prn8099 - Number 21, February 1999

First, the Aedes mosquitoes and the in famous dengue fever. Since 1990 the disease has been on the rise where the infection rate increased from 27.5 per 100,000 to 38.2 people per 100,000 in 1995. In 1998, the dengue infection rate reached 120 people per 100,000. There was an overall 42% increase in dengue-related cases totalling 27,370 in 1998 compared to the previous year.

Then, late last year, the Culex mosquitoes joined in the foray with the Japanese encephalitis virus. Like the dengue, `Japanese encephalitis' soon becomes a household word especially after at least 14 death reported.

There is yet still another viral disease making its grand entrance recently. This time its chikungunya - a rare viral disease. According to the Health Minister twenty-seven people have been diagnosed as suffering from the new disease since early January. This is the first time the disease is detected in Malaysia - a disease first discovered in Tanzania, Africa, in 1952. Chikungunya in fact is Swahili for "that which bends up", in reference to the stooped posture of the patients. This is due to the severe joint pain associated with this disease.

To date, most of the victims are reported to be Indian women in Port Klang. Epidemics are sustained by human-mosquitoe-human tranmission. The etiologic agent, chikungunya virus has been placed in the family Togaviridae, genus Alphavirus. The epidemic cycle is similar to those of dengue, so are the clinical appearances. Human infections are suspected by the bite of infected Aedes aegypti mosquito, a vector similar to dengue.

Other then being mosquitoes-borne, there are no known cure for all of these diseases except for symptomatic and supportive treatment. Vaccines when available cannot give full protection. All these make preventive measures an all-important strategy. Another common factor in all the three diseases is their association with unattended environmental conditions. Thus while rapid and accurate diagnosis is important, prevention is still the preferred control mechanism.

Better care for eco-hygiene

Especially in the case of Japanese encephalitis and chikungunya fever it is the deplorable state of affairs that seems to encourage the breeding of infected mosquitoes.

For example, going by various on-sites reports, this is indeed the case in many of the pig farms inspected thus far. Most have ponds of stagnant water, often dirty and polluted, conducive to the breeding of the Culex larvae. While pigs are important hosts where hundreds of mosquitoes freely feed on their blood and become infected, the current unhygenic farming practices are equally implicated. Especially when the animal is part of the food chain.

In fact, it has been recorded on several occassions that pig farming practices have resulted in the polluting of rivers and waterways. The Sepang River of late, is a case in point. At times pig carcasses were seen afloat in such waters - some of which serving other communities downstream. There also were frequent reports of air pollution coupled with foul smell and unhealthy odour of pig wastes. Too often residential areas were oberwhelmed with stench from the farms located nearby. Recent reports citing cases of illegal or unlicensed pig farms add further concern to the existing problem. They will only add to the burden of regulation and enforcement, and hence the overall management of the Japanese encephalitis outbreak.

It is no wonder therefore that Japanese encephalitis which was reported to be endemic with small-scale sporadic outbreaks occurring in 1974, 1988 and 1992 turned epidemic in the last quater of the 1990s affecting mainly pig farming workers and the neighbouring residents.

There are about 3 million pigs being reared in this country. Proportionally this makes pig farming a rather substantial activity with more than RM 1 billion total ex-farm value of the livestock products in 1996. For this reason alone, the pig industry has to be more closely monitored and regulated. Failing to do this means that the likelihood of Japanese encephalitis to spread into an epidemic proportion is considerably greater. The fact the at least 14 have died to date (4 in Seremban, 1 in Malacca and 9 in Perak by end of January), mostly associated pig farming is a case in point. Since pig farming also poses a variety of environmental concern that could translate to health problems it further adds urgency to the situation nationwide.

Similarly inspections of Port Klang, where chikungunya was first noted, also reported deplorable conditions with rubbish thrown about indiscriminately. In other words in all these cases the problems are multi-faceted with both serious health and environment ramifications. These is no single step that could satisfactorily tackle the current situation in a concerted way without taking preventive action into consideration.

Although it is heartening to note that attempts are being taken to put the problem under control it cannot be sustained unless support of the people to keep the environment and the immediate compounds mosquitoe-free. This an uphill task considering that many people are still apathetic and not willing to fully cooperate with authorities in controlling the breeding of mosquitoes nationwide. A total community effort therefore it essential to contain the waves of current epidemics.

 UN to Consider Ban on Toxic POPs

A global treaty to ban 12 persistent organic pollutants POPs was discussed at the second session of the United Nations (UN) POPs conference, held last month in Nairobi, Kenya. They include: Aldrin, Chlordane, DDT, Dieldrin, Dioxins, Endrin, Furans, Heptachlor, Hexachlorobenze, Mirex, PCBs, and Toxaphene.

