Drugs that causes Long QT Syndrome

LQTS is the most common and best understood type of channelopathy. It occurs in about 1 in 5,000 people. In 7 in every 10 people with LQTS, the ion channels involved have been identified. In most cases two of the potassium channels that regulate the movement of potassium ions from the inside to the outside of the cell are affected. In a small proportion of people with LQTS, a sodium channel that regulates the flow of sodium ions from the outside to the inside of cells is affected.

In people with potassium channel associated LQTS, the channels do not behave as efficiently as normal. They let potassium ions into the cell too slowly. If the sodium channel is affected, too many sodium ions are allowed into the cell. (See the LQTS diagram - figure 2B - below.) This results in an electrical disturbance in the cells of the heart called 'prolonged repolarisation'. This can be seen on an ECG recording as a lengthening of the time period known as the 'QT interval'.  This is where the name Long QT Syndrome comes from.

Rare forms of LQTS known as Andersen's and Timothy Syndromes have been associated with potassium and calcium channel abnormalities respectively.

What are the symptoms?

LQTS varies greatly in severity. Symptoms vary according to the type of channel involved, whether the person is male or female, their age, and the length of the QT interval on the ECG. Males are more likely to have symptoms before puberty, while females are more likely to have them in adolescence and early adulthood. Relatives from the same family who have inherited the same mutation may have very different experiences. For example, some may have a normal QT interval and not have any symptoms; some may have a very abnormal QT interval but no symptoms; and some may have a very abnormal QT interval and have many events that put them at risk.

The most common symptom of LQTS is blackouts. Sometimes palpitations due to extra or 'ectopic' heartbeats can be a problem.

Potassium channel LQTS is associated with sudden death which is related to exercise or when the person has been startled or awoken suddenly ('sudden arousal'). The sodium channel form is associated with death while asleep.

Are there any physical signs?

There are no physical signs of LQTS. However, people with Andersen's Syndrome may also have muscle weakness or minor abnormalities of the skull, chin, fingers and toes.

How is it diagnosed? 

Diagnosis involves having an ECG. Sometimes it is possible to tell which ion channel has been affected just by looking at the ECG recording. Unfortunately, in many people who might be carriers, the ECG does not show any sign of the condition. Repeated ECGs, exercise tests and 24-48 hour tape monitoring may be needed before any hint of the condition is seen, and even then there may be no sign of it (we describe all these tests in cardiac tests).

Genetic testing can sometimes identify carriers of LQTS. Unfortunately, this form of testing is limited at the moment, as 3 in every 10 people who are known to have LQTS do not have mutations of the genes known to be associated with LQTS. An additional problem is that most families who do have the mutations appear to have a specific change to the DNA code which is not found in other families (known as a 'private’ mutation). This sometimes makes it difficult to decide whether a mutation is causing the disease or not. Things are further complicated by the fact that people with the same mutation can have effects that vary greatly in severity. All of this makes it very difficult for doctors to decide on the best way to treat people with this condition.

Treatment and advice

If you have LQTS, your doctor will advise you to avoid excessive exercise or strenuous athletic activities. He or she will also advise you to avoid certain drugs that can make the condition worse and which could increase the risk of blackouts and sudden cardiac death.

1) In Normal Heart potassium flows out of the cell to 'repolarise' the heart, and sodium flows into the cells to activate the heart.

2) In people with LQTS: The flow of potassium is usually reduced. In some people with LQTS, the flow of sodium may be increased.

In people with Brugada Syndrome or PCCD. The flow of sodium into the heart cells is reduced.

The level of risk of sudden death helps decide on the need for treatment. Those who are statistically at greatest risk of sudden death are people with one or more of the following features: 

• A previous cardiac arrest
• Blackouts
• A very long QT interval on the ECG
• Sodium channel mutations
• Young adult women.

Children who are most at risk tend to be young boys before puberty, and girls who are passing into puberty.

Drugs

The first line of treatment is with drugs. The most commonly used drugs are betablockers. These block the effects of adrenaline and associated natural chemicals in the body that make the heart pump harder and faster. They therefore also block the effects of exercise on the heart. They are effective in the most common forms of LQTS as they reduce symptoms and the risk of sudden death. However, they are less effective in people with the sodium channel form of LQTS. 

There are other more recent trends in drug treatment that look promising, but their long-term benefits are unknown. These involve using antiarrhythmic drugs. These drugs block disturbances in the heart rhythm that can cause sudden death. Potassium supplement pills have also been tried with occasional success.

Antiarrhythmics

Class 1: ajmaline*, cibenzoline*, dihydroquinidine*, disopyramide, encainide*, flecainide, mexiletine, pirmenol*, procainamide, propafenone quinidine*

Class 3: almokalant*, amiodarone, azimilide*, bretylium, dofetilide*, dronedarone*, d-sotalol*, ersentilide*, ibutilide*, nifekalant*, sematilide*, sotalol, terikalant*

Anti-anginals/vasodilators

bepridil*, lidoflazine*, prenylamine*, ranolazine, terodiline*, vardenafil

Anti-hypertensives

indapamide, isradipine, moexipril/hydrochlorthiazide, nicardipine

Antihistamines

astemizole*, azelastine, diphenhydramine, ebastine*, hydroxyzine, terfenadine*

Serotonin agonists and antagonists

cisapride*, dolasetron, granisetron, ketanserin*, ondansetron

Antimicrobials

Macrolide antibiotics: azithromycin, clarithromycin, erythromycin, roxithromycin*, spiramycin, telithromycin

Quinolone antibiotics: ciprofloxacin, gatifloxacin*, gemifloxacin*, grepafloxacin*, levofloxacin, moxifloxacin, ofloxacin, sparfloxacin*

Antifungals: cotrimoxazole, fluconazole (caution with itraconazole), ketoconazole, voriconazole

Others: pentamidine, trimethoprim sulfa (bactrim)

Antiviral: foscarnet (HIV)

Antimalarials

amantidine, chloroquine, halofantrine*, quinine

Psychiatric drugs

Tricyclic antidepressants: amitriptyline, amoxapine*, clomipramine, desipramine*, doxepin, imipramine, nortriptyline, protriptyline*, trimipramine

Phenothiazines: chlorpromazine, fluphenazine, prochlorperazine, thioridazine*, trifluoperazine

Others: atomoxetine, citalopram, clozapine, droperidol*, fluoxetine, haloperidol, levomethadyl*, lithium, maprotiline, mesoridazine, methadone, paroxetine, pericycline, pimozide, quetiapine, risperidone, sertindole, sertraline, trazodone, venlafaxine, zimeldine*, ziprasidone

Anticonvulsant

felbamate*, fosphenytoin (prodrug of phenytoin)

Anti-migraine

naratriptan, sumatriptan, zolmitriptan

Anti-cancer

arsenic trioxide, geldanamycin*, sunitib, tacrolimus, tamoxifen

Others

alfuzosin, chloral hydrate, clobutinol*, domperidone, galantamine, octreotide, organophosphates*, perflutren lipid microspheres, probucol, solifenacin, tizanidine, tolterodine, vasopressin

Stimulant drugs

Some cold remedies contain these drugs so it is important always to check the label.

adrenaline (epinephrine), amphetamine, cocaine, dexmethylphenidate, dobutamine, dopamine, ephedrine, fenfluramine, isoprenaline (isoproterenol), levalbuterol, metaproterenol, methylphenidate, midodrine, norepinephrine (noradrenaline), phentermine, phenylephrine, phenylpropanolamine, pseudoephidrine, ritodrine, salbutamol (albuterol), salmeterol, sibutramine, terbutaline.

