Vitamin Supplementation.

It is generally considered that healthy persons eating a normal balanced diet should have no need for vitamin supplementation. A review of the topic pointed out that the vitamins that people chose foe self medication are often not the ones that are actually present in inadequate amounts in their diets and that the commercial preparations available often do not make it clear whether the amounts or many times greater. Supplementation should concentrate on groups of people at risk of deficiency such as neonate, who need vitamin K; pregnant and lactating women, who need calcium, folic acid, and iron; and certain groups, who need vitamin D; vegans and their infants may require vitamin B₁₂ supplements. A multivitamin supplement might be considered for some groups such as the elderly and those with reduced calorie intake. However, one might have difficulty in finding a good multivitamin preparation containing all 13 vitamins bit no non-vitamins. Also with many of the multivitamin preparation the doses and ratios varied inexplicably.

A review of supplementation specifically in children concluded that, provided school children and adolescents eat a wide variety of foods, there was no need for vitamin supplementation. However, it was recommended that supplementation with vitamins A, C, and D should be given to those between the ages of 6 month and 2 years and preferably up to the age of 5 years.

A subsequent study supports the suggestion that supplementation may be of some benefit in the elderly। Supplementation resulted in an improvement in immune response and a decreased frequency of infection in elderly subjects. It was suggested that dosage might be crucial and that excessive doses of micronutrients could impair rather than improve immune response.

Hypercholesterolemia is a major risk factor for the development of atherosclerosis and consequently ischemic heart disease. Since oxidation of lipids, particularly low-density-lipoprotein (LDL) cholesterol has been proposed as a factor in atherogenesis, the possibility of preventing atherosclerosis by the use of dietary antioxidants such as vitamin E and C and betacarotene has been investigated. Prospective epidemiological studies have revealed a reduced risk of ischemic heart disease in individuals taking vitamin E supplement, and those with a high carotene intake (particular smoker). In a further prospective cohort study, dietary vitamin E consumption, but not vitamin E supplementation, was associated with decreased risk of death from ischemic heart disease. Conversely, in these studies, intake of vitamin C did not appear to be associated with a decreased risk of ischemic heart disease. Data from some studies assessing serum or fat concentrations also provide evidence that high betacarotene concentrations are associated with decreased cardiovascular disease.

Did you reach the goals you set for your self?

The basics of setting a goal is an open secret known by top-caliber
athletes, successful businessmen and businesswomen and all types of
achievers in all the different fields. The basics of setting goals
give you short-term and long-term motivation and focus. They help
you set focus on the acquisition of required knowledge and help you
to plan and organize your resources and your time so that you can
get the best out of your life.

Setting clearly defined short term and long term goals will enable
you to measure your progress and achieve personal satisfaction once
you have successfully met your goals. Charting your progress will
also enable you to actually see the stages of completion leading to
the actual realization of your goals. This eliminates the feeling
of a long and pointless grind towards achieving your goal. Your
self-confidence and level of competence will also improve as you
will be more aware of your capabilities as you complete or achieve
your goals.

The basics of goal settings will involve deciding what you really
want to do with your personal life and what short term and long
term goals you need to achieve it. Then you have to break down
goals into the smaller and manageable targets that you must
complete in your way to achieving your lifetime targets. Once you
have your list waste no time in tackling your goals.

A good way to have a manageable list is to have a daily and weekly
set of goals. By doing this you will be always in the position of
going towards you life plan goals. Everyday will give you the
opportunity to fulfill a certain goal giving you the feeling of
accomplishment.

Here are some pointers that should be taken into consideration in
setting goals and achieving them.

Attitude plays a very big role in setting and achieving your goals.
You must ask yourself  if any part of you or your mind holding you
back towards completing your simplest goals? If there are any part
of your behavior that is being a hindrance or puts your plans into
disarray? If you do have problems in these areas then the immediate
thing to do is to address this problem. Solutions may include a
visit to a doctor or psychiatrist to control your emotions.

Careers are made by good time management practice. Failing in a
career is often attributed to bad time management. Careers require
a lot from an individual which often makes the career the life of
the individual. Plan how far do you want to go into your career.

Education is key in achieving your goals. If your goals require you
to have a certain kind of degree or require a certain
specialization or demand a certain skill to be developed, make
plans in getting the appropriate education.

Your family should never be left out of your plans. If you are just
starting out then you have to decide if you want to be a parent or
when you want to be a parent. You also have to know if you really
would be a good parent and how well would you relate to extended
family members

Personal financial situations also play a major role in achieving
your goals. Have a realistic goal on how much you really want to
earn. You also must be able to create plans or stages by which you
will be able to reach your earning potential.

Physically gifted individuals may be able to achieve sports related
goals like being in the National Basketball association or National
Football League. Determining your physical capabilities should be
one of your priorities. Physical limitations could however be
conquered with proper planning.

As the saying goes -'All work and no play makes Jack a dull boy',
or something to that effect, is by all means true down to the last
the letter. Giving yourself a little pleasure: should be included
into your plans.

To start achieving your lifetime goals, set a quarter of a century
plan, then break it down to 5 year plans then break it down again
to 1 year plans, then 6 month plans then monthly plans, then
weekly, then daily.

Then create a things-to-do list for the day.

Always review your plans and prepare for contingencies.

The basics of goal settings should not be so difficult once you get
to be familiar with them.

PHARMACOLOGY DATA OF CEFOPERAZONE PLUS SULBACTAM

Cefobactam injection 1 gm and 2 gm

Cefoperazone (as sodium) IM /IV

Sulbactam (as sodium) 1:1

QUALITATIVE AND QUANTATIVE COMPOSITION;

Sulbactam sodium /cefaperazone sodium combination is available as a dry powder for reconstitution in a 1:1 ratio in term of free SBT/CPT. Sulbactam sodium is a derivative of the basic penicillin nucleus. It is an irreversible beta-lactamase inhibiters for Paranteral use only.

Chemically it is sodium penicillinate sulfone. It contains 92mg sodium (94 mEq) per gram. Subactam is an off-white crystalline powder which is highly soluble in water. The molecular weight is 255.22.

Cefaparazone sodium semisynthetic broad-spectrum cephalosporin antibiotic for parenteral use only it contains 34mg sodium (5.1mEq) per gram cefoperazone is a white crystalline powder which is freely soluble in water. The molecular weight is 667 . 65.

Pharmaceutical form

Vials of the 1:1 product contain the equivalent of 500mg+500mg+1000mg+1000mg of sulbactam and cefoperazone, respectively.

Clinical particulars

Therapeutic indications

Mono-therapy

Sulbactam /Cefoperazone are indicated for the treatment of the following infections when caused by susceptible organism;

Respiratory tract infections (upper and lower), urinary peritonitis cholecysitic , cholangits, and other intra-abdominals infections septicemia, meningitis, skin and soft tissue infections bone and joint infections, pelvic inflammatory diseases, endometritis gonorrhea, and other infections of the genital tract.

