herbal antimalerial

CONTENTS

S.No. Title Page No.1.

1.11.21.31.41.51.6

Introduction History of Malaria Distribution of Malaria Parasite and vector of Malaria Life Cycle of PlasmodiumResistance History of Treatment and Prophylaxis

1 – 201 – 5

66

7 – 1010 – 1112 - 20

2. Antimalarial Drugs 21 – 243.

3.13.23.33.4

Herbal Antimalarial Drugs Cinchona (Quinine)Artemisia Vulgaris Cryptolepis Yingzhaosu

25

3.1 Cinchona (Quinine)A. Source, and History of cinchonaB. Properties and Action C. Phytochemical StudyD. Pharmacological Study E. Uses and Application F. Biological Activities and Clinical ResearchG. Formulation

26 – 3726 – 28

2930 – 3131 – 3232 – 33

3435 - 37

3.2 Artemisia Vulgaris A. Source and Properties B. Morphological Study and Cultivation C. Production Profile D. Market and Market Potential

38 – 4541 – 4242 – 4444 – 45

453.3 Cryptolepis

A. History B. Nomenclature and TaxonomyC. Morphological Study D. Pharmacological Study E. Uses

46 – 5746

46 – 4747 – 4848 – 5454 – 57

3.4 Yingzhaosu 584. Conclusion 59 – 60

5. References 61 - 66

1. INTRODUCTION

The term malaria comes from 'mal' 'aria', or bad air. The Romans noticed that

they got sick when they took walks in the night air. Approximately 100 years

ago, Dr. Ronald Ross, a British Medical Officer in Hyderabad, India discovered

that mosquitoes transmitted malaria. He first recognized that the black pigment

associated with human disease was also present in the gut of the mosquito and

later showed that when infected mosquitoes bit chickens the disease was indeed

transmitted. For his studies he received the 1902 Nobel Prize in Medicine.

Malaria remains one of the most serious tropical diseases in many parts of the

world. The malaria situation is deteriorating in many areas impairing the

prevention and treatment of malaria, despite major control campaigns.

Resistance of the malaria parasite to antimalarial drugs is increasing and

becoming more widespread. 1 The incidence of travel-related malaria is

increasing, especially in visitors to endemic African countries. 2,4,6,8

The eradication of malaria in the Midwestern United States was achieved by (i)

breeding fish that ate mosquito larvae and (ii) increasing the standard of living.

The female Anopheline mosquito is highly prevalent in the Southern United

States. Thus, the emergence of drug resistant parasites elsewhere and more

frequent international travel increases the risk of malaria in the US. The CDCP

predicts that the highest risk of entry is Florida, due to immigration from Haiti.

The blood stages of infection are responsible for all of the clinical symptoms

and pathoglogies associated with malaria. These stages are our main focus of

interest. The parasite has a complex life as shown in Figure 3 (below). When a

mosquito bites a human host, sporozoites are released from the salivary glands

of the mosquito into the bloodstream. These reach the liver and undergo a cycle

of development in hepatocytes. The resulting merozoites lyse out of liver cells

and subsequently infect erythrocytes to undergo asexual proliferation as shown

Maharishi Arvind College of Pharmacy Page 1

in Figure 4 (below). Here a single merozoite gives rise to ~16 daugther cells,

which then re-infected red cells and thereby maintain the asexual cycle. The

length of the cycle determines the periodicity of the fevers and chills associated

with malaria. In falciparum malaria, the parasite development in the red cell

takes 48 hours. Fever occurs concomitant with release of merozoites into the

blood stream, every two days.

1.1 History of Malaria

Deadly fevers - probably malaria - have been recorded since the

beginning of the written word (6000-5500 B.C.) References can be found

in the Vedic writings of 1600 B.C. in India and by Hippocrates some

2500 years ago.

There are no references to malaria in the "medical books" of the Mayans

or Aztecs. It is likely that European settlers and slavery brought malaria

to the New World and the awaiting anophelines within the last 500 years.