* = Drugs which are unlicensed, withdrawn or suspended in the international market.

Source: FDA

by

AKSHAYA SRIKANTH

Pharm.D Resident

India

ATAXIA: What Does it Mean

 Ataxia is a Poor coordination and unsteadiness due to the brain's failure to regulate the body's posture and regulate the strength and direction of limb movements. Ataxia is usually due to disease in the cerebellum of the brain, which lies beneath the back part of the cerebrum.

General analysis of the case:

A) Patient complains:

1. Instability of walking and repeated falling down (poor balance or decreased equilibrium)
2. Shaking of the hand at the start of the action( intention tremor)

B) Signs which has been seen by the physician:

1. Slurred speech (dysarthria)

C) Other condition of the patient:

1. He is known hypertensive case for 10 years; his BP is 190/90 with medication.

D) Important negative data:

1. No alcohol consumption, because alcohol can produce the same clinical picture.

E) Provisional diagnosis:

All symptoms and signs indicating cerebellar disease because:

1. Instability of walking and repeated falling down --> poor balance ---> balance is the function of vestibulocerebellum.
2. Intention tremors ---> loss of damping function which is a function of the spinocerebellum.
3. Dysarthria ----> loss of timing function which is a function of the cerebrocerebellum.

Tasks:

Tasks 1 & 2:

• Head region tests:
• Eye examination Nystagmus
• Hypotonia of the face and neck muscles and this result in pulling of the face toward the normal side ((defective attitude))
• Dysarthria broken speech because cerebellum controls the vocal cords.
• Upper limbs teat:
• Finger – nose – finger test. Overshooting and missing of the wanted point. Dysmetria or post-pointing or intention tremors.
• Fast alternative movements ((Dysdiadochokinesia))
• Rebound phenomena. The patient hand will slip to hit his face.
• Lower limbs test:
• Straight line test. The patient is unable to walk in a straight line and he has a drunken gait.
• Heel-shin test. The heel wavers away from the line of the shin.
• Reflexes:
• Cerebellar damage --> muscle Hypotonia.
• Deep tendon reflexes (knee reflex) --> pendular and weak (hyporeflexia)
• Superficial reflexes (plantar reflex) --> weakened.

Task3:

C.T. or MRI.

Task 4:

By executing a Romberg’s test we can identify the site of the lesion 

1. Positive Romberg’s test suggest a dorsal column lesion (( sensory ataxia))
2. Negative Romberg’s test suggests lesion to the midline and adjacent structures of the cerebellum.

The lesion could be:

• Tumors.
• Hemorrhage.
• Infarction.
• Abscesses.
• Multiple sclerosis.

Task 5:

The loss of the damping function of the cerebellum ---> overshooting ---> correction ---> repeated overshooting and correction leads to the shaking of the hands. (Intention tremors).

Task 6:

Because the equilibrium function (controlling the contraction of the agonist and antagonist muscle groups) of the cerebellum is disturbed. 

Task 7:

Dr.Wajid said that we should cross this question because it is unreasonable.

Task 8:

He has this problem because the formation of words depends on rapid and orderly succession of individual muscle movements in the larynx, mouth, and respiratory system. Lack of coordination among these and inability to adjust in advance either the intensity of sound or duration of each successive sound causes jumbled vocalization, with some syllables loud, some weak, some held for long intervals, some held for short intervals, and resultant speech that is often unintelligible. This is called dysarthria.

Task 9:

They are the Anterior and posterior spinocerebellar tracts.

You need to know these facts about these tracts:

• Course.
• Contra or ipsilateral tract.
• Number of synapses.
• Type of information transmitted.

These information can be found in neuroanatomy by Snell pages 147-150  and figure 4-13 page 149 and the table 4-3 page 150

by

Akshaya Srikanth

Pharm.D Resident

Hyderabad, India

BREATHING NEW LIFE INTO OLD MEDICINES

Discovering and developing new treatments for disease is a challenging, time-consuming, and expensive endeavor. For every drug that eventually makes it to the pharmacy, hundreds of compounds fail to deliver results and millions of dollars are spent without a direct return on investment. However, in these economically challenging times, existing drugs and compounds—whether in development, already on the market, or even ones that have failed clinical trials due to lack of efficacy—are being re-examined by pharmaceutical companies and research institutions. The goal of this approach—called drug repurposing— is to find potential new uses for these drugs.

High-throughput drug screening platforms in Sanford-Burnham's Conrad Prebys Center for Chemical Genomics will be used to screen existing drugs for new applications.

There are three main benefits to drug repurposing—it’s safer, faster, and cheaper. Since a repurposed drug has already passed a significant number of toxicity and other tests, its risks are better known and the chance of failure is reduced. More than 90 percent of new drugs fail during development, contributing to the high cost of pharmaceutical research and development. A new therapy based on a repurposed drug could benefit patients sooner—ultimately saving and improving more lives.

In the past, drug repurposing efforts were hampered by the lack of a complete drug collection. Fortunately, a comprehensive listing of clinically approved drugs was recently made available by the NIH. Now, in order to make the promise of drug repurposing a reality, Sanford-Burnham researchers are building the world’s most comprehensive library (collection) of repurposed drugs, which can be leveraged against our strengths in stem cell biology, phenotypic cell-based screening, and high-throughput drug screening. Moreover, this library will be made available to other non-profit research institutions to advance translational medicine.

Despite the promise of drug repurposing, serendipitous discovery of new applications for existing drugs happens rarely, and only at the point when people are actually taking them. With the advent of stem cell-based human disease models—called disease in a dish—researchers can now test large numbers of approved drugs for their efficacy against a number of diseases before they reach clinical testing in humans. In this technique, researchers at Sanford-Burnham and elsewhere take skin samples from a patient or healthy volunteer, dial them back developmentally to stem cells, and induce their differentiation into the desired cell type (neurons, for example, if studying Alzheimer’s disease). The advantage to disease-in-a-dish modeling is that it generates large numbers of otherwise hard-to-access cell types, complete with an individual’s genetic and epigenetic make-up—making it a valuable tool for discovering and developing therapies that are more personalized to the individual.