Combination therapy

Because of the broad spectrum of activity of sulbactam/cefoperazone most infection can be treated adequate with these antibiotic alone. However sulbactam /cefoperazone may be used concomitantly with others antibiotic if such combination is indicated. If aminoglycoside is used (see section 6.2 incompatibilities animoglyside), renal function should be monitored during the course the therapy (posology and method of administration Use in renal dysfunction).

Posology and method of administration use in adults

Daily dosage recommendation for sulbactam/cefoperazone in adults is as follow:

Sulbactam Cefoperazone

Ratio SBT/CPZ (g) Activity (g) Activity (g)

………………………………………………………………………………………………………

1:1 2.0 – 4.0 1.0 – 2.0 1.0 – 2.0

Doses should be administrated every 12 hour in equally divided doses.

In sever or refractory infections the daily dosage of sulbactam/cefoperazone may be in creased up to 8g of the 1:1 ratio (I .e., 4gcefoperazone activity).

Patient receiving the 1:1 ratio may require additional cefoperazone administrated separately. Dose should be administrated every 12 hour in equally divided dose.

The recommended maximum daily dosage of sulbactam is 4g.

Use in hepatic dysfunction

Special warnings and special precautions for use

Use in renal dysfunction

Dosage regimens of sulbactam/cefoperazone should be adjusted in patients with marked decreased in renal function (creatinine clearance of less than 20ml/min) to compensate for the reduced clearance of sulbatam. patients with creatinine clearance between 15 and 30ml/min) should received a maximum of 1g of sulbactam administrated every 12 hours

(Maximum daily dosage of 2g sulbactam), while patients with creatinine clearance of less than 15m/min should receive a maximum of 500mg of sulbactam every 12 hour. (Maximum daily dosage 1m of sulbactam). In sever infections it may be necessary to administrator additional cefoperazone.

Athe pharmacokinetic profile of sulbactam is significantly altered by hemodialysis.

The serum half-life of cefoperazone is reduced slightly during hemodialysis thus

Dosing should be scheduled to follow a dialysis period

Use in elderly

Pharmacokinetic properties

Use in children

Daily dosage recommendation for sulbactam/Cefoperazone in children is follows;

Sulbactam Cefoperazone

Ratio SBT/CPZ(g)

Mg/kg/day Activity Mg/kg/day Activity Mg/kg/day

………………………………………………………………………………………………………

1:1 40 – 80 20 – 40 20 – 40

............................................................................................................................................

Doses should be administrated every 6 hour in equally divided doses.

In serious or refractory infections , these dosages may be increased up to 160mg/kg/day. Doses should be administrated in tow to four equally divided doses (special warning and especial precautions for use in infancy and preclinical safely data use in pediatrics).

Use in neonates

For neonates in the first week of life the drugs should be given every 12 hour. The maximum daily doses of sulbactam in pediatrics should not exceed 80mg /kg/day.

If more than 80mh/kg/day of cefoperazone cactivity are necessary, additional cefoperazone should be administrated separately (especial warning and especial precaution for use infancy).

Intravenous administration

For intermittent infusion each vial of sulbactam /cefoperazone should be reconstitute

The appropriate amount (instructions for use/handing reconstitution)of 5% dextrose in water ,0.9% sodium chloride injection or sterile water for injection and then diluted to 20ml with the same solution followed by administration over to 15 to 60 minutes.

Located ranger solution is a suitable vehicle for intravenous infusion, however not for initial reconstitution (incompatibilities located rangers solution and instruction for use/handing located rangers solution).

For intravenous injection each vial should be reconstitute as above and administrated over minimum of 3 minutes.

Intra muscular administration

Lidocaine HCI2% is a suitable vehicle for intra muscular administration, how ever not for initial reconstitution (incompatibilities lidocain and instructions for use/handing lidocain)

Contraindication

Sulbacam/cefoperazon is contraindication in patients with know allergy to penicillin,sulbactam,cefoperazone, or any of the cephalosporin.

Special warning and special precaution use.

Hypersensitivity

Serious and occasionally fatal hypersensitivity (anaphylactic reaction has been reported in patients receiving beta-lactamase or cephalosporin therapy). These reactions occur, the drugs in individual with the history of hypersensitivity reaction to multiple allergens. If an allergic reaction occur, the drug should be discontinuous and the appropriate therapy institute. Serious anaphylactic reaction required immediate emergency treatment epinephrine. Oxygen, intravenous steroid, and airway management, including incubation, should be administrated as indicated.

Use in hepatic dysfunction

Cefoperazone is extensively excreted in bile. The serum half-life of cefoperazone is usually prolonged and urinary excretion of the drug increased in patients with hepatic disease and/or biliary obstruction. Even with sever hepatic dysfunction, therapeutic concentration of cefoperazone are obtain in bile and only a 2- to -4 fold increased in half-life is seen. Dose modification may be that condition. In patients with hepatic dysfunction and concomitant renal impairment, cefoperazone serum concentrations should be monitoring of serum concentrations.

Use in fancy

Sulbactam/cefoperazone has been actively used in infant. It has been extensively studied in premature. Instituting therapy (preclinical safety data use in in pediatric).

Cefoperazone does not displace bilirubin from plasma protein binding site.

Interaction with others medicaments and others form of interaction.

Pregnancy and lactation

Usage during pregnancy

Reproduction studies have been performed in rats at doses up to 10 times the human dose and have revealed no evidence of impaired fertility and no teratological findings. Sulbactam and cefoperazone cross the placental barrier. There are how ever, no adequate and well-controlled studies in pregnant woman because animal reproduction studies are not always predictive of human response; this drug should be used during pregnancy only if clearly needed.

Usage in nursing mothers

Only small quantities of sulbactam and cefoperazone are excreted in human milk. Although both drugs pass poorly onto breast milk of nursing mothers, caution should be exercised when sulbactam and Cefoperazone is administrated to a nursing mother.

Pharmacological properties

Pharamcodynamic properties

The antibacterial component of sulbactam and Cefoperazone is Cefoperazone a third generation cephapolosorin, which act against sensitive organism during the stage of active multiplication by inhibiting biosynthesis of cell wall mucopeptide. Sulbactam dose not possesses any usual antibacterial activity, except against Neissiareae. And Antibacterial

However biochemical studies with cell-free bacterial system have shown it to be and irreversible inhibitors of most important beta lactmases produced by beta-lactamase antibiotic resistant organism.

The potential for sulbactam’s preventing the destruction of penicillin’s and cephalosporin by resistant organism was confirmed in whole-organism studies using resistant strains in which sulbactam exhibited marks synergy with pencilins and cephalosporin’s.