Quinine, a toxic plant alkaloid made from the bark of the Cinchona tree in

South America, was used to treat malaria more than 350 years ago.

Jesuit missionaries in South America learned of the anti-malarial

properties of the bark of the Cinchona tree and had introduced it into

Europe by the 1630s and into India by 1657.

Malaria existed in parts of the United States from colonial times to the

1940s. One of the first military expenditures of the Continental Congress,

around 1775, was for $300 to buy quinine to protect General

Washington's troops.

In the summer of 1828 "swamp fever" broke out in the settlement of

Bytown (Ottawa) and along the construction route of the Rideau Canal.

According to some accounts, the "malaria" was not native to North


America but had been introduced by infected British soldiers who had

returned from India. Numerous deaths had occurred by the time the

epidemic subsided in September when the mosquitoes disappeared.

During the American Civil War (1861-65), one half of the white troops

and 80% of the black soldiers of the Union Army got malaria annually.

More than an estimated 600,000 cases of malaria occurred in the U.S. in

1914, according to information from the Centers for Disease Control and

Prevention in Atlanta, Georgia.

In 1927, J. Wagner von Jauregg was awarded the Nobel Prize in

Medicine for his work in treating syphilis using malaria. Patients were

inoculated with a type of malaria to produce fevers that would literally

burn up the temperature-sensitive syphilis bacteria. After three or four

cycles of the fever, the patient was administered quinine for a relatively

rapid parasitological cure for the malaria.

Malaria therapy for syphilis, using monkey and human parasites,

continued until the mid-1950s when it was replaced by antibiotic

chemotherapy.

The Dutch bought Cinchona seeds from British trader, Charles Leger,

who brought them from Peru. They established Cinchona plantations in

Java (Indonesia) in the mid 1800s and soon had a virtual monopoly on

quinine.

When the Japanese captured Java during the second World War, quinine,

except for some old stocks became unavailable. The need for a new

synthetic antimalarial became a priority at that time.

In 1880, the first true sighting of the malaria parasite was made in Algeria

by a French Army physician, Charles-Louis-Alphonse Laveran, while


viewing blood slides under a microscope. Laveran's discovery was

rejected by the medical community and it was not until 1886 that his

discovery was accepted by Italian scientists, the leaders in the field at the

time.

In 1882 the mosquito transmission hypothesis - guilt by association - was

first made.

The December 18, 1897 issue of the British Medical Journal reported that Dr.

Ronald Ross discovered malaria cysts in the stomach wall of anopheline

mosquitoes that fed on a malaria patient.

While it was recognised that the Anopheles mosquito played a key role in the

transmission of the disease it was not until 1948 that all the stages in its life

cycle were identified. The parasite undergoes a development stage in the

mosquito and the female of the species requires a blood meal to mature her

eggs. She bites a human and injects material from her salivary glands, which

contains primitive malarial parasites called sporozoites, before feeding. These

sporozoites circulate in the blood for a short time and then settle in the liver

where they enter the parenchymal cells and multiply; this stage is known as pre-

erythrocytic schizogony. After about 12 days there may be many thousands of

young parasites known as merozoites in one liver cell, the cell ruptures and the

free merozoites enter red blood cells. The blood stages of the four species of

malaria can be seen in the section on Diagnosis. I n the case of P. vivax, and

P.ovale the liver cycle continues and requires a course of primaquine to

eliminate it. P.falciparum on the other hand does not have a continuing liver

cycle.1,7,9,12

In the red blood cells the parasites develop into two forms, a sexual and

an asexual cycle. The sexual cycle produces male and female

gametocytes, which circulate in the blood and are taken up by a female


http://www.rotary9600.org/RAM/

mosquito when taking a blood meal. The male and female gametocytes

fuse in the mosquito's stomach and form oöcysts in the wall of the

stomach. These oöcysts develop over a period of days and contain large

numbers of sporozoites, which move to the salivary glands and are ready

to be injected into man when the mosquito next takes a meal. In the

asexual cycle the developing parasites form schizonts in the red blood

cells which contain many merozoites, the infected red cells rupture and

release a batch of young parasites, merozoites, which invade new red

cells. In P.vivax, P.ovale and probably P.malariae, all stages of

development subsequent to the liver cycle can be observed in the

peripheral blood. However, in the case of P.falciparum only ring forms

and gametocytes are usually present in the peripheral blood. Developing

forms appear to stick in the blood vessels of the large organs such as the

brain and restrict the blood flow with serious consequences.