Using cells from a patient with muscular dystrophy and a small library of FDA-approved drugs, Sanford-Burnham scientists have already identified a series of agents that reverse the functional defect causing the disease, providing an initial proof-of-concept for this approach. Spurred on by this exciting data, the team is now developing disease-in-a-dish screens for other genetic diseases.

While we are making substantial progress, one challenge is the incompleteness of the current drug repurposing library available to us. The more complete this library, the greater the chance we will find a drug that can potentially be repurposed to treat a child with a genetic condition like muscular dystrophy or other diseases.

“Regrettably, pharmaceutical companies are not likely to engage in drug repurposing efforts for rare childhood diseases,” Sanford-Burnham’s Layton Smith told Drug Discovery News. “This is in part due to the smaller patient populations and challenges in running clinical trials in these indications. In addition, competition with generic drugs makes this effort commercially unviable, in spite of its great potential to benefit human health. Even if companies were motivated to engage in these efforts, it is very difficult for the pharmaceutical industry to perform the type of screens Sanford-Burnham is doing because of their limited access to patient samples.”

Non-profit research institutes such as Sanford-Burnham, on the other hand, are well positioned to respond to this market and research opportunity.

Source: Drug News

by

AKSHAYA SRIKANTH

Pharm.D

India

ADVERSE DRUG REACTION CASE REPORTS IN ELDERS

Ciprofloxacin Delirium and myoclonus in an elderly patient: case report

An 85 year old man received oral ciprofloxacin 500mg daily for an infected right hip joint. On the seventh day he experienced generalized myoclonic jerks, hallucination and delirium which improved with a small dose of clonazepam. Ciprofloxacin was permanently withdrawn after his symptoms recurred twice following re-administration. No further episodes of delirium myoclonic jerks occurred.

Jayathissa S. Eet al. Myoclonus and delirium associated with ciprofloxacin. Age and Ageing 39: 762, No. 6, Nov 2010.

Metformin Lactic acidiosis and vision loss in an elderly patient: case report 

A 67 year old woman developed lactic acidiosis and transient vision loss during treatment with metformin for type 2 diabetes mellitus. The woman, who had a history of coronary disease, hypertension and osteoarthritis, and who had been receiving metformin (dosage, route and duration of treatment not stated), presented to an emergency department with acute bilateral vision loss. Her vision loss had started the previous afternoon. Examination revealed a rectal temperature of 32.3o, a HR 55 beats/min, a BP of 117/94mm Hg, a respiratory rate of 34 breaths/min and a pulse oximeter reading of 98%. She was awake and alert but her visual acuity and fields were not intact and she had mid-sized pupils that were slow to react. Laboratory tests showed a pH OF 6.65 and a lactate level of 10.9mmol/L. Her creatinine level was 7.0 mg/dL from a baseline of 1.3 mg/dL and her serum metformin concentration was 28 microgram/mL. She also had hyperkalaemia with a potassium level of 7.1mmol/L. The woman was treated with calcium gluconate, insulin and glucose for hyperkalaemia and sodium bicarbonate for her metabolic acidiosis. Following a lack of response, emergency haemodialysis was initiated. Her vision returned 10 hours after admission with an acuity of 20/30 bilaterally. Her blood pH increased to 7.48, her hypothermia resolved and her laboratory values normalized. She was discharged without metformin therapy. Author comment: ‘’This patient’s metabolic acidiosis resulted from long-term metformin use in the setting of an elevated creatinine, which ultimately caused decreased excretion of the drug. Her presenting complaint was vision loss’’.

Kreshak AA, et al. Transient vision loss in a patient with metformin-associated lactic acidiosis. American Journal of Emergency Medicines 28: 1059e5-1059e7, No.9, Nov 2010.

Corticosteroids/methotrexate Kaposi’s sarcoma in an elderly patient: case report

A 65-year old man developed kaposi’s sarcoma with colonic and skin lesions, following treatment with methotrexate and corticosteroids, including prednisone for ulcerative colitis(UC).

Following a diagnosis of left sided UC and spondyloarthropathy in November 1993, immunomodulatory therapy with mercaptopurine and azathioprine was initiated; treatment was subsequently withdrawn due to gastrointestinal intolerance. In June 2001, methotrexate (dosage and route not stated) was introduced but was suspended in November 2007 to prevent potential drug-related toxicities; prednisone 5mg/day (route not stated) was administered continuously throughout this period. In August 2008, he was admitted for IV steroid therapy (details not stated) following an acute disease episode. During admission he developed violaceous reddish-brown nodules on both legs (time to reaction onset not clearly stated). Investigation revealed active UC with multiple reddish elevated lesions in the last 25cm of the colon, and thickening of the rectum and sigmoid colon walls. Skin histology showed a small, non-encapsulated dermal lesion composed of dilated, irregular and spiculated blood vessels, lined by few prominent endothelial cells; lymphocytes and macrophages comprised an associated infiltrate. Immunohistochemistry with CD34 and CD31 were positive; staining for human herpes virus 8 (HHV-8) showed moderate and focal nuclear positivity. Colonic kaposi’s sarcoma was the preliminary diagnosis. Anti-HHV-8 serology demonstrated an IgG antibody titre of 1/40. A protocolectomy was performed, confirming the presence of multiple nodular lesions of the sigmoid colon and rectum. Labelling for HHV-8 was positive. Multifocal kaposi’s sarcoma of the colon was the final diagnosis. The man’s skin lesions resolved after surgery and steroid withdrawal. At 12 months follow-up, he had no symptoms and no recurrence of skin lesions.
Rodriguez-Pelaez M, et al. kaposi’s sarcoma: An opportunistic infection by human herpesvirus-8 in ulcerative colitis. Journal of Crohn’s and colitis 4: 586-590, No.5, Nov 2010.

Influenza virus vaccine/influenza A virus vaccine H1N1 Guillain-Barre syndrome in an elderly patient: case report

A 75 year old man, with severe chronic obstructive pulmonary disease and dyspnoea, was hospitalized with worsening dyspnoea, cough and purulent expectoration. He reported a progressive debility in his lower limbs for the past week. Neurological examinations revealed grade 4/5 debility in his lower limbs and loss of osteotendinous reflexes. He had received a seasonal influenza virus vaccine 8 weeks earlier and an influenza A viral vaccine, H1N1 vaccine 2 weeks before the onset of the symptoms (route and doses not stated ). A lumber puncture and an electromyogram revealed albumino-cytological dissociation and acute demyelinating neuropathy affecting his lower limbs, respectively. Guillain-Barre syndrome secondary to influenza vaccine was suspected. He received immunoglobulins and rehabilitation. The weakness in his extremities and his respiratory process improved markedly; he was discharged and monitored. Author comment: There was casual effect between the vaccinations and Guillain-Barre syndrome, although it was not possible to determine which of the two was supposed to be responsible, whether it was the result of a sum of probabilities or a cumulative effect of antigen stimulation. Nieto ML, et al. Gullain-Barre syndrome secondary to H1N1 influenza vaccine.