As sulbactams also bind with some pencilins binding with patients, sensitive strains are also often rendered more susceptible to sulbactam/sefoperazone than to sefoperazone alone.

The combination of sulbactam and sefoperazone is active against all organisms sensitive to sefoperazone. In addition demonstrates synergistic activity (up to fourfold reduction and minimum inhibitory concentrations for the combination versus those for each component)

And a verity of organism, most markedly the following: homophiles influenza, Bactericides species, staphylococcus species, and a cinetobector calcobaceticus, introbacter aerogenenes, Escherichia coli, proteus, mirabilis, klebsiella, pneumonia, morganella morgganii, citrobacter freundii, entrobacter cloacae, citrobacter devises.

Sulbactam/sefoperazone active in vitro against wide variety of clinically significant organisms:

Staphyloccosus aurous Penicillin’s and non-pencilinase producing strains, staphylococcus epidermindis, streptococcus pneumoniae (formally diplococcic pneumonia) streptococcus pyogenes (group a beta-hemolytic streptococci), streptococcus agalactiai (Group B beta-hemolytic streptococci)

Most others strains of beta-hemolytic streptococci

Money strains of streptococcus faecalis (enterococcus)

Gram-negative organism:

Escherichia coli, klebsiella morganii species, enterobacter species, haemophilus influenzae, proteus mirabilis, proteus vulgaris morganella morganii (formerly proteus morganii), providencia retteri (formerly proteus retteri), providencia species, serratia species (including S. marcescens), salmonella and shigella species, pseudomonas aeruginosa and some other pseudomonas species, Acinetobacter calcoaceticus, neiseria gonorrhea, neisseria meningitis, borddetella pertussis, yersinia enterrocolitica.

Anaerobic organisms:

Gram negative bacilli (including bactericides, other bactericide species, and fusobacteium species)

Gram positive and gram-negative cocci (including peptococcus and veilonella species)

Gram positive bacilli (including clostridium and lactobacillus species)

Use in hepatic dysfunction

Special warning and special precaution for use

Use in renal dysfunction

In patient with deferent degree of renal function administrated sulcabtam/sefoperazonw the total body clearance of sulbatam was highly correlated estimated creatinine clearance,

Patients who are functionally anaphric showed a significant logger half-life of sulbatam (mean 6.9 and 9.7 hour in separate studies). Homedailysis significantly altered the half-life today body clearance and volume of distribution of sulbactam. No significant deferent have been observed in the pharmacokinetics of cefaperzone in renal failure patients.

Use in elderly

The pharmacokinetics of selbatam/sefaperzone has been situated in elderly individually with renal insuffiency and compromised hepatic function. Both sulbatam and cefoperazone inxhibited longer half-life lower cleanse and larger volume of distribution when compared to data from normal volunteers the pharmacokinetic of sulbactam correlated well with the degree of renal dysfunction whittle for sefoperazonw there way a good correlation with the degree of hepatic dysfunction.

Use in children

Studies conducted in pediatric have shown no significant change in the pharmacokinetic of the components of sulbactam/sefoperazone compared to adult values.

The mean half-life in children has ranged from from 0.90 to 1.42 hour for sulbactam and from 1.44 to 1.88 hour for cefoperazone

Preclinical safety data

Use in pediatric

Cefoperazone has adverse effect on the tested of prepurats at all dose tested

Subcutaneous administration of 1,000mg kg per day (approximately 16 times the average adult of human dose)

Resulted in reduced testicular weight, arrested spermatogenesis, and reduced germinal cell population and vacoulation of sertoil. Cell cytoplasm

The severity of lesion was dose dependent in the 100 to 1,000/kg/day range; the low dose caused a minor decree in spermatocytes. This effect has not been observed in adult rats.

Histological the lesions were reversible at all but the highest dosage levels. How ever these studies did not evaluate subsequent development of reproductive function in the rats.

The relationship of these finding to human is unknown.

When sulbactam cefoperazone (1:1) was given subcutaneously to neonatal rats for 1 month reduced testicular weights and immature tubules were seen in group given 300+300mg/kg/day. Because there is a great individual variation in t his degree of testicular maturation in rat pups and because immature tests were found in control any relation to study drug is uncertain. No such findings were seen in infant dogs at doses over 10 times the average adult’s dose.

Pharmaceutical particulars

Instruction of use/handing

Reconstitution

Sulbactam/sefoperazone is available in 2.0g strength vials.

……………………………………………………………………………………………………

Total equivalent dosage of volume of maximum final

Dosage (g) sulb + cefoperazone (g) diluent conc. (Mg/ml)

1.0 0.5 +0.5 3.4 125+125

2.0 1.0 +1.0 6.7 125+125

………………………………………………………………………………………………………

Sulbactam/cefoperazone has been shown to be compatible with water injection 5% dextrose in 0.225% saline, 5% dextrose in normal saline at concentration of 10mg cefoperazone and 5mg sulbactam per ml and up to 250mg cefoperazone and 125mg sulbactam per ml

Lactated ringers solution

Sterile water for injection should be used for reconstitution (see section 5.1 incompatibilities lactate ed ringers solution) a toe step dilution is required using sterile water for injection (shown in table above) further diluted with lactated ringers solution) to a sulbactam concentration of 5mm/ml (use 2ml initial dilution in 50 ml or 4ml initial dilution in 100ml located ringers solution.

Lidocaine

Sterile water for injection should be used for reconstitution (see section 5.1 incompatibilities lidicaine) for a concentration of cefoperazone of 250mg/ml or larger a tow step dilution required using sterile water for injection (shown in table above) further dilution with 2% lidocaine to yield solution containing up to 250mg cefoperazone and 125mg sulbactam per ml in approximately a 0.5% lidocaine HCI solution.

Simvastatain

Simvastatain (BAN, USAN, rINN)

L-644158-000U; MK-733; Simvastatain; synvinolin; velastatin.

(IS, 3R, 7S, 8S.8a-HEXAHYDRO-3, 7-dimethyl-8

{2-[(2R.4R)-tetrahydro-4hydroxy-8oxo-2H-pyaran-2-yl] ethyl}-l –naphtyl 2, 2-dimethylbutyrate.

C25H38O5 =418.6.

CAS—79902–63–9

ATC—C 1 0AA 0 1

Pharmacopoeias in Eur. (see p.vi) and US

Pharmacopoeia description

Ph. Eur.: A white or almost white crystalline powder.

Practically insoluble in water freely soluble in alcohol; every soluble in dichloromethane. Store under nitrogen in airtight containers Protect from light

U.S.P 25: A white to off-white powder.

Practically insoluble in water freely soluble freely in alcohol, in chloroform, and in methyl alcohol; sparingly soluble in petroleum spirit store under nitrogen

Usage and administration

Simvastatain is a lipid regulating drug.