1.2 Distribution of Malaria

GLOBAL DISTRIBUTION

Malaria occurs in many parts of the tropics and subtropics in North, Central

and South America, Africa, Asia and Oceania (Figure 1).

DISTRIBUTION IN SOUTH AFRICA

Malaria occurs in limited areas in South Africa. The endemic malaria areas are

the low altitude areas (below 1000 metres) of the Northern Province,

Mpumalanga, and the north eastern part of KwaZulu-Natal (Figure 2).

Occasionally limited focal transmission may develop in the North-West and

Northern Cape provinces along the Molopo and Orange Rivers. Infections are

very seldom contracted outside the malarious areas and are then possibly a

consequence of the importation of infected mosquitoes by motor or other

transport.


1.3 Parasite and vector of malaria

Malaria is a protozoal disease transmitted by the Anopheles mosquito, caused

by minute parasitic protozoa of the genus Plasmodium, which infect human and

insect hosts alternatively. It is a very old disease and prehistoric man is thought

to have suffered from malaria. It probably originated in Africa and accompanied

human migration to the Mediterranean shores, India and South East Asia. In the

past it used to be common in the marshy areas around Rome and the name is

derived from the Italian, (mal-aria) or "bad air"; it was also known as Roman

fever. Today some 500 hundred million people in Africa, India, South East Asia

and South America are exposed to endemic malaria and it is estimated to cause

two and a half million deaths annually, one million of which are children.

1.4 Biology of Plasmodium Parasites and Anopheles Mosquitos

The Plasmodium genus of protozoal parasites (mainly P.falciparum, P.vivax,

P.ovale, and P.malariae) have a life cycle which is split between a vertebrate

host and an insect vector. The Plasmodium species, with the exception of

P.malariae (which may affect the higher primates) are exclusively parasites of

man. The mosquito is always the vector, and is always an Anopheline mosquito,

although, out of the 380 species of Anopheline mosquito, only 60 can transmit

malaria. Only female mosquitos are involved as the males do not feed on blood.

The basic life cycle of the parasite is shown below:


Life Cycle of the Malaria Parasite

Malaria is an infectious disease caused by a one-celled parasite known as

Plasmodium. The parasite is transmitted to humans by the bite of the female

Anopheles mosquito. The Plasmodium parasite spends its life cycle partly in

humans and partly in mosquitoes. (A) Mosquito infected with the malaria

parasite bites human, passing cells called sporozoites into the human’s


bloodstream. (B) Sporozoites travel to the liver. Each sporozoite undergoes

asexual reproduction, in which its nucleus splits to form two new cells, called

merozoites. (C) Merozoites enter the bloodstream and infect red blood cells. (D)

In red blood cells, merozoites grow and divide to produce more merozoites,

eventually causing the red blood cells to rupture. Some of the newly released

merozoites go on to infect other red blood cells. (E) Some merozoites develop

into sex cells known as male and female gametocytes. (F) Another mosquito

bites the infected human, ingesting the gametocytes. (G) In the mosquito’s

stomach, the gametocytes mature. Male and female gametocytes undergo sexual

reproduction, uniting to form a zygote. The zygote multiplies to form

sporozoites, which travel to the mosquito’s salivary glands. (H) If this mosquito

bites another human, the cycle begins again.

The spozozoites from the mosquito salivary gland are injected into the human as

the mosquito must inject anticoagulant saliva to ensure an even flowing meal.