Revista Clinica Espanola 210: 485-486, No. 9, Oct 2010.

by

Akshaya Srikanth

Pharm.D Resident

Hyderabad, India

HEART DISEASE PASSES FROM FATHER TO SON

Coronary artery disease, which kills tens of thousands each year, may be passed genetically from father to son, according to a new study.

The study, led by the University of Leicester, shows that the Y chromosome - a part of DNA only present in men - plays a role in the inheritance of the disease.

Coronary artery disease involves the narrowing of blood vessels delivering blood to the heart, and can lead to angina symptoms, such as constriction of the chest, and heart attacks.

Scientists analysed DNA from over 3,000 men enrolled in a heart health study and found that 90 per cent of British Y chromosomes belong to one of two major groups.  

The risk of coronary artery disease among men who carry a Y chromosome in one of the two groups is 50 per cent higher than for other men, and is independent of traditional risk factors such as high cholesterol, high blood pressure and smoking.  

The researchers believe the increased risk is down to the specific group's influence on the immune system and inflammation.  

Principal investigator Dr Maciej Tomaszewski said:

“We are very excited about these findings as they put the Y chromosome on the map of genetic susceptibility to coronary artery disease. We wish to further analyse the human Y chromosome to find specific genes and variants that drive this association.

“The major novelty of these findings is that the human Y chromosome appears to play a role in the cardiovascular system beyond its traditionally perceived determination of male sex.

Dr Hélène Wilson, research advisor at the British Heart Foundation (BHF), which was the main funder of the study, said:

“Lifestyle choices such as poor diet and smoking are major causes, but inherited factors carried in DNA are also part of the picture.

"The next step is to identify specifically which genes are responsible and how they might increase heart attack risk."

“This discovery could help lead to new treatments for heart disease in men, or tests that could tell men if they are at particularly high risk of a heart attack.

The study is published in The Lancet in February 2012 . LINK: LANCET

by

AKSHAYA SRIKANTH

Pharm.D Resident

Hyderabad, India

A Sense of Urgency

Bladder issues such as urinary tract infections, overactive bladder, interstitial cystitis, and incontinence are the top healthcare problems in the United States today. The best-selling items in pharmacies are now adult diapers, reaching 2.2 billion dollars in sales per year.

As men and women age, the incidence of bladder problems and urinary incontinence increases for both sexes. These problems are far more common in women, but many women just ignore them, thinking that leaking small amounts of urine when sneezing or laughing are not a real medical problem. They may feel too embarrassed to seek assistance, or they may look at it as just another normal part of aging.

Incontinence is defined as the involuntary release of urine and, while it often accompanies aging, it can be caused by many factors. For example, removal of the uterus can lead to weakening or prolapse of the bladder, resulting in incontinence, simply due to the lack of physical support from that organ. Incontinence can also result from a lack of estrogen, which weakens the bladder and urinary tract structures. Diseases like diabetes or the aftermath of stroke can cause incontinence. Constipation can also be a source of incontinence, as a result of straining. Men with benign prostatitis can develop incontinence. And, people with a history of bedwetting during childhood are more likely to experience some incontinence as an adult.

As incontinence becomes more frequent or worsens, coping behaviors increase. Using sanitary napkins or other feminine hygiene products, refusing to travel, mapping out the location of toilets, urinating again (just in case), avoiding fluid intake, stopping exercise, and wearing dark clothes can all be indicators of a problem with incontinence.

So, what can be done to help control incontinence, or at least deal with it better?

Some women try using feminine pads to catch the urine released unexpectedly with incontinence. However, those pads are not designed to capture the amount of fluid that may be present. The adult incontinence pads are a much better choice because they are designed like kitty litter, to form a gel when in contact with fluid, and they can also help control odor.

For women who are overweight, losing even just 5 to 10 pounds can dramatically reduce incontinence. Dietary changes, such as eliminating caffeine and avoiding spicy foods that can irritate the bladder, may help some people reduce incontinence. Fluid management throughout the day, and especially within 3 to 4 hours before bedtime, may be necessary to control “urge incontinence” (another name for overactive bladder). Avoiding alcoholic beverages may be essential for some people because it contributes to the loss of muscle control.

Many healthcare practitioners recommend Kegel exercises, which strengthen the pelvic floor muscles, for reducing incontinence. Dr. Michael Platt of the Platt Wellness Center suggests adding testosterone, applied vaginally daily, because it helps rebuild the muscles that have atrophied. He also believes that adrenaline may be part of the equation when it comes to understanding the causes for incontinence, and suggests that progesterone (as the natural balancer of adrenaline) may be used to reduce it. In addition to bioidentical hormone therapies, prescription drugs and surgeries are also options that may provide relief for some people.

If you are experiencing incontinence (or are close to someone who is), it is best to speak with a healthcare practitioner about it early on, so they can help you explore remedies before the problem escalates.

Source: WIP

by

AKSHAYA SRIKANTH

Pharm.D Resident

Hyderabad, India

How the heart works, and how it can cause sudden death

The heart is a specialised muscle that contracts regularly and continuously, pumping blood to the body and the lungs. The pumping action is caused by a flow of electricity through the heart that repeats itself in a cycle. If this electrical activity is disrupted - for example by a disturbance in the heart's rhythm known as an 'arrhythmia' - it can affect the heart's ability to pump properly. 

The heart has four chambers - two at the top (the atria) and two at the bottom (the ventricles). The normal trigger for the heart to contract arises from the heart's natural pacemaker, the SA node, which is in the top chamber.

The heart's natural pacemaker - the SA node - sends out regular electrical impulses from the top chamber (the atrium) causing it to contract and pump blood into the bottom chamber (the ventricle). The electrical impulse is then conducted to the ventricles through a form of 'junction box' called the AV node. The impulse spreads into the ventricles, causing the muscle to contract and to pump out the blood. The blood from the right ventricle goes to the lungs, and the blood from the left ventricle goes to the body.

The SA node sends out regular electrical impulses causing the atrium to contract and to pump blood into the bottom chamber (the ventricle). The electrical impulse then passes to the ventricles through a form of 'junction box' called the AV node (atrio-ventricular node). This electrical impulse spreads into the ventricles, causing the muscle to contract and to pump blood to the lungs and the body. Chemicals which circulate in the blood, and which are released by the nerves that regulate the heart, alter the speed of the pacemaker and the force of the pumping action of the ventricles. For example, adrenaline increases the heart rate and the volume of blood pumped by the heart.