It is a competitive inhibitor of 3-hydroxy-3-methylglutary. Coenzyme A reeducates (HMG-CoA reeducate)

The redeterming enzyme for cholesterol synthesis HMGoA reeducate inhibitors (also called satins) reduce total cholesterol; low density lipoprotein (VLDL) cholesterol concentration in plasma.

They also tend to reduce triglycerides and to increase high density lipoprotein (HDL) cholesterol concentration. They are considers to exert their hypercholesterolemic action by stimulating an increase in LDL receptors on hepatocyte membrane thereby increasing the clearance of LDL from the circulation.

Simvastatain is used to reduced LDL-cholesterol apoloporotein B, and triglycerides, and to increase HDL-cholesterol in the treatment of hyperlipidaemias (below), including hypercholesterolemia and combined (mixed) hyperlipideamia (type IIa of IIb hyperlippoproteinaemias) statins can be effective as adjunct therapy in patient with homozygous familial hypercholesterolemia who have some LDL-receptor function.Simvastatin is also given prophylactically to hypercholesterolemia patient with ischemic heart disease.

Simvastatain is given by mouth in an initial dose of 5 to 10 mg in the evening; an initial dose of 20 mg may be used in patient with ischemic heart disease. The dose may be adjusted at interval of not less than 4 weeks up to a maximum of 80 mg once daily in the evening. Patient with homozygous familial hypercholesterolemia may be treated with 40mg once daily in the evening, or 80mg daily in three divided dose of 20mg, 20mg, and an evening dose of 40mg.A maximum of 10 mg daily is recommended in those taking cyclosporine, fibrin acid

Derivatives, or nicotinic acid, and the risk of myopathy must be considered.

Pharmacokinetics

Simvastatain is absorbed from the gastrointestinal tract and is hydrolyzed to its active metabolites heave been detected and a number of inactive metabolites are also formed. Simvastatain undergoes extensive first-pass metabolism in the liver, its primary site of action. Less than 5% of the oral dose has been reported to reach the circulation as active metabolite. Both Simvastatain and its β-hydroxyacid metabolite are about 95%bound to plasma protein. It is metabolites. About 10 to 15% is recovered in the urine, mainly in inactive forms. The half-life the active metabolite is 1.9 hour.

Adverse Effects and Precautions

The comments adverse effects of therapy with Simvastatain and other statins are gastrointestinal disturbance. Other adverse effects reported include headache, skin rash, dizziness, blurred vision, insomnia, and dysgeusia. Reversible increases in serum-aminotransferase concentration may occur and liver function should be assessed before treatment is initiated and then monitored periodically unite one year after the last elevation in dose. Hepatitis and pancreatitis heave been reported. A hypersensitivity syndrome whose feature heave included angioedema has been reported. Myopathy, characterized by myalgia and muscle weakness and associated with increased creatinine phosphokinase concentrations, has been reported, especially in patients taking Simvastatain concurrently with cyclosporine, fabric acid derivatives, or nicotinic acid

may develop.

Simvastatain should be given to patients with acute liver diseases or unexplained persistently raised serum aminotransferase concentration. It should be avoided during pregnancy since there is a possibility that it could interfere with fetal sterol synthesis; there have been a raw reports of congenital abnormalities associated with statins (but see pregnancy, below). It should be discontinued if marked or persistent increase in serum- aminotransferase or creatinine phosphokinase concentration accrue it should be used with cautions in patients with sever renal impairment.

Interactions

There is an increase risk of mayopathy if certain drug is given concurrently with stains.

Concomitant administration of drug that inhibit that cytochrome P450 isoenzyme CYP3A4, such as ciclorin, itraconazole ketoconazole, erythromycin, clarithromycin, HIV-protease inhibitors and nefazodone might produce high plasma levels of Simvastatain thus increasing the risk of myothathy. Drugs that alone can cause myopathy, such as fabric acid derivative or nicotinic acid can increase the risk of this reaction when given with Simvastatain.

For further details see effects on skeletal muscles, under adverse thrombin time have effects, above.

Bleeding and increase in prothombin time have been reported in patients taking Simvastatain with coumarin anticoagulants. Raised concentrations of Simvastatain have occurred in patients also given mibefradil.

Montelukast

Montelukast Sodium (17380-f)

Montelukast Sodium (BANM, USAN, rINM).

MK-476.SodiumI-[({(R)-m-[(E)-2-(7-cholro-2-quinoly)-viny]-α-[o-(I-hydroxy-I-methylethyl) phenethyl]-benzyl} thio) methyl] cyclopropaneacetate,

C₃₅H₃₅CINNaO₃S = 608.2.

CAS — 158966-92-8 (montelukast); 151767-02-1 (montelukast sodium),

Montelukast Sodium 10.37mg is equivalent to montelukast 10mg.

Adverse Effects and Precautions

Suspected adverse effects reported to the UK Committee on Safety of Medicine following the launch of montelukast included oedema, agitation and restlessness, allergy including anaphylaxis, angioedema, and urtic

Aria, chest pain, tremor, dry mouth, vertigo and arthralgia

Further suspected adverse effects included nightmares, sedation, palpitations and increased sweating.

Churg-Strauss syndrome. Churg-Strauss syndrome has been reported in association with montelukast. For discussion of the unresolved role of leukotriene antagonists in this disorder and precaution to be observed.

Hepatic and renal impairment. Although there is some evidence of effects on the liver patients receiving montelukast, and although it is largely eliminated by hepatic metabolism, montelukast (unlike zafirlukast) is not considered by its UK manufacturer to be contra-indicated in hepatic impairment, and not dose adjusted is considered necessary in mild to moderate hepatic impairment.

No dosage adjustment is anticipated to be necessary in patients with renal impairment.

Interactions

The manufacturer recommends clinical monitoring when potent hepatic enzyme inducers such as phenytoin, Phenobarbital, or rifampicin are given with montelukast.

Phenobarbital. Peak serum concentration after a single dose of montelukast 10mg were reduced by 20% in 14 healthy subjects who took Phenobarbital 100mg daily for 14 days, and area under the serum concentration-time curve was reduced by 38%. However, it was not though that montelukast doses would need adjustment if given with Phenobarbital.

Pharmacokinetics

Peak plasma concentration of montelukast are achieved in 2 to 4 hours after oral administration. The mean oral bioavailability is 64%. Montelukast is more than 99% bound to plasma protein. It is extensively metabolized in the liver by cytochrome P450 isoenzymes CYP3A4, CYP2A6, and CYP2C9, and is excreted principally in the faeces via the bile. Metabolism was reduced and the elimination half-life prolonged in patients with mild to moderate hepatic impairment.