In the previous issue of prn8099 (No. 20, Oct. 1998), PRN has voiced its concern over their dangers in this country. Since October 1, 1998, chlordane has been banned as a pest control poison in this country. This is a move in the right direction and needs more action against the other POPs.

POPs are highly toxic chemicals that persist in the environment and travel via air, wind, and water around the globe. The chemicals are known to concentrate in human and animal fat cells, and studies suggest that they may cause reproductive abnormalities, neurological defects, and cancer (see prn8099, No. 20).

These 12 POPs were chosen because a scientific consensus agrees that they are toxic to humans and the environment. The goal of the treaty is not only to eliminated these POPs from the environment, but also to develop a plan aimed at addressing other chemicals in the future.

DDT, dioxins and furans are likely to be the most intensely discussed at this point with regard to control measures. DDT because of its life-saving uses against malaria-carrying mosquitoes, and dioxins and furans because they are by-products of industrial emissions. The other nine pesticides is expected to have general support for phasing out production and use.

"The major industrial product is PCB. The United States, Canada, and industrialized countries still have very large quantities in use in electrical equipment or in storage waiting for disposal. This is a very large, big money item", an official to the conference was quoted as saying.

It is hoped that this convention would be ratified and in operation in 2003 or 2004. Countries like Canada, Mexico and the USA are already working cooperatively to implement a continental action plan on DDT, chlordane and PCBs. These countries have already eliminated the manufacture and use of most of the other POPs pesticides. POPs generally cannot be managed and its difficult to regulate. The answer is to simply eliminate them, said a special advisor to Kenya's Greenbelt Movement, Ms. Njoki Njehu.

The World Wildlife Fund, representing the International POPs Elimination Network of 150 non-governmental organizations cited a study of Mexican children who lived in a valley where pesticide use, including POPs, was high. These children had lower physical and cognitive abilities when compared with similar children who live where natural farming techniques were used.

 1998 A Rewarding Year for PRN

1998, turns out to be a rewarding year for the country's only poison centre, PRN. Despite the economic downturn that besets much of its planning last year, PRN managed to chalk up a doubling of the number of poison cases handled since its inception four (4) years ago. In addition, PRN made history by being

• designated as the region's first WHO Collaborating Centre for Drug Information in April 1998, and
• the inaugural recipient of USM Quality Award for the Service Sector, 1998.

The third historic event is a Silver Award given to a research effort led by Assoc. Prof. Mohamed Isa Abd. Majid, Head of PRN Toxicology Laboratory at I.TEX 1998 held in Kuala Lumpur.

With these highpoints, PRN is better poised to play a role as the centre of excellence in the related areas of expertise. Since beginning operation in 1995, PRN has received other commendations such as:

• CCM Bioscience Product Stewardship Award in 1995
• Admitted to the Malaysia Book of Record in 1996, and
• Admitted to International Society of Drug Bulletin in 1997.

Persistant Bioaccumulative Toxic Chemicals: More Public Info Needed

In December 1998, the US Environmental Protection Agency (EPA) plans to provide the public with more information about a particularly worrisome category of toxic chemicals that pose long-term health concerns, namely the so-called `persistent bioaccumulative toxic chemicals, or PBTs.

These are chemicals such as mercury, dioxins and PCBs that accumulate over long periods of time in the environment and over years of exposure can pose significant health concerns including reproductive disorders and cancer. They are released from power plants, pulp and paper mills and industrial plants.

Under the EPA proposal, eight PBT chemicals will be added to the list of toxic substances subject to annual public reporting. The threshold for reporting will be significantly lower for 14 other chemicals already on the list.

The new requirements are another major step foward to ensure substantial information about the public's exposure to these chemicals in their communities. Currently facilities do not have to report releases of mercury or many of the other persistent bioaccumultive toxic chemicals unless they process more than 25,000 pounds annually or use more than 10,000 pounds annually. Under those requirements releases data on many of the chemicals do not have to be reported at all.

However under the EPA's proposed regulation, the thresholds for reporting would be lowered for most of the chemicals to either 100 pounds or in many cases to 10 pounds, EPA officials said. In the case of PCBs data would have to be made public if more than 0.1 grams are released annually.