The electrical activity of the heart can be detected by doing an 'electrocardiogram' (also called an ECG).

A death is described as sudden when it occurs unexpectedly, spontaneously and/or even dramatically. Some will be unwitnessed; some may occur during sleep or during or just after exercise. Most sudden deaths are due to a heart condition and are then called sudden cardiac death (SCD). Up to 95 in every 100 sudden cardiac deaths are due to disease that causes abnormality of the structure of the heart. The actual mechanism of death is most commonly a serious disturbance of the heart's rhythm known as a 'ventricular arrhythmia' (a disturbance in the heart rhythm in the ventricles) or 'ventricular tachycardia' (a rapid heart rate in the ventricles). This can disrupt the ability of the ventricles to pump blood effectively to the body and can cause a loss of all blood pressure. This is known as a cardiac arrest. If this problem is not resolved in about two minutes, and if no-one is available to begin resuscitation, the brain and heart become significantly damaged and death follows quickly.

by

Akshaya Srikanth*, Dr.Chandra Babu

RIMS Medical College, Kadapa

A.P, India

POTENTIALLY INAPPROPRIATE DRUGS FOR ELDERLY (BEERS LIST)*

• ALPRAZOLAM (use lowest effective dose)
• AMIODARONE (may cause arrhythmias; questionable efficacy in older adults)
• AMITRIPTYLINE (anticholinergic effects and sedation)
• AMPHETAMINES (may cause dependence, hypertension, angina, MI, CNS stimulation)
• ANOREXIC AGENTS (may cause dependence, hypertension, angina, and MI)
• BARBITURATES, except phenobarbital or for seizures (highly addictive, cause more adverse effects in elderly than most other hypnotic/sedatives)
• BELLADONNA ALKALOIDS (anticholinergic effects and questionable effectiveness; avoid its use, esp. long-term)
• BISACODYL (bowel dysfunction with long-term use; may be appropriate with opiate analgesics)
• CARISOPRODOL (poorly tolerated due to anticholinergic effects and possibly less effective at tolerated doses)
• CASCARA SAGRADA (bowel dysfunction with long-term use; may be appropriate with opiate analgesics)
• CHLORAZEPATE (prolonged sedation; short-acting benzodiazepines are preferred)
• CHLORDIAZEPOXIDE (prolonged sedation; short-acting benzodiazepines are preferred)
• CHLORDIAZEPOXIDE-AMITRIPTYLINE (anticholinergic effects and prolonged sedation; short-acting benzodiazepines preferred)
• CHLORPHENIRAMINE (causes anticholinergic effects; non-anticholinergic antihistamines preferred for treating allergic reactions)
• CHLORPROPAMIDE (may cause prolonged hypoglycemia and/or SIADH)
• CHLORZOXAZONE (poorly tolerated by elderly due to anticholinergic effects and possibly less effective at tolerated doses)
• Cimetidine (may cause confusion, other CNS adverse effects)
• CLIDINIUM-CHLORDIAZEPOXIDE (anticholinergic effects, prolonged sedation; short-acting benzodiazepines preferred) clidinium is of questionable effectiveness; avoid its use, esp. long-term)
• Clonidine (may cause orthostatic hypotension, adverse CNS effects)
• Cyclandelate (uncertain efficacy at doses studied)
• CYCLOBENZAPRINE (poorly tolerated by elderly due to anticholinergic effects and possibly less effective at tolerated doses)
• CYPROHEPTADINE (causes anticholinergic effects; non-anticholinergic antihistamines preferred for treating allergic reactions)
• DEXCHLORPHENIRAMINE (causes anticholinergic effects; non-anticholinergic antihistamines preferred for treating allergic reactions)
• DIAZEPAM (prolonged sedation; short-acting benzodiazepines preferred)
• DICYCLOMINE (causes anticholinergic effects and is of questionable effectiveness; avoid its use, esp. long-term)
• Digoxin (increased risk of toxic effects with decreased renal function; use low doses except when treating atrial arrhythmias)
• DIPHENHYDRAMINE (causes anticholinergic effects and sedation; non-anticholinergic antihistamines preferred for treating allergic reactions; should be used only at lowest effective dose if used for allergic reactions; should not be used as a hypnotic)
• Dipyridamole, short-acting (may cause ortho-static hypotension)
• DISOPYRAMIDE (may cause heart failure and anticholinergic effects; avoid its use)
• Doxazosin (hypotension, dry mouth, urinary problems)
• DOXEPIN (anticholinergic effects and sedation)
• Ergot mesyloids (uncertain efficacy at doses studied)
• Estrogens only, oral forms (carcinogenicity and lack of cardioprotective effect in older women)
• Ethacrynic acid (may cause hypertension, fluid/electrolyte imbalances; use safer alternatives)
• Ferrous sulfate (doses over 325mg/day are not reliably absorbed but may cause constipation)
• FLUOXETINE, daily use forms (may cause excessive CNS stimulation, agitation, sleep disturbances; use safer alternatives)
• FLURAZEPAM (prolonged sedation may result in falls/fractures; medium or short-acting benzodiazepines preferred)
• GUANADREL (orthostatic hypotension)
• GUANETHIDINE (orthostatic hypotension)
• HALAZEPAM (prolonged sedation; shortacting benzodiazepines preferred)
• HYDROXYZINE (causes anticholinergic effects; non-anticholinergic antihistamines preferred for treating allergic reactions)
• HYOSCYAMINE (causes anticholinergic effects and is of questionable effectiveness; avoid its use, esp. long-term)
• INDOMETHACIN (causes the most CNS side effects among NSAIDs)
• Isoxsurpine (uncertain efficacy)
• KETOROLAC (avoid immediate and long-term use in elderly, because they may have asymptomatic pathological GI conditions)
• LORAZEPAM (use lowest effective dose)
• MEPERIDINE (may cause confusion; is of questionable efficacy at commonly used oral doses)
• MEPROBAMATE (very addicting and sedating; slow withdrawal needed after prolonged use)
• MESORIDAZINE (CNS and extrapyramidal adverse effects)
• METAXALONE (poorly tolerated by elderly due to anticholinergic effects; possibly less effective at tolerated doses)
• METHOCARBAMOL (poorly tolerated by elderly due to anticholinergic effects; possibly less effective at tolerated doses)
• METHYLDOPA and METHYLDOPA-HCTZ (may cause bradycardia and worsen depression in elderly)
• METHYLTESTOSTERONE (may cause prostatic hypertrophy, cardiac problems)
• MINERAL OIL (potential for aspiration and other adverse effects; use safer alternatives)
• NAPROXEN (avoid long-term, full-dose use due to potential to cause GI bleed, renal failure, high BP, heart failure)
• NEOLOID (bowel dysfunction with long-term use; may be appropriate with opiate analgesics)
• NIFEDIPINE, short acting (may cause hypotension, constipation)
• NITROFURANTOIN (may cause renal impairment; use safer alternatives)
• ORPHENADRINE (sedation, anticholinergic effects; use safer alternatives)
• OXAPROZIN (avoid long-term, full-dose use due to potential to cause GI bleed, renal failure, high BP, heart failure)
• OXAZEPAM (use lowest effective dose)
• OXYBUTYNIN (poorly tolerated by elderly due to anticholinergic effects; possibly less effective at tolerated doses; do not consider extended-release form)
• PENTAZOCINE (may cause more CNS adverse effects than other narcotics)
• PERPHENAZINE-AMITRIPTYLINE (anticholinergic effects, sedation)
• PIROXICAM (avoid long-term, full-dose use due to potential to cause GI bleed, renal failure, high BP, heart failure)
• PROMETHAZINE (causes anticholinergic effects; non-anticholinergic antihistamines preferred for treating allergic reactions)
• PROPANTHELINE (causes anticholinergic effects and is of questionable effectiveness; avoid its use, esp. long-term)
• Propoxyphene and combination products (risks may outweigh benefits)
• QUAZEPAM (prolonged sedation; short-acting benzodiazepines preferred)
• RESERPINE (may cause depression, impotence, sedation, and orthostatic hypotension at doses over 0.25mg)
• TEMAZEPAM (use lowest effective dose)
• THIORIDAZINE (greater potential for CNS and extrapyramidal adverse effects)
• THYROID, DESSICATED (possible cardiac effects; use safer alternatives)
• TICLOPIDINE (aspirin, or other alternative drugs, may be preferable due to efficacy and safety)
• TRIAZOLAM (use lowest effective dose)
• TRIMETHOBENZAMIDE (less effective, and may cause extrapyramidal symptoms)
• TRIPELENNAMINE (causes anticholinergic effects; non-anticholinergic antihistamines preferred for treating allergic reactions)