Uses and Administration

Montelukast is a selective leukotriene receptor antagonist with actions and uses similar to those of zafirluoinst although it is reported to have a longer duration of action. It is used as the sodium salt in the management of chronic asthma, in doses equivalent to 10mg of montelukast once daily at bedtime; children aged 6 to 14 years may be given the equivalent of 5mg at bedtime and children aged 2 to 5 years may be given 4mg. It should not be used to treat an acute asthma attack.

Asthma. Montauks produced modest improvement compared with place in both adults and children. It was not as effective as low-dose inhaled beclometasone in 1 study, but did permit reduction in the dose of concomitant inhaled corticosteroid in another. Miontelukast has been reviewed, and further general references for leukotiene antagonists can be found under Zafirlukast.

Pharmacological Data of Multi- Vitamins Plus minerals(Trace Elements)

Trace Elements

Trace elements are inorganic substance found in small amounts in the tissue and required for various metabolic processes; together with the vitamins (see below) they are sometimes referred to as micronutrients. The elements considered essential are chromium, copper, fluorine, iodine, iron, manganese, molybdenum, selenium, and zinc. Iron, in the form of haem, plays an essential role in oxygen transport while iodine is required by the thyroid for the formation of thyroid hormones; most of the other essential trace elements are cofactors for various enzymes. Boron, nickel, silicon, and vanadium may also be essential, and it has been suggested on the basis of animal studies that there might be a requirement for tin.

Well-defined deficiency syndromes exist for copper, iodine, iron, selenium, and zinc; although deficiency of other trace elements is possible, their deficiency syndromes are not well defined because of their ubiquity in the diet. Guidance concerning the intake of various trace elements has been published—see also Human Requirements under Vitamins, below.

Vitamins

Vitamins are organic substance required by the body in small amounts for various metabolic processes. Most are not synthesized in the body, or are synthesised in small or insufficient quantities. Vitamins are sometimes classified as fat soluble or water soluble. Substances in the vitamin A, D, E, and K groups are generally fat soluble, and biotin, folic acid, niacin, pantothenic acid, vitamins B₁, B₂, B₆, and B₁₂, and vitamin C substances are generally water soluble.

Vitamin deficiency may result from an inadequate diet, perhaps due to increased requirements such as during pregnancy, or may be induced by disease or drugs. Vitamin may be used clinically for the prevention and treatment of specific vitamin deficiency states and details of these uses are provided under the individual drug monographs.

Large doses of vitamins (megavitamin therapy) have been proposed for a variety of disorders, but adequate evidence of their value is lacking. Excessive intakes of most water-soluble vitamins have little effect due to their rapid excretion in urine, but excessive intakes of fat-soluble vitamins accumulate in the body and are potentially dangerous.

Stability.

Water-soluble vitamins are liable to degrade in solution especially if exposed to light. Addition of vitamin mixtures to infusion solutions for parenteral nutrition should therefore be carried out as possible before infusion. Solutions should be used within 24 hours of preparation and be protected from light.

Human requirements.

Vitamin and trace elements are essential nutrients and in many countries guidance has been published concerning their intake.

In the UK various terms are used to define intake:

· Estimated average requirement (EAR) is used for the requirements of energy, proteins, vitamins, or minerals of a group of people and usually about half will need more and half less than the specified figure.

· Lower reference nutrient (LRN) is applied to proteins, vitamins, or minerals and is that amount that is enough for only a few people who have low needs.

· Reference nutrient intake (RNI) is also applied to proteins, vitamins, or minerals and is an amount that is enough, or more than enough, for about 97% of people in a group.

· A safe intake is used to indicate an intake or range of intakes where there is not enough information to estimate EAR, LRNI, or RNI, but rather it is an amounts enough for almost everyone but is not so large as to cause undesirable effects.

· Dietary reference value (DRV) is used to cover EAR, LRNI, RNI, and safe intake.

It is emphasised in the report that these intakes are not meant to be recommendation for any individual or group; they do not reflect either a recommendation that such an amount should be taken daily in the diet or as a supplement. They are intended rather as yardsticks for the assessment of dietary surveys and food supply statistics; to provide guidance on appropriate dietary composition and meal provision; or for food labeling purposes in which case it is envisaged that an ERA will be used.

In the USA the National Academy of Science has traditionally set recommended dietary allowances (RDAs), defined as the levels of intake of essential nutrients that, on the basis of scientific knowledge, are judged to be adequate to meet the known nutrient needs of practically all healthy persons. The allowances are amounts that are intended to be consumed as part of a normal diet. However, new dietary reference intakes (DRIs) are being developed, which will include 3 reference values in addition to the traditional RDA as follows:

• The estimated average requirement is the intake that meets the needs of half the individuals in a group
• The adequate intake is the mean intake level that appears to sustain a desired marker of health, and will be set when there is insufficient evidence to establish an RDA
• The tolerable upper intake level is the maximum intake that is not likely to adversely affect health.

Information pertaining to the requirements of specific vitamins and minerals is provided under the individual monographs.

Supplement

An adequate dietary intake of vitamins is necessary for good health but whether vitamin supplementation in the absence of any demonstrable deficiency is beneficial or even worthwhile remains debatable.

It is generally considered that healthy persons eating a normal balanced diet should have no need for vitamin supplementation. A review of the topic pointed out that the vitamins that people chose foe self medication are often not the ones that are actually present in inadequate amounts in their diets and that the commercial preparations available often do not make it clear whether the amounts or many times greater. Supplementation should concentrate on groups of people at risk of deficiency such as neonate, who need vitamin K; pregnant and lactating women, who need calcium, folic acid, and iron; and certain groups, who need vitamin D; vegans and their infants may require vitamin B₁₂ supplements. A multivitamin supplement might be considered for some groups such as the elderly and those with reduced calorie intake. However, one might have difficulty in finding a good multivitamin preparation containing all 13 vitamins bit no non-vitamins. Also with many of the multivitamin preparation the doses and ratios varied inexplicably.

A review of supplementation specifically in children concluded that, provided school children and adolescents eat a wide variety of foods, there was no need for vitamin supplementation. However, it was recommended that supplementation with vitamins A, C, and D should be given to those between the ages of 6 month and 2 years and preferably up to the age of 5 years.

A subsequent study supports the suggestion that supplementation may be of some benefit in the elderly. Supplementation ments resulted in an improvement in immune response and a decreased frequency of infection in elderly subjects. It was suggested that dosage might be crucial and that excessive doses of micronutrients could impair rather than improve immune response.

MENTAL FUNCTION. Administration of vitamin and mineral supplement to children was reported in 1988 to increase non-verbal intelligence and the topic has science remained highly controversial. In the following two years more studies were published but these failed to substantiate the earlier possible effect and concluded that vitamin supplementation did not improve mental functioning or reasoning in children. Suggestions were made shortly after these publications that there might be a subset of children with poor nutritional status who would receive some benefit but this again was disputed.