PRN CONSULT

Review on

Poisoning Involving Lithium

by Syed Azhar Syed Sulaiman, Pharm.D

Q U I C K R E F E R E N C E G U I D E

Lithium belongs to the group of alkali metals with a monovalent cation and has some chemical properties of calcium and magnesium. It was discovered by a Brazilian, Jose Bonifacio de Andrade Silva in the early 19th century. It was J.J. Berzelius, a Swedish chemist, that proposed the name lithion for this new element, based on the Greek word meaning a stone or mineral. Major sources of lithium are from minerals such as Spodumene, Amblygonite, Lepidolite and Petalite, and sea water. Lithium is used industrially in batteries, alloys, and lubricating greases. Lithium batteries release toxic gases, such as sulphur dioxide and thionyl chloride when it malfunctions. However, lithium toxicity does not occur with these products.

Lithium is used to treat primary treatment of recurrent bipolar (manic-depressive) disorders and for short term therapy of mania. Other indication of lithium include:

1. prophylactic therapy for schizo-affective disorders
2. periodic pathological aggression in children and adolescents
3. Kleine-Levin's Syndrome
4. treatment of inappropriate secretion of anti-diuretic hormone
5. as an immunological adjuvant

The side-effects of lithium have led to non-psychiatric uses in neutropenia, thyrotoxic crisis, thyroid cancer, migraine and cluster headaches.
Lithium has a narrow therapeutic index which is associated with numerous adverse effects and a high potential for toxicity. Renal system and CNS will be predominantly affected in lithium poisoning. Excessive dosage prescription or altered drug kinetics during chronic maintenance therapy contributes to most of the reported lithium poisoning.
Only a few cases have been reported with acute self-poisoning. Lithium poisoning is serious and may cause prolonged or permanent neurological and renal dysfunction or even death. Lithium poisoning is largely preventable with a thorough understanding of the clinical conditions that lead to lithium retention and with early recognition of the often subtle initial symptom complex.

Lithium is available commercially as the citrate and carbonate salts. In Malaysia, lithium carbonate is available as Lithicarb and Priadel.

The actual mechanism is not known. However lithium affects the brain's monoaminergic neurotransmitter concentrations at the synapse. It has strong effects on biologic membranes, and intracellularly inhibits the conversion of inositol monophosphate to free inositol. This latter effect, may, in turn reduce neuronal excitability. Lithium alters cation transport across cell membrane in nerve and muscle cells and influences reuptake of serotonin and/or noreadrenalin.

Lithium excretion is dependent on glomerular filtration rate as well as sodium and water homeostasis. Sodium and lithium ions are handled by kidneys in a similar manner which pass freely into the glomerular filter and are reabsorbed by a similar transport mechanism in the proximal tubules. Therefore, any factor that decreases glomerular filtration or increased proximal tubular reabsorption of sodium and water promotes lithium retention. Thus sodium deficiency, dehydration and cardiac failure may lead to lithium retention and possible intoxication.
Lithium itself may also contribute to water and salt loss. It can also cause diarrhea and can impair renal concentrating ability with resultant polyuria.

With high level of lithium in the body, it depresses neural excitation and synaptic transmission. Lithium is completely absorbed within 6-8 hours after ingestion and excreted renally. It enters slowly into the brain, which explains the delay effect after an acute intoxication. It has a long half-life of 15-30 hours. Since the uptake by the CNS and other tissues occurs slowly, this may account for delays in clinical improvement of lithium toxicity due to slow redistribution of lithium in the tissues.

Risk of lithium toxicity is increased if patient is unable to maintain a sufficient water intakes. Dehydration that ensues can lead to increase renal conservation of sodium and lithium.

Kidney disease from any cause may also adversely affect lithium clearance, thereby enhancing the risk of toxicity. Dose adjustment should be done for patient with renal impairment. For patient with creatinine clearance between 10 - 50 ml/min, the lithium should be administered at 50 - 75 % of the normal dose while those with clearance less than 10 ml/min only 20-25% of the normal dose should be given. About 90-98 % of the drug will be excreted in the urine as unchanged drug. Table 1 shows the common dosages of lithium for adult and children.
Lithium may be dosed according to the specific conditions that the patient might have in order to prevent toxicity from occuring. Table 2 illustrates the baseline data determination for a patient before starting lithium therapy.
Certain drugs may adversely interact with lithium to reduce renal lithium clearance and thus increase the risk of adverse effects and poisonings. Non-steroidal anti-inflammatory drugs and thiazide diuretics may increase serum lithium by decreasing the renal clearance. Neurotoxic effects of lithium carbonate will be increased in patient taking haloperidol and the phenothiazines concurrently. Among the most commonly used drugs that may interact with lithium are listed in Table 3.

The usual daily doses of lithium ranges from 200 mg to 2400 mg with a therapeutic level of 0.6-1.2 mEq/L. Table 4 shows the range of lithium levels that corresponds to their clinical effects.