Once in the human bloodstream, the sporozoites arrive in the liver and penetrate

hepatocytes, where they remain for 9-16 days, multiplying within the cells. Next

they return to the blood and penetrate red blood cells, in which they produce

either merozoites, which reinfect the liver, or micro- and macrogametocytes,

which have no further activity within the human host. Another mosquito

arriving to feed on the blood may suck up these gametocytes into its gut, where

exflagellation of microgametocytes occurs, and the macrogametocytes are

fertilized. The resulting ookinete penetrates the wall of a cell in the midgut,

where it develops into an oocyst. Sporogeny within the oocyst produce many

sporozoites and, when the oocyst ruptures, the sporozoites migrate to the

salivary gland, for injection into another host. This highly specialised life cycle

requires specialised biology on the part of the Plasmodium species. The reason

that not all mosquitos are vectors for Plasmodium parasites is that refractory


mosquitos posses substances toxic to Plasmodium within their cells . A higher

trypsin-like activity was also found in the midgut of resistant species, possibly

inhibiting ookinete development. Plasmodium parasites seem capable of

adapting to any suitable anopheline mosquito, given sufficient time and contact.

Sporogeny within the mosquito are governed by environmental temperature as

Anopheline mosquitos are poikilotherms.

Once injected into the human host, all Plasmodium species will penetrate

hepatocytes. However, P.falciparum and P.malariae sporozoites trigger

immediate schizogony whereas P.ovale and P.vivax sporozoites may either

trigger immediate schizogony or have a delayed trigger, resulting in dormant

hypnozoites. Some strains, such as the North Korean strain, seem to consist of

sporozoites with universally delayed triggers, so they all form long lasting

hypnozoites. P.vivax may have an incubation period of up to 10 months.

Gametocytes produced in the primary attack seem to contain all the genetic

information required to create sporozoites of several different activation times.

The same seems true for gametocytes produced in relapses where the

hypnozoites become activated.

Sexual development of Plasmodium begins as the merozoites invade the

erythrocytes after their release from the liver. Within the erythrocyte, shizogony

occurs to produce either more merozoites (taking 22 1/2 hours in the case of

P.berghei), or the sexual micro and macrogametocytes (taking 26 hours). In

P.falciparum, erythrocytic schizogony takes 48 hours and gametocytosis takes

10-12 days. Normally a variable number of cycles of asexual erythrocytiic

shizogony occurs before any gametocytes are produced . The immune system

may produce antibodies to the gametocytes at this stage.

1.5 Resistance:-


Drug resistance occurs selectively in the species P. falciparum. The other three

species have no documented resistance apart from the regionalized choroquine

resistance observed in P. vivax, concentrated largely in Papua New Guinea and

Irian Jaya (Indonesia). The reasons for the development and spread of drug

resistance involve the interaction of drug-use patterns, characteristics of the

drug itself, human host factors, parasite characteristics, and vector and

environmental factors. However, only gene mutations confer resistance to the

parasites in nature. A summary on the determinants of drug resistance is shown

in the Table1.

The gene pfmdr1, encoding P-glycoprotein homologue 1 (Pgh1), is linked to

chloroquine resistance through mutation. In multi-drug-resistant mammalian

cancer cells, the P-glycoprotein is an ATP–dependent pump that expels

chemotherapeutic agents from the cell. In P. falciparum, the P-glycoprotein is

located mainly in the membrane of the digestive vacuole of the parasite and

evidence suggests it is involved in nucleotide-dependent transport across the

membrane. Mutations in other (unidentified) genes are also required to confer

complete resistance to the parasites.

Changes in Pgh1 can modulate resistance to quinine, mefloquine and

halofantrine.

Artemisinin also showed decreased sensitivity against various strains of P.

falciparum due to this mutation. Another gene, pfcrt, coding for a vacuolar

membrane transporter protein (PfCRT ) is also associated with chloroquine

resistance.

Resistance to chloroquine arises due to the ability of the P. falciparum to

release chloroquine 40-50 times more rapidly than a normal susceptible

parasite. Calcium channel blockers like verapamil, vinblastine and daunomycin


enhanced the accumulation of chloroquine in a resistant parasite and also

inhibited the release of chloroquine.