In 1991 another study was published, this time coinciding with the lunch of the proprietary product used in the study, with the publication of a book on the subject, and with the showing on British television of a documentary concerning the study. This study purported to demonstrate that supplementation with exactly the recommended dietary allowance of vitamin improved the IQ of children, a finding that was said not to occur significantly with other quantities of vitamin supplementation. This view attracted extremely harsh criticism from physicians, nutritionists, psychologists, and epidemiologists.

PROPHYLAXIS OF ISCHAEMIC HEART DISEASE. Hypercholesterolaemia is a major risk factor for the development of atherosclerosis and consequently ischemic heart disease. Since oxidation of lipids, particularly low-density-lipoprotein (LDL) cholesterol has been proposed as a factor in atherogenesis, the possibility of preventing atherosclerosis by the use of dietary antoxidants such as vitamin E and C and betacarotene has been investigated. Prospective epidemiological studies have revealed a reduced risk of ischaemic heart disease in individuals taking vitamin E supplement, and those with a high carotene intake (particular smoker). In a further prospective cohort study, dietary vitamin E consumption, but not vitamin E supplementation, was associated with decreased risk of death from ischaemic heart disease. Conversely, in these studies, intake of vitamin C did not appear to be associated with a decreased risk of ischaemic heart disease. Data from some studies assessing serum or fat concentrations also provide evidence that high betacarotene concentrations are associated with decreased cardiovascular disease.

However, despite these promising epidemiological data, results from randomised placebo-controlled trials have failed to find any befit for betacarotene supplements in the primary or secondary prevention of inconclusive, in the Alpha Tocopherol, Beta Carotene Cancer Prevention (ATBC) study, which monitored cardiovascular disease as a secondary end-point, vitamin E was not associated with a decreased incidence of ischaemic heart disease, and betacarotene was associated with a small increased risk. In further analyses, neither supplement appreciably altered the incidence of angina pectoris, nor showed any beneficial effects on cardiovascular deaths in the subset of men with previous myocardial infractions. In has been suggested that the lack of effects of vitamin E in this study may be due to an insufficiently high dose of tocopherol. Similarly, neither the Betacarotene and Retinol Efficacy Trial (CARET) nor the Skin Cancer Prevention Study found on effects for betacartene supplementation on the risk of death from cardiovascular disease. In studies specifically on cardiovascular end-points, no benefit from betacarotene supplements was seen in a large, randomised, placebo-controlled study in healthy men, and an initial study of supplementation with high-dose vitamin E in patients with evidence of ischaemic heart disease failed to show any beneficial effects on cardiovascular deaths. However, there was a reduction in non-fatal myocardial infraction and major cardiovascular events. The Heart Outcomes Prevention Evaluation (HOPE) study also showed that vitamin E treatment for 4 to 6 years had no effect on cardiovascular events in high-risk patients. Another large-scale study is underway; the Heart Protection Study is assessing the effects of a ‘cocktail’ of vitamin E, vitamin C, and betacarotene on the development of ischaemic heart disease in high risk subjects. Until results from all studies are known, it has been recommended that the emphasis should be on consuming a balanced diet including anotoxidant-rich fruits, vegetables, and whole grains rather than vitamin supplements. For a discussion of the possibility that folic acid may reduce ischaemic heart disease through its homocysteine-lowering effects.

PROPHYLAXIS OF MALIGNANT NEOPLASMS. There is evidence that a diet rich in fruit and vegetables is associated with a lower incidence of malignant disease, particularly of the respiratory and digestive tracts. It has been hypothesised that some of the benefits of such a diet derive from the role of antoxidant vitamins such as the carotenoids and vitamins C and E in scavenging free radicals. However, it is by no means certain that these are the only, or necessary the most important, dietary components responsible for benefit, since components such as dietary fibre may also play a role. In addition, different antioxidants may vary in their properties and efficacy, and the appropriate dosage remains largely conjectural, and perhaps as a result the evidence of benefit is often conflicting.

Several clinical trials of the use of vitamin A or betacarotene in the secondary or primary prevention of malignancy have been reported. Prolongation of disease-free intervals in patients with various malignant neoplasms was reported in 1 study of betacaroten, and another reported remission of oral leukoplakia in patients treated with betacarotene and vitamin A. Vitamin A alone was reported to reduce the incidence of primary tobacco-related neoplasms in a study of patients treated surgically for lung cancer. However, other results have largely failed to substantiate any benefit for secondary prevention. No reduction in the incidence of new skin cancers, or in malignant transformation of cervical dysplasia, or in new colorectal adenomas was reported in 3 other studies. In a primary prevention study, a combination of betacarotene, vitamin E and selenium was associated with a reduction in stomach and oesophageal cancers in a population at high risk of these cancers and with a diet low in micronutrients in China. In contrast, other primary prevention studies have failed to show any benefit, and possibly some harm, from betacarotene supplements in will-nourished populations. A study in smokers showed an increase in lung cancer and associated mortality in those receiving bectacarotene (20 mg daily), but not these receiving vitamin E (50 mg daily). Similarly, an increased risk of lung cancer was noted in recipients of betacarotene (30 mg daily) with vitamin A (25 000 units daily) in another study in individual at high risk of lung cancer, and this study was stopped early as a result. A third study in healthy men found no benefit or harm for betacarotene supplements (50 mg on alternate days) in terms of incidence of malignant neoplasms, including those of the lung.

Vitamin C has also been proposed for this purpose but there is no real evidence to justify it. It certainly appears to be ineffective as adjuvant therapy in the treatment of advanced malignancy, and combination with betacarotene and vitamin E failed to show any effect in preventing colorectal adenoma. At physiological concentration vitamin C is an important antoxidant, but supplementation is unlikely to be justified in anyone eating a balanced diet.

Vitamin E substances are also known to play an important antoxidant role in the body. Animal studies have suggested that they should inhibit tumour production, and the Chinese study mentioned above found combined antoxidant therapy including vitamin E to be benefit in the primary prevention of stomach and osophageal cancers. Other studies in western populations have generally been disappointing; vitamin E had no effect on lung cancer incidence in those at risk, and did not prevent the development of new colorectal adenomas.

However, further analysis of the lung-cancer study suggests that vitamin E may have protected against prostate cancer.

Result from the Nurses’ Health study have indicated that prolonged use of multivitamins was associated with reduced risk of developing cancer of the colon. This effect was thought to be due to the folate component and could be demonstrated after 15 years of use, but not after shorter-term ingestion. Dietary folate was also associated with a modest reduction in risk for colon cancer.

At present, therefore, the only conclusion that appears uncontroversial is that a diet involving frequent consumption of fruit and vegetable is likely to be beneficial. However, given the present difficulties in treating many malignancies once they develop interest in the topic seems likely to continue.