In mild to moderate toxicity, patients may experience lethargy, tremor, ataxia, slurred speech, muscular weakness and myoclonic jerks. Extrapyramidal effects and rigidity may also be seen. Agitation, convulsions, coma and hyperthermia may occur in severe intoxication. The ECG will usually show T-wave inversions and less commonly bradycardia or sinus node arrest. Elevation of white cell count may also be seen. In acute ingestion systemic signs of toxicity are usually minimal with initial presentation of nausea and vomiting. The systemic effects are delayed for few hours while lithium distributes into tissues. In chronic intoxication, systemic manifestations may appear on admission, usually with elevated BUN and creatinine levels. Patient may present with dehydration and hyper-natremia or renal insufficiency. Signs and symptoms of lithium intoxication are summarized in Table 5.

Diagnosis of lithium intoxication is usually done in suspected psychiatric patient who is confused, tremulous or ataxic and supported by elevated serum level of lithium. Other useful laboratory data should include electrolytes, glucose, BUN, creatinine and ECG monitoring.
Little correlation exists between serum lithium levels and severity of intoxication in acute lithium overdoses. Following acute overdose,  levels as high as 3-6 mEq/L in patients not chronically taking lithium have not resulted in any symptom.
Determination of serum concentration of lithium is an important part of treatment plan since not only does it confirm toxicity but it can also be used to giude therapy and managing lithium intoxication. However, blood levels taken after an acute overdose is not reliable because it does not reflect the intracellular pool of the agent. Though lithium absorption is fast, tissue distribution is delayed.

There is NO specific antidote. However thiazides and indomethacin have been used in patients with nephrogenic diabetes insipidus induced by lithium.

General management

Treatment is usually aimed at quickly removing lithium from the body, restoring and maintaining fluid and electrolytes balances, and providing good supportive medical care. In an emergency case, maintain the airway and assist ventilation if necessary in obtunded patient. Supplemental oxygen may be given. If the patient is comatose, hyperthermic or having convulsions, treat accordingly. Intravenous crystalloid should be given to dehydrated patients to avoid further complications.

Specific management

1. GI emptying

   The initial management of a significant acute overdose should include gastric emptying with gastric lavage. Decontamination is appropriate after an acute ingestion but not in chronic intoxication. Activated charcoal does not absorbed lithium but may be useful if co-drug ingestion is suspected and should be administered along with a cathartic.

2. Diuresis

   Saline infusion should be started to correct the sodium and fluid deficits that frequently exist in patients who are lihium-toxic. It is effective in promoting lithium diuresis in situations where volume repletion restores a reduced glomerular filtration rate. Mannitol and urea have been reported being used for the same reason. However, once the glomerular filtration rate is normalized, saline and osmotic diuresis is of limited benefit.
   Thiazide and loop diuretics plays no role in the management of lithium toxicity. In fact , they may promote lithium retention if they lead to dehydration or sodium depletion. Urinary alkalinization may potentially increase renal elimination of lithium, however, its use has not proved to be effective.

3. Dialysis

   Hemodialysis is the most effective way of reducing the serum lithium ion concentration. The decision to use dialysis is dependent on:

   1. the serum lithium level
   2. severity of signs and symptoms
   3. the rate of elimination of lithium by the kidney

Hemodialysis is the treatment of choice for severe toxicity. A serum level of 4.0 mEq/L or higher is an indication for immediate hemodialysis even if the patient is asymptomatic, as is the case after a large acute ingestion. Hemodialysis is also indicated in patient exhibiting severe neurotoxic or cardiotoxic signs and symptoms.

Prolonged dialysis for 8-12 hours is required to give sufficient time for extracellular and intracellular to equlibrate. It may need to be repeated to compensate for a rebound increase in serum lithium levels that can occur after redistribution of lithium from tissues to blood. The goal is to achieve a serum lithium level of less than 1.0 mEq/L 6 to 8 hours after cessation of dialysis. Although hemodialysis can result in a rapid reduction of serum lithium levels, clinical recovery is often delayed owing to the extensive tissue distribution. The treatment plan for lithium toxicity is shown in Table 6.

Potentially serious toxicity may occur with ingestion of more than 20-30 tablets in adults. Chronic intoxication usually occurs in stabilized patients on lithium. Any changes in clinical situation involving renal status may lead to serious intoxication. Excessive dehydration, sodium depletion or excessive sodium reabsorption, acute gastroenteritis, diuretic use may lead to lithium toxicity. Appropriate monitoring and evaluating the risk factors may help to overcome lithium intoxication.