These changes were not found in normal susceptible parasites.13 Calcium

channel antagonists are thought to interact with the P-glycoprotein transport

system in the membrane of the parasite.

1.6

History of Treatment and Prophylaxis

Antimalarial drugs fall into several chemical groups and it is useful to have

some knowledge of their chemistry. The aim here is to give a brief outline of

anti-malarial drugs and their usefulness today, when drug resistant strains of

malaria have become a major problem. It is not a comprehensive history nor

does it include a number of drugs which are no longer used.

Quinine.

Quinine has been used for more than three centuries and until the 1930's it was

the only effective agent for the treatment of malaria. It is one of the four main

alkaloids found in the bark of the Cinchona tree and is the only drug which over

a long period of time has remained largely effective for treating the disease. It is

now only used for treating severe falciparum malaria partly because of

undesirable side effects. In Africa in the 1930's and 40's it was known for

people to take quinine when they thought they had "a touch of malaria" and the

association of repeated infections with falciparum malaria and inadequate

treatment with quinine, resulted in the development in some of acute massive

intravascular haemolysis and haemoglobinuria ie. black water fever. 12,9,7

Atebrin(mepacrine).

This drug is a 9-amino-acridine developed in the early 1930's. It was used as a

prophylactic on a large scale during the second world war (1939-45) and was


then considered a safe drug. It had a major influence in reducing the incidence

of malaria in troops serving in South East Asia. It is now considered to have too

many undesirable side effects and is no longer used .

Chloroquine.

A very effective 4-amino-quinoline both for treatment and prophylaxis. It was

first used in the 1940s shortly after the Second World War and was effective in

curing all forms of malaria, with few side effects when taken in the dose

prescribed for malaria and it was low in cost. Unfortunately most strains of

falciparum malaria are now resistant to chloroquine and more recently

chloroquine resistant vivax malaria has also been reported.

Proguanil.

This drug falls into the biguanide class of antimalarials and was first synthesised

in 1946. It has a biguanide chain attached at one end to a chlorophenyl ring and

it is very close in structure to pyrimethamine.

The drug is a folate antagonist and destroys the malarial parasite by binding to

the enzyme dihydrofolate reductase in much the same way as pyrimethamine. It

is still used as a prophylactic in some countries.

Malarone.

In 1998 a new drug combination was released in Australia called Malarone.

This is a combination of proguanil and atovaquone. Atovaquone became

available 1992 and was used with success for the treatment of Pneumocystis

carrinii. When combined with proguanil there is a synergistic effect and the

combination is at the present time a very effective antimalarial treatment. The

drug combination has undergone several large clinical trials and has been found

to be 95% effective in otherwise drug resistant falciparum malaria. How long it

will be before resistant strains of malaria appear remains to be seen. It has been

claimed to be largely free from undesirable side effects but it should be noted


that proguanil is an antifolate. This is not likely to be a problem with a single

treatment course of the drug but some caution should be exercised when using it

for prophylaxis. In Australia it is due to become available for prophylaxis at the

end of 1998. At present it is a very expensive drug.

Maloprim.

A combination of dapsone and pyrimethamine. Resistance to this drug is now

widespread and its use is no longer recommended

Fansidar.

This is a combination drug, each tablet containing sulphadoxine 500mg. and

pyrimethamine 25mg. It acts by interfering with folate metabolism. Resistance

to Fansidar is now widespread and serious side effects have been reported. It is

no longer recommended.

Mefloquine(Lariam).

First introduced in 1971, this quinoline methanol derivative is related

structurally to quinine. The compound was effective against malaria, resistant to

other forms of treatment when first introduced and because of its long half life

was a good prophylactic, but widespread resistance has now developed and this

together with undesirable side effects have resulted in a decline in its use.

Because of its relationship to quinine the two drugs must not be used together.