Pharmacological Data of Tramadol

Tramadol Hydrochloride (6263-c)

Tramadol Hydrochloride (BANM, USAN, rlNNAM).

CG-315; U-26225A. (±)-trans-2-Dimethylaminomethly -I-(3-methoxyphenyl) cyclohexanol hydrochloride.

C6H₂₅NO_2, HCL = 299.8.

CAS–27203-92-5 (Tramadol); 22204-88-2 (Tramadol hydrochloride); 36282-47-0 (Tramadol hydrochloride).

Incompatibilities.

An injection of Tramadol hydrochloride 50 mg per mL is reported to be incompatible with injection of diazepam, diclofenac sodium, indomethacin, midazolam, and piroxicam if mixed in the same syringe.

Uses and Administration

Tramadol Hydrochloride is an opioid analgesic (p.68). It also has noradrenergic and serotonergic properties that may contribute to its analgesic activity. Tramadol is used for moderate to sever pain.

Tramadol Hydrochloride is given by mouth, intravenously, or rectally as a suppository. The intramuscular route has also been used. It may also be given by infusion or as part of a patient controlled analgesia system. Usual doses by mouth are 50 to 100 mg every 4 to 6 hours. Tramadol hydrochloride may also be given orally as a modified-release preparation once or twice daily. The total daily dosage by mouth should not exceed 400 mg.

A dose of 50 to 100 mg may be given every 4 to 6 hours by intravenous injection over 2 to 3 minute, or by intravenous infusion. For the treatment of postoperative pain, the initial dose is 100 mg followed by 50 mg every 10 to 20 minutes if necessary to a total maximum (including the initial dose) of 250 mg in the first hour. Thereafter doses are 50 to100 mg every 4 to 6 hours up to a total daily dose of 600 mg.

Rectal dose by suppository are 100 mg up to 4 times daily. The dosage interval should be increased to 12 hours in patients with a creatinine clearance less then 30 mL per minute; in the USA the manufactures suggest that the maximum dose by mouth should not be exceed 200 mg daily in these patients.Tramadol should not be given to patients with more sever renal impairment (creative clearance less than 10 mL per minute).A dosage interval of 12 hours is also recommended in sever hepatic impairment.

Pharmacokinetics

Tramadol is readily absorbed following oral administration but is subject to first –pass metabolism. Tramadol is metabolized by N-and O-demethylation and glucuronidation sulfation in the liver. The metabolite O-desmethyltramadol is pharmacologically active.Tramadol excreted mainly in the urine predominantly as metabolites. Tramadol is widely distributed, crosses the placenta , and appears in small amount in breast milk. The elimination half-life following oral administration is about 6 hours.

Adverse effect and treatment

As for Opioid Analgesics in general, p.67.

Tramadol may produce fewer typical opioid adverse affects such as respectively depression and constipation.

In addition to hypotension hypertension has occasionally occurred. Anaphylaxis hallucination, and confusion heave also been reported.

Respiratory depression has been reported after Tramadol infusion anesthesia, although in a postoperative study Tramadol had no significant respiratory depressant effect when equianalgesic dose of morphine, pentazocine, pethidine, piritramide , and Tramadol were compared.

Precautions

As for opioid Analgesics in general,

Tramodol should be used with caution in patients with renal or liver impairment and should avoid if renal impairment is sever. Removed by haemodialysis is reported to be very slow. Tramadol should be used with care in patient with a history of epilepsy or those susceptible to seizures. See also effects on the CNS under Adverse Effect above.

Interactions

For interaction associated with opioid analgesics, see p.68.Carbamazepine is reported to diminish the analgesic activity of Tramadol by reducing serum concentrations.

The risk of seizures is increased if Tramadol is administered concomitantly with other drugs that heave the potential to lower the seizure threshold. See also under Effects on the CNS under Adverse Effects, above

Tramodal inhibits reuptake of noradrenaline and serotonin enhance serotonin release and there is the possibility that it may interact with other drugs that enhance monoaminergic neurotransmission including lithium , tricycles antidepressants, and selective serotonin reuptake inhibitors; it should not given to patients receiving MAOIs or within14 days of their discontinuation.

Pharmacological data of Artemether

Artemether (12024-p)

Artemether (BAN, rlNN)

Dihydroarthemether Methyl Ether; Dihydroqinghaosu Methyl

Ether;o-Methyldihydroartemisinin;SM-224.(3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3,j]-1,2-benzodioxepin.

C₁₆H₂₆O₅ = 298.4.

CAS — 71963-77-4.

Adverse Effects and Precautions

Treatment with Artemether and its derivatives appears to be generally well tolerated, although there have been reports of mild gastrointestinal disturbance, dizziness, tinnitus, neutropenia, elevated liver enzyme values, and ECG abnormalities including prolongation of the QT interval.

Evidence of severe neurotoxicity has been seen in animals given high doses.

General reference to adverse effects associated with Artemether derivatives.

1. Price R, et al. Adverse effects in patients with acute falciparum malaria treated with Artemether derivatives. Am J Trop Med Hyg 1999; 60: 547-55.

Effects on the heart. Bradycardia was reported in 10 of 34 patients who received Artemether orally for 4 days.¹

1. Karbwang J,et al. Comparison of oral Artemether and mefloquine in acute uncomplicated falciparum malaria. Lancet 1992; 340: 1245-8.

Effects on the nervous system. Neurotoxicity has been reported in animals given artemotil.¹ an in vitro study² has shown that dihydroatemisinin, the metabolite common to all Artemether derivatives currently used, is neurotoxic. There has been a report ³ of acute cerebellar dysfunction manifesting as ataxia and slurred speech in a patient who took a 5-day course of articulate by mouth.

1. Brewer TG, et al. Neurotoxicity in animals due to Artemether and Artemether. Trans R Soc Trop Med Hyg 1994; 88 (suppl 1): 33-6.

2. Wesche DL, et al. Neurotoxicity of arthemether analogs in vitro. Antimicrobial Agents Chemother 1994; 38: 1813-19.

3. Miller LG, Panosian CB. Ataxia and slurred speech after artesunate treatment for falciparum malaria. N Engl J Med 1997; 336: 1328.

Pregnancy. Artesunate or Artemether was used to treat multidrug resistant falciparum malaria in 83 pregnant women in Thailand; of 73 pregnancies resulting in live births none showed evidence of any congenital abnormality.¹ sixteen of the women had received artesunate during the first trimester; of these, 12 had normal deliveries, 1 was lost to study, and 3 had spontaneous abortions.

No undue adverse effects on the neonates occurred in a study² involving 45 women treated for multidrug-resistant malaria during their second or third trimester of pregnancy with Artemether or Artemether plus mefloquine.