Source: Nando Media, 1998

 Protecting Against Mosquito-Borne Diseases

In view of the current situation where mosquito borne diseases are reported to be prevalance in some areas transmitting diseases like encephalitis and of late "chikungunya" fever listed below are suggestions of how best one could be protected against being infected.

One sure way of protecting yourself is to ensure that your environment is mosquito free by observing hygenic practices in every respect. It will further help if you take these precautions:

1. Eliminate standing water near or in your home.
2. Minimize exposure to mosquitoes by staying inside from dust to dawn, when mosquitoes bite.
3. Wear clothing clovering most of your body. Shirt collars and sleeves should be snug against the skin. Tuck shirts into pants and pant legs into socks.
4. Know the season when the mosquitoe are most active, so be vigilant during those months, especially the rainy seasons.
5. Know the animals host that are involved in spreading the disease. Keep away from these animals.
6. Be aware of the symptoms of the insect-transmitted diseases. Seek medical attention if you experience flu-like symptoms after being outdoors.

Insect repellents can help prevent bites from mosquitoes and other biting insects reducing the risk of disease. Various forms and concentrations are available. The following guidelines from the US Chemical Specialties Manufacturers Association can help you select the proper insect repellent:

1. Liquid, cream, lotion, and stick products offer more precise skin applications.
2. Aerosol and pump-spray products are preferred for treating clothing as well as for applying to skin. They provide an even application.
3. Lower-concentration products (25 to 30 percent) are appropriate for most situations where exposure to insects is minimal or for shorter exposure periods.
4. Products with higher concentrations can give increased protection in highly infested areas, for people more prone to insect bites, and against difficult to repel species such as black files. These products also provide longer protection (from 6 to 8 hours).

If you are planning to having outdoor activities areas where insects and mosquitoes are prevalent, applying an insect repellent is one effective way of protecting them from potentially serious bites. Here are a few guidelines:

1. Read the entiere product label before using the repellent.
2. Do not apply on wounds or scratches. Avoid eyes and mouth.
3. Apply to clothing for added protection if necessary as directed on the product label.
4. Avoid over-saturation - it is not necessary for adequate protection.
5. Only apply insect repellents to exposed skin taking care to avoid the eyes and mouth.
6. Reapply repellent after exercise or swimming or as directed on product.
7. Cleanse the skin with soap and water after returning indoors.
8. Keep out of the reach of children, because like many chemicals can be toxic if ingested.
9. A small percentage of children and adults may be sensitive to chemicals. If there is a suspected reaction to an insect repellent, wash the area and seek medical attention.
10. Do not apply to the hands of small children, since they frequently put their hands in their mouth.
11. The American Association of Pediatrics recommends that parents using insect repellents use products containing 6 to 10 percent DEET (diethyltholuamide) and that they only apply it on children over the age of two.

 TEN Guiding Principles for Teaching Chilren and Adolescents About Medicines:

This principles are intended to encourage activities that will help children, through adolescence, become active participants in the process of using medicines to the best of their abilities. Recognizing that children of the same age vary in developement, experience, and capabilities, these principles do not specify children's ages.

1. Children, as users of medicines, have a right to appropriate information about their medicines that reflects the child's health status, capabilities, and culture.
2. Children want to know Health care providers and health educators should communicate directly with children about their medicines.
3. Children's interest in medicines should be encouraged, and they should be taught how to ask questions of health care providers, parents, and other care givers about medicines and other therapies.
4. Children learn by example. The actions of parents and other care givers should show children appropriate use of medicines.
5. Children, their parents, and their health care providers should negotiate the gradual transfer of responsibility for medicine use in ways that respect parental responsibilities and the health status and capabilities of the child.
6. Children's medicine education should take into account what children want to know about medicines, as well as what health professionals think children should know.
7. Children should receive basic information about medicines and their proper use as a part of school health education.
8. Children's medicine education should include information about the general use and misuse of medicines, as well as about the specific medicines the child is using.
9. Children have a right to information that will enable them to aboid poisoning through the misuse of medicines.
10. Children asked to participate in clinical trials (after parents consent) have a right to rejoceive appropriate information to promote their understanding before assent and participation.

Developed by the Division of Information Development, United States Pharmacopeia. Primary responsibility resided with the USP Pediatrics Advisory Panel and its Ad Hoc Advisory Panel on Children and Medicines.

For further information contact:

Patricia J. Bush, PhD.
United States Pharmacopeia
12601 Twinbrook Parkway
Rockville, MD 20852
Tel: (301) 816-8118

E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.