There have been reports of various undesirable side effects including several

cases of acute brain syndrome, which is estimated to occur in 1 in 10,000 to 1 in

20,000 of the people taking this drug. It usually develops about two weeks after

starting mefloquine and generally resolves after a few days.

Halofantrin(Halfan).

This belongs to a class of compound called the phenanthrene-methanols and is

not related to quinine. It is an effective antimalarial introduced in the 1980s, but


due to its short half life of 1 to 2 days, is therefore not suitable for use as a

prophylactic. Unfortunately resistant forms are increasingly being reported and

there is some concern about side effects. Halofantrin has been associated with

neuropsychiatric disturbances. It is contraindicated during pregnancy and is not

advised in women who are breastfeeding. Abdominal pain, diarrhoea, puritus

and skin rash have also been reported.

Artemisinins.

Artemisinin (qinghaosu) is a naturally occurring sesquiterpene lactone peroxide

structurally unrelated to any known antimalarial. Qinghaosu, derived from

cultivated Artemisia annua, is available as the parent compound artemisinin

(oral, parenteral, and suppository formulations) and as three semi-synthetic

derivatives: a water-soluble hemisuccinate salt (artesunate) for parenteral or oral

administration; and two oil-soluble compounds (artemether and arteether) for

intramuscular injection.

All are metabolized to a biologically active metabolite, dihydroartemisinin.

Artesunate is a prodrug for dihydroartemisinin and as such is the most rapidly

active of the derivatives examined to date.

All compounds have their antiparasitic effects on the younger ring-form

parasites, thereby decreasing the numbers of late parasite forms that can

obstruct the host’s microvasculature

All artemisinin preparations have been studied and used only for treatment.

They are recommended for treatment use only and not for prophylaxis. All

compounds are at least as efficacious as quinine in the treatment of severe and

complicated malaria. Qinghaosu and its derivatives lead to faster parasite

(mean: 32% faster) and fever (mean: 17% faster) clearance times than do any

other anti-malarials. In spite of the more rapid antiparasitic action of qinghaosu


compounds, these agents have not been shown to decrease mortality compared

with quinine.

Artemisinin-related compounds act rapidly against drug-resistant P. falciparum

strains but have high recrudescence rates (about 10% to 50%) when used as

monotherapy for less than 5 days. Recent3 studies have examined longer

durations of therapy (7 days) and combinations of qinghaosu derivatives and

mefloquine in order to prevent recrudescence. In vitro synergy has been

demonstrated between artemisinin derivatives, mefloquine, and tetracycline. In

Thailand, treatment with oral artesunate (over 3 to 5 days) combined with

mefloquine (15 to 25 mg/kg) was more effective than mefloquine or artesunate

alone. Combination therapy results in > 90% cure rates of primary and

recrudescent P. falciparum infections.

Malaria Treatment In Respect To Different P.Species. P.

falciparum.

This species was originally sensitive to chloroquine, however, strains resistant

to this and other antimalarial drugs are now commonplace. Because the parasite

is able to multiply very rapidly and sequester within the microvasculature, a life

threatening illness may develop in a very short space of time.

Uncomplicated malaria (where patients can take oral therapy) can be treated

with one of three regimens:

1. Quinine sulphate 10 mg salt/kg 8 hourly for seven days plus doxycycline

100 mg daily for 7 days. Patients will usually develop 'cinchonism'

(tinnitus, high-tone hearing loss, nausea, dysphoria) after 2-3 days but

should be encouraged to complete the full course to avoid recrudescence.

2. MalaroneTM (atovaquone 250 mg plus proguanil 100 mg) 4 tablets daily

for 3 consecutive days. This combination therapy has only recently come


on the market and is relatively expensive. Data on efficacy are promising

but limited.

3. Mefloquine (LariumTM) given as 15 mg/kg in a divided dose followed by

10 mg/kg the following day. Antipyretic and antiemetic agents may need

to be given prior to mefloquine administration to reduce the risk of

vomiting.

