-dependent diabetes mellitus)

• Retinopathy develops in 70-100% of people with type 1 diabetes and remains a common cause of visual impairment and eventual blindness.
• The only intervention that prevents development and shows progression of retinopathy is tight glycaemic control.
• Blood pressure is a important risk factor for the development of retinopathy.
• EUCLID Study (EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus) shows that Lisinopril may decrease retinopathy progression in non-hypertensive patients who have type 1 diabetes with little or no nephropathy.

ERECTILE DYSFUNCTION

• It is caused by a wide range of factor:

• organic
• psychological
• psychiatric
• pharmacological.

• The first physical treatment for male sexual dysfunction was the introduction of intracavernosal injections of vasoactive drugs such as papaverine and prostaglandin E1.
• Sildenafil is an oral drug that enhances relaxation of smooth muscle in the corpus cavernosum through inhibition of the cyclic guanosine monophosphate phosphodiesterase (cGMP) enzyme à enhancing cGMP activity à nitric oxide function in smooth-muscle relaxation.

FAMILIAL ADENOMATOUS POLYPOSIS

• Familial Adenomatous Polyposis is a rare inherited disease in which numerous polyps form in the colon and may progress to cancer.
• Cells taken from the regressed polyps have higher rates of apoptosis compared with normal mucosal cells.
• FGN-1 is the sulfone metabolite of sulindac which lacks the prostaglandin synthesis inhibiting activity of the parent compound, but maintains its antineoplastic activity.
• FGN-1 inhibits the growth of colonic polyps by a novel node of action: augmenting apoptosis in abnormal cells.

HEPATITIS

¨ THERAPY

LAMIVUDINE for hepatitis B
Lamivudine interferes with replication of the hepatitis B virus and seems to reduce liver inflammation.
Lamivudine, administered once a day (100 mg), produces:

• improvement in liver histology
• more frequent HBeAg seroconversion
• more frequent alanine aminotransferase normalization.

The most common adverse events of Lamivudine are:

• ear, nose, and throat infections
• malaise
• fatigue.

RIBAVIRIN for hepatitis C
Ribavirin is indicated for hepatitis C for whom Interferon has failed.

INFLUENZA

Influenza is a viral respiratory infection.

The efficacy of inactivated vaccines depends on how closely the vaccine is matched to the epidemic strain.

¨ THERAPY

Amantadine, Rimantidine
Amantadine and its analogue Rimantidine have not been widely successful therapeutically or prophylactically because of:

• adverse effects;
• relative lack of activity against influenza B;
• rapid development of viral resistance.

Amantadine acts by blocking the ion-channel function of the virus protein M2. This protein is not present in influenza B subtype, which is therefore insensitive to these drugs.

Neuraminidase inhibitors
Neuraminidase is an enzyme essential for viral replication.
Zanamivir, one of the neuraminidase inhibitors, has been studied the most.

LUNG TRANSPLANTATION

The most common indication for lung transplantation is emphysema.
However lung transplantation does not confer a survival benefit in patients with end-stage emphysema by 2 years of follow-up.

MONOCLONAL GAMMOPATHIES

Monoclonal gammopathies are B-cell lymphoproliferative disorders caused by a clonal expansion of plasma cells that produces a unique immunoglobulin.

Monoclonal gammopathies in patients with hepatitis C virus (HCV) infection.
The prevalence of monoclonal gammopathies in patients with HCV-related chronic liver disease is striking and is often associated with genotype 2a/c infection.

[P. Andreone et al. Ann Intern Med 1998; 129: 294-298]

MULTIPLE SCLEROSIS

u Copolymer-1

The first data seems to indicate that copolymer-1 has fewer side-effects and the lack of neutralising antibodies than beta-interferons.
Neutralising antibodies to beta-interferon occur in up to 40% of patients and cancel the positive effects of the drug on relapse rate and MRI scans.
Some patients under treatment with copolymer-1 develop a panic-like reaction with chest tightness which lasts approximately 10 minutes [1997].

OBESITY

¨ GENETIC FACTORS

There is increasing evidence of genetic factor leading to obesity.
Mutation in the leptin gene or the leptin-receptor gene have been reported.
These mutations seem to be rare.
Only a few obese subjects have been found to have the mutations.
Mutations of the Beroxisome-proliferator-activated receptor g (PPAR g 2) gene might predispone people to obesity.
PPAR g 2 is a transcription factor that directs the differentiation of preadipocytes to adipocytes.
A Pro115Gln mutation in PPAR g 2 accelerates the differentiation of adipocytes and may cause obesity.

[Ristow M. et al., N Engl J Med 1998; 339: 953-959].