*Listings in ALL CAPS denotes “high severity”
Source: ARCHIVES OD INTERNAL MEDICINE
by
AKSHAYA SRIKANTH
Pharm.D RESIDENT
Hyderabad, India

Pharmacovigilance – current trends and future perspective

Drug use could lead to better outcome’ is undoubtly accepted by all but favourable outcome is hardly seen with increased number of problems like irrationality, resistance, medication errors and lack of root cause analysis. The other side of the story is equally dangerous. The delayed reflexes were picked up way back in 1960s with Thalidomide tragedy and then origin of international drug monitoring activities in 1968 making it mandate for manufacturers, stakeholders, regulators, drug authorities and healthcare professionals to vigilantly monitor drug use. No wonder “Pills for ill” concept adopted as “Pills make ill”.

Regulations for drugs are proposed by authorities but execution delay interrupted the whole network. Pharmacovigilance network is well sustained in developed countries but still on its way to progress in developing countries. With increased number of new chemical entities (NCE), pharmacovigilance has become mandatory requirement for pharmaceutical companies. With this view, phase IV studies are critically analyzed and executed with the aim to monitor and capture long term safety outcomes and report ongoing safety review to regulatory authorities in terms of periodic safety update reports (PSUR). It also insists manufacturers to update safety information in product leaflet or summary of product characteristics (SPC) within stipulated time period.

Regulatory authorities are concerned about drug safety and implementing risk minimization plan to: improve patient outcome, prevent drug associated injury or hazard, minimize healthcare associated cost especially cost attributed to ADRs, create awareness among consumers, healthcare professionals, stakeholders, third party payers and managed care organizations (MCOs), frame prevention strategies for highly vulnerable population, plan management strategies for effective care, disseminate safety information via communication network, develop guidelines for effective management of drug safety issues and execution and implementation of well framed guidelines based on recent information and ongoing safety review.

Regulatory authorities are constantly working to promote effective management strategies and risk minimization plan. Some of the responsibilities delegated to triage cover healthcare professionals, stakeholders and the consumers. 

Good reporting practices

Good reporting practices (GRP) could improve the quality of ADR reports and also minimize the subsequent occurrence of ADRs. Adverse drug reactions once notified should be subjected to analysis to establish causality. For analysis of ADR, standard scales are used to assess causality, severity and preventability aspects. Clinical interpretation of ADRs is of clinical importance to attribute the causality link between drug and reaction. In many clinical situations causality link is difficult to establish due to contradictory information or lack of proper data. Certain parameters which must be included for analysis are previous history, demographics, date of onset of reaction, onset time, time temporal relationship, suspected drug, description of the reaction, dechallenge, rechallenge, management and outcome of the reaction. 

The scales commonly preferred for analysis are causality analysis  as per WHO probability scale, Naranjo’s algorithm, French imputation method, European ABO method etc.). Severity analysis based on Hartwig et al scale. Preventability analysis as per the Modified Schumock and Thornton scale.

In order to improve the patient outcome, constant efforts are required to build up a strong pharmacovigilance network. In India, we do not have robust structure which could in turn compromise the safety and lead to adverse outcome. We still remember the Rofecoxib story of devastation. Drugs are meant to treat not to harm but practically speaking drugs could alter the normal physiology of patients despite targeting the affected organ which in turn could lead to adverse effects. Adverse effects could be avoided by vigilant monitoring and reporting.

In developing countries like India, the pharmacovigilance programme was initiated by Central Drugs Standard Control Organization (CDSCO) in Nov 2004 under the aegis of ministry of health and family welfare based on the recommendations made in the WHO document entitled “Safety monitoring of medicinal products-guidelines for setting up and running a pharmacovigilance centre” with the objective to monitor ADRs and report through hierarchy of pharmacovigilance network and disseminate the information with global healthcare community through WHO-Uppsala Monitoring Centre. Under this programme, 26 peripheral centres, 5 regional centres and 2 zonal centres were established. The National Pharmacovigilance Advisory Committee (NPAC) was constituted to assess the performance and recommend possible regulatory measures based on the data received from various centres. 

Due to lack of sufficient information and under reporting, the programme has been modified as Pharmacovigilance Programme of India (PvPI) and reinitiated in June 2010 with the aim to expand the existing structure and proactively report ADRs. The purpose of PvPI is to collect, collate and analyze data to recommend regulatory interventions and communicating risks to healthcare professionals and consumers. The National Coordinating Centre (NCC) i.e. Indian Pharmacopeia Commission, Ghaziabad will operate under the supervision of a Steering Committee which would consist of DCGI, New Delhi as chairman and other govt officials as constituent members. The following programme will be executed and monitored by Steering Committee and Strategic Advisory Committee. Technical support for the programme will be provided under different panels: Signal Review Panel, Core Training Panel and Quality Review Panel.