1. McGreevy R, et al. Arthemether derivatives in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 1998; 92: 430-3.

2. Sowunmi A, et al. Randomized trial of Artemether versus Artemether and mefloquine for the treatment of chloroqwuine/sufadoxine[sic]-pyrimethamine-resistant flaciparum malaria during pregnancy. J Obstet Gynaecol 1998; 18: 322-7.

Interactions

Grapefruit juice. The oral bioavailability of artemether may be increased by concomitant administration of grapefruit juice.

1. van Agtmael MA, et al. The effect of grapefruit juice on the time dependent decline of artemether plasma levels in healthy subjects. Clin Phamacol Ther 1999; 66: 322-7.

Pharmacokinetics

Peak plasma concentrations have been achieved in about 3 hours after oral administration of artemether, in about 6 hours after intramuscular injection of artemether, and in about 11 hours after rectal administration of artemisinin. Arthemetherand its derivatives are all rapidly hydrolyzed to the active metabolite dihydroartemisinin. Reported elimination half-lives have been about 45 minutes after intravenous administration of artesunate, about 4 hours after rectal artemisinin, and about 4 to 11 hours after intramuscular or oral artemether. There is very little published data on the pharmacokinetics of artemotil, but its elimination half-life appears to be longer than that of artemether.

Reviews.

1. White NJ, et al. Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet1999; 37: 105-25.

2. Navaratnam V, et al. Pharmacokinetics of artemisinin-type compounds. Clin Pharmacokinet 2000; 39: 255-70.

Uses and Administration

Arthemetheris a sesquiterpene lactone isolated from Artemisia annua, a herb that has traditionally been used in China for the treatment of malaria, it is a potent and rapidly acting blood schizontocide active against Plasmodium vivax and against both chloroquine-sensitive and chloroquine-resistant strains of P. falciparum.

Arthemetherand its derivatives are used usually in combination with other antimalarials for the treatment of malaria resistant to conventional drugs.

The following doses are those suggested by WHOM for the treatment of malaria in areas of multidrug resistance. For oral administration in uncomplicated falciparum malaria, Artemether or sodium artesunate may be given as a 3-day course. The dose of arthemetheris 25 mg per kg body-weight on the first day with 12.5 mg per kg on the second and third days. For artesunate, the initial dose is 5 mg per kg on the first day with 2.5 mg per kg on days two and three. In both case a single dose of mefloquine 15 mg per kg (or occasionally 25 mg per kg if necessary) is given on the second day to affect clinical cure.

For oral treatment of uncomplicated flaciparum malaria, artemether is given in combination with lumefantrine, over a period of 60 hours in a dose of 80 mg administered at diagnosis and repeated after 8, 34, 36, 48 and 60 hours (total dose 480 mg). If the oral arthemether compounds have to be used alone they should be given for a minimum of 5 days.

For parenteral administration is server malaria, artemether or artesunate are employed. The loading dose of artemether is 3.2 mg per kg body-weight intramuscularly, followed by 1.6 mg per kg daily for a artesunate maximum of 6 days. The loading dose of artesunate is 2.4 mg per kg intravenously, followed at 12 and 24 hours by a dose of 1.2 mg per kg, and then 1.2 mg per kg daily for a maximum of 6 days. For both drugs the patients should be transferred to oral therapy as soon as possible. Additionally a single oral dose of mefloquine should be given to effect clinical cure.

Reviews

1. de Vries PJ, Dien TK. Clinical pharmacology and therapeutic potential of arthemether and its derivatives in the treatment of malaria. Drugs 1996; 52: 818-36.

2. Mclntosh HM, Olliaro P. Artemether derivatives for treating uncomplicated malaria (updated 20 February 2001). Available in The Cochrane Library; Issue 4. Oxford: Update Software; 2001.

3. Mclntosh HM, Olliaro P. Artemether derivatives for treating severe malaria (updated 29 August 2001). Available in The Cochrane Library; Issue 4. Oxford: Update Software; 2001.

Administration of Artemether derivatives.

To overcome the poor solubility of arthemetherin water a number of dosage forms and routes of administration have been tried. Also several more potent derivatives with more suitable pharmaceutical properties have been developed.^1-3 notably the methyl ether derivative, artemether, and the ethyl ether derivative, artemotil, which are more lipid soluble; the sodium salt of the hemisuccinate ester, sodium artesunate, which is soluble in water but appears to heave poor stability in aqueous solutions; and sodium artelinate which is both soluble and stable in water. Other derivatives which have been studied include artefline. Several preparation of Artemether derivatives are available either commercially or for studies organized by bodies such as WHO.³ These include oral formulations of artemether, artesunate, Artemether itself, and dihydroartemisinin; intramuscular formulations of artemotil, artemether, and artesunate, intravenous formulations of artelinic acid and artesunate; and suppositories of Artemether and artesunate.

1. Titulaer HAC, et al. Formulation and pharmacokinetics of Artemether and its derivative. Int J Pharmaceutics 1991; 69: 83-92.

2. WHO. WHO model prescribing information: drugs are used in parasitic diseases. 2^nd ed. Geneva: WHO, 1995.

3. Olliaro PL, Trigg PI. Status of antimalarial drugs under development. Bull WHO 1995; 73: 565-71.

Malaria

Arthemetherand its derivatives have been shown in many studies to be effective in the treatment of both acute uncomplicated and sever malaria, the overall management of which is caused further on p.428. In an attempt to delay the developed of resistance to these compounds, WHO has recommended that their use be restricted to the treatment of malaria in areas of documented multidrug resistance and that they should not be used at all for prophylaxis; in practice, however, they appear to be more widely used. Recrudescence rates are high when Artemether compounds are given alone and they should therefore, when possible, be given with another antimalarial such as mefloquine in order to affect a clinical cure.

In acute uncomplicated malaria the drugs are usually given by mouth. Those used have been artemisinin, artemether or artesunate usually with mefloquine additionally. Artemether is also used with lumefantrine. The combination of artesunate with pyrimethamine-sulfadoxine is under investigation for use as first-line treatment in areas of chloroquine resistance. Artemotile may be given intramuscularly in acute malaria.

Parenteral therapy is generally necessary in sever malaria and good result in multidrug-resistant areas have been obtained with artemether, artemotil, or rtesunate intramuscular, usually followed by oral mefloquine. Artesunate has also been given intravenously. Rectal administration of artemisini, followed by oral mefloquine, has been successful.

Alternatives to standard treatment of cerebral malaria with intravenous quinine have been sought, partly because of the problems associated with giving intravenous infusions in the field. Several studies have shown intramuscular artemether to be effective, but the wisdom of such use when there is no multidrug resistance has been severely questioned. Also, although artemether has compared favorably with quinine in the treatment of severe (including cerebral) falciparum malaria, in other studies artemether, although an effective alternative to quinine, was either associated with slightly longer coma-recovery times or did not reduce mortality significantly compared with quinine.