The five year PvPI has been scheduled under five phases covering the Initiation phase (2010-11), Expansion and consolidation phase (2011-12), Expansion and maintenance phase (2012-13), Expansion and optimization phase (2013-14) and the Excellence phase (2014-15)

As per proposed plan under Phase 1, 40 ADR monitoring centres will be enrolled. An additional 60, 100 and 100 centres will be enrolled under respective Phase 2, Phase 3 and Phase 4 comprises of 300 centres overall.

Adverse drug reaction information will be entered in safety database ‘Vigiflow’ programmed by WHO-Uppsala Monitoring Centre. The performance of individual centre will be continuously monitored and evaluated based on quality parameters and indicators.

The prevention strategies cover intensive monitoring and timely reporting of ADRs, prophylactic treatment for known reactions, ADR database for safety information and history of known allergy, patient education, dissemination of safety information.

Adverse drug reactions could be effectively managed by strong build up of causality link, discontinuation of drug therapy, reintroduction of drug therapy, if necessary. Introduction of  definitive therapy in case of certain or probable reactions, intensive monitoring and reporting of ADRs, and follow-up plan for patients who experienced ADRs. 

Strategies to enhance ADR reporting can include creation of  reporting culture, awareness about monitoring, sensitize healthcare professionals for enhancing ADR reporting, training sessions, reminders, reporting aids such as ADR drop box, ADR posters, ADR newsletter, fax and web reporting, periodic meeting, scientific newsletters and appreciation to reporter. 

Pharmacovigilance network will be expanded further to cover broader region. There is a need for proactive monitoring and reporting. Quality control system should be installed to constantly monitor the quality of ADR reports generated and authenticate the channel of network. Adoption of good pharmacovigilance practices (GPP) could create good reporting environment for healthcare professionals. Drug utilization may improve with strapping evidence based clinical practice and could lead to better patient outcome.

Source: PB

by

Akshaya Srikanth*, Tarun Wadhwa, Prof. MS Ganachari

Hyderabad, India

Post-Marketing Pharmacovigilance for a New Drug

Pharmacovigilance is the scientific study of medicinal products intended to treat a particular disease or indication for humans. It aims to establish drug safety profiles; knowledge about efficacy; metabolism and excretion; and other important clinical information. Within the EU and elsewhere, the regulatory authorities require all new medicinal products to have successfully completed a series of clinical trails before being granted a Marketing Authorisation which allows them to go on sale. This article explains some key points about the need for clinical trials and studies after the drug reached the market.

Pre-Marketing Clinical Studies Have Their Limitations

During the phase before a Marketing Authorisation is granted, clinical studies could have involved up to 10,000 patients. However, this is not always the case: it is also possible for the study size to have been much smaller. For example, ‘orphan drugs’ are those intended to treat relatively rare diseases. There may be cases where these drugs have been studied using smaller trials, with perhaps only dozens to hundreds of patients taking part.

Although pre-marketing trials must have been conducted in an extremely rigorous manner in order to meet EU drug safety regulations, they nonetheless have their limitations. The number of patients involved in even the largest trial means that uncommon and rare adverse reactions are statistically unlikely to have been detected with any certainty. The trials are able to produce important data but for example, at 5% probability level the absence of an adverse reaction within a study of 10,000 patients produces a true rate of occurrence of less than 1 in 3,333.

Pre-Marketing Trials May Not Include All Patient Groups

It could be that clinical trials did not include all the patient groups for whom the drug would be prescribed to. An example here could be studies involving patients with a maximum age of 60 years participating in clinical trials before the drug goes on sale, and subsequent prescribing to older patients once it reaches the market. There are a number of issues which could be relevant within this example. This patient group could be taking numerous other prescribed medications; they could present variations of metabolism and body mass index in comparison to younger patients; and they could present with a heightened sensitivity to certain types of medication. There could be issues around food intake, for example, if these patients are unable to follow a regularly timed meal schedule for any reason. Although there may have been some investigation into issues of polypharmacy, metabolism, the effects of food intake and so on during the pre-marketing studies, it could be that this particular patient group were not included in those studies.

Once the drug has been placed onto the market, the first 500,000 to 1,000,000 patients who take the new drug represent the first large scale safety test. Nurses, doctors and pharmacists around the world report suspected adverse reactions as spontaneous reports. They may do so via the regulatory agencies; national pharmacovigilance centres; or directly to the pharmaceutical companies. If a pharmaceutical company receives one of these reports, it must report it to the regulatory authorities. This will be generally within a 15 day timescale, subject to national and international laws.

Please note it is impossible to provide an exhaustive description of this topic within this short article; readers are therefore advised that this information cannot be considered as any type of professional advice.

by

Akshaya Srikanth

Pharm.D Resident 

India

Lymphatic Filariasis

Enlarged, red and painful legs, thick and creamy urine, monstrously large limbs or scrotums, fits of asthma... lymphatic filariasis manifests itself in many different forms depending on the individual. These symptoms are due to the obstruction of lower lymphatic vessels by worms of the genus filaria, transmitted to man by the stings of diverse species of mosquitoes.

At the beginning of the 20the Century, the essential elements of the fundamental data concerning the disease are known. The Colonial Health Service determines the geographical distribution of this endemic which, in the zone under French influence, affects dozens of millions of individuals. These physicians participate in the study of the acute manifestations of the disease. The considerable longevity of the worms (more than 15 years) explains the chronic evolution of the ailment with various manifestations, of which the most spectacular is Elephantiasis.

Up to 1947, no medical treatment is efficacious. Only surgery can relieve those who suffer from Elephantiasis. Techniques, which vary in the course of the century, are proposed one after the other and put into practice. In spite of the precarious conditions, success is often remarkable.

The advent of anti-filaria remedies permits the undertaking, notably in Polynesia, of the first chemoprophylaxis mass campaigns.

In 1862, in Paris, Demarquay discovers embryos of filaria in the blood of a Cuban. The same phenomenon is observed by Wücherer in Brazil in 1866, then in India and Guadeloupe... but it is Bancroft who finds the adult filaria in Australia in 1876. It is named bancroftian filariasis and, later, Wuchereria bancrofti. At the same time, P. Manson designates the mosquito as the transmitting agent of the parasite and Low, in 1900, demonstrates that this transmission is due to the stinging of the insect.

Later, three lymphatic filaria are identified but only Wuchereria bancrofti, a cosmopolitan parasite which only contaminates humans, is to be found in the French colonial domain.

Filaria are thin round worms a few centimetres long. Doted with remarkable longevity, the female, in the course of 15 years, emits millions of larvae (microfilaria). These manifest relatively little aggressiveness and are incapable of evolving into the adult stage in their environment, as passage through mosquitoes is essential for that. At night, they leave the lymphatic vessels to enter the blood stream. At sunrise, as Manson showed in 1877, they are no longer there.

When absorbing their repast, nocturnal mosquitoes imbibe microfilaria together with the blood of a patient.

Adult filaria abide exclusively in the lower lymphatic vessels of the abdomen.

Microfilaria of Bancroft seen through a microscope

In Indochina as in the Indian Trading Posts, the physicians of the Colonial Health Service have reported the disease since 1908 in Cochin China (Noc*), in Tonkin (Mathis* and Léger*). The rate of infection is estimated as 15 % in the population of Saigon.

The Pacific Islands are greatly affected (Brochard*). In 1940, 60 % of the population is smitten.

In the West Indies, lymphatic filariasis has been identified since 1907 (Dufougéré*). In 1914, Léger* and Gallen* report the presence of the parasite in 15 % of the population. The situation is the same in Guyana.

Geographical distribution of lymphatic filariasis

In sub-Saharan Africa, Thiroux* in 1912 and Léger in 1913 show the widespread nature of the endemic in the countries of French West Africa (AOF) and French Equatorial Africa (AEF).

In the Indian Ocean, it is the same as in the other territories, notably in Reunion Island (Thiroux*) and the Comoro Islands (Rouffiandis* 1910). There more than 80 % of the population is infected.

The rates of infection are very much superior to the number of patients who show symptoms of filariasis. "Healthy carriers" are numerous and contribute towards the perpetuation of the endemic.

ACUTE MANIFESTATIONS

A few months after contamination, there follow the first acute manifestations. Their repetitive character attracts attention. It is a question of very high fever accompanied by pains in the scrotum and the inguinal region or acute repetitive lymphangitis of the limbs. The leg is swollen and painful, the skin red and glistening. In the groin, the lymph glands are sensitive.

Acute lymphangitis of the leg

The explanation of these troubles opposes, for a long time, those who favour a microbic origin and those who advocate a filarial origin. The extremely inflammatory aspect leads to the search for a microbic component : besides the streptococcus, some think there is the intervention of a particular germ called the lymphococcus by Dufougéré* and the dermococcus by Le Dantec*. The filaria theory, upheld by Manson, is confirmed by the experience of American military physicians in the Pacific, between 1947 and 1950 : the use of recently-discovered anti-filaria remedies cures their patients afflicted with lymphangitis.

The explanation of the symptoms of filariasis is arrived at thanks to lymphography, x-rays of the opacification of the lymphatic vessels. The obstruction of the vessels by clusters of adult worms, often dead, is responsible for most of the acute manifestations, in particular adenitis and oedemas, which can become more complicated in the case of a microbic superinfection.

The colonial physicians make a great contributions towards the recognition and study of this vascular obstruction, notably in Dakar, Dejou* in 1952, Carayon* in 1962 and Datchary* in 1963. Nowadays, besides the progress in the immunological diagnosis of the disease, non-interventional methods (lymphoscintigraphy and ultrasonography) permit the early detection of lower lymphatic obstructions. When precociously administered, the medical treatment proves to be efficacious.

CHRONIC EVOLUTION - ELEPHANTIASIS

Elephantiasis of the leg 

The repeated pressure of acute lymphangitis brings about the fibrous thickening of the skin and the subcutaneous tissue which, at length, can result in monstrous deformations called "Elephantiasis".

Elephantiasis of the foot

The parts of the body in which they usually occur are the legs, the scrotum and sometimes the penis, the vulva, the breasts... The lower limbs can look like the paws of a pachyderm. As for scrotums, becoming huge, they could weigh 30 to 40 kg, so that walking becomes impossible and the use of a wheelbarrow is obligatory for getting about. The penis disappears, embedded in the mass of flesh, but it remains unharmed as are the testicles too. Elephantiasis is here the consequence of a definitive obstruction of the lymphatic vessels, as lymphography confirms.

Lymphatic vessel walls are narrow and fragile and their distension in case of obliteration could end up in their rupture and fistulation. Chyle, abdominal lymph made creamy by fat globules from the digestive tract, then flows in the peritoneum (chyloperitoneum), in the intestine (chylous diarrhoea) or in the urinary tracts (chyluria).

THE TREATMENT OF LYMPHATIC FILARIASIS

Before the Second World War, no medical treatment yields satisfactory results : iodides, mercurial and arsenical derivatives, anti-streptococcal serum, electro and radiotherapies. Only surgery reduces distressing disabilities of the limbs and the genital organs by ablation of the fibrous mass in order to make the patient once again agile and virile.

Lemoine* is the first to practise "certain palliative interventions" in Tahiti in 1910. He sets about performing vast cutaneous resections called "melon slicing" ("en tranches de melon"). Other techniques are attempted but soon abandoned, such as external draining of the lymph or lympho-venous anastomosis...

In what concerns the scrotum, it is a matter of excising the skin after having extricated the testicles and the penis and then detaching the fibrous mass in one block. A primary obstacle is the volume of these scrotal masses, sometimes huge. The difficulty stimulates the imagination of the surgeons. Some of them suspend this mass from a pulley attached to the ceiling. Guyomarc'h*, about 1910, in French Equatorial Africa (AEF), begins the operation with a large incision in the middle which separates the mass into two symmetric parts. Then he extracts the testicles, the penis... It is the epoch of heroism : the patient is on a stretcher, the operation lasts about thirty minutes. The patient is glad to see his penis once again and to be able to resume sexual activity. Continued by Bernard* in 1911 and by Ouzilleau*, this procedure is used for a long time. The latter writes in 1913: "We have had only four failures in 182 operations". Unfortunately, the recurrence of the ailment is the rule, sooner or later.

After the Second World War, agreement is reached on well-codified techniques to be used in treating elephantiasis of the limbs. Servelle's techniques or those of Gibson and Touch are used by the surgeons of the Colonial Health Service.

To remedy filarial chyluria, the resection of lymph vessels of the affected kidney, proposed in 1964 by L. Léger, is used with success, particularly in Tahiti, by Fouques*, Huet*, Montangerand* and Roch* in 1967.

MASS ANTI-FILARIA CAMPAIGNS

They only become possible after the discovery of Notezine and they have two aspects :

Several varieties of Elephantiasis

- The fight against mosquito vectors and their breeding grounds, already undertaken in the combat against Malaria, may explain why today the filarial endemic with its spectacular examples of Elephantiasis is on the decline.

- Chemoprophylaxis, reserved for regions where filarial endemics rage. The whole population may receive Notezine (sometimes incorporated into kitchen salt) during 12 days every three months. Another procedure consists of taking the remedy every two weeks. In 1949, Laigret* begins a campaign in Polynesia and notes, in the population, a great reduction in the density of microfilaria in the blood.

These mass campaigns remain rare and are limited, for, in general, filariasis is not considered a priority. In 1998, the WHO, in a resolution of the General Assembly, demands member states to classify it as a public health problem.

Source: ASNOW

by

Akshaya Srikanth

Pharm.D Intern

Hyderabad, India