Choice of regimen is based on :-

Local cost and availability of antimalarial drugs.

Area of malaria acquisition (i.e. drug resistance pattern of P.

falciparum).

Prior chemoprophylaxis.

Known allergies.

Concomitant illnesses other than malaria.


Age and pregnancy.

Likely patient compliance with therapy.

Risk of re-exposure to malaria after treatment.

In uncomplicated cases in which nausea and vomiting preclude oral therapy,

quinine dyhidrochloride 10 mg salt/kg base can be given I.V. in 5% w/v

dextrose or normal saline as a 4-hour infusion 8-hourly until the patient can take

medication by mouth.

Severe malaria. (where patients have coma, jaundice, renal failure,

hypoglycaemia, acidosis, severe anaemia, high parasite count, hyperpyrexia) is

ideally treated in an intensive care or high dependency unit where patients can

be monitored closely both clinically and biochemically. Intravenous quinine is

the treatment of choice but rapid injection can lead to hypotension,

dysrhythmias and death.

In patients who have not received quinine in the previous 48 hours, one of two

regimens can be used:

1. Quinine dihydrochloride 20 mg salt/kg base given I.V. in 5% w/v

dextrose or normal saline as a once-only 4 hour infusion followed, 4

hours later, by quinine dihydrochloride 10 mg salt/kg base 4-hour

infusions 8 hourly.


2. Where a syringe pump or other accurate infusion device is available,

quinine dihydrochloride 7 mg salt/kg base over 30 minutes followed

immediately by quinine dihydrochloride 10 mg salt/kg base over 4 hours

then, starting 4 hours later, quinine dihydrochloride 10 mg salt/kg base as

4 hour infusions, 8 hourly.

P.vivax.

Most strains of P. vivax are still sensitive to chloroquine although some

chloroquine resistant strains have been reported in Papua New Guinea,

Indonesia, Thailand and India. This drug will clear the erythrocyte stages of the

parasite but it has no effect on the exo-erythrocytic liver stage and a course of

primaquine (an 8-amino-quinoline) is required for radical cure. The Chesson

strain of P. vivax found in New Guinea shows some resistance to primaquine

and an increased dose of primaquine is required. If primaquine is not given, the

patient may suffer a relapse which will occur weeks or months after the original

attack.

Adult treatment.

Based on Chloroquine tablets containing 150mg base.

Day 14 tablets (600mg base) or 10 mg/kg first dose.

2 tablets (300mg base) or 5 mg/kg 6-8 hours later.

Day 2 2 tablets (300mg base) or 5 mg/kg.

Day 3 2 tablets (300mg base) or 5 mg/kg

Next 14

days

primaquine 2 tablets (each tablet contains 7.5mg base daily

with food ).

The primaquine is preferably started after the chloroquine. When the infection is

acquired in New Guinea, 3 tablets of primaquine (22.5mg base) should be given

daily for 14 days. In the case of a relapse repeat both chloroquine and


primaquine treatment. Up to three relapses may occur before the parasite is

finally eliminated. Unfortunately there is no other effective treatment. Patients

should have their G6PD status checked before primaquine is prescribed.

Patients with G6PD deficiency may undergo haemolysis if given a daily dose of

primaquine and it is recommended that these patients be given 30-45mg once a

week for 8 weeks.

P. malariae, P. ovale.

Treatment for the eradication of these two strains of malaria is the same as that

for P. vivax except it is not necessary to give primaquine to those patients with

P. malariae


2. ANTIMALARIAL DRUGS

Antimalarials are antiprotozoal drugs that are primarily used to treat malaria.

Certain antimalarials are useful in treating other conditions as well, including

quinine for leg cramps and hydroxychloroquine for severe cases of rheumatoid

arthritis.

Classification

A. On the basis of use .

Antimalarial drugs are designed to prevent or treat malaria. There are many of

these drugs currently on the market. Here is a partial list.

1. Antimalarial drugs currently used for treatment

• amodiaquine

• artemisinin/artemether/artesunate (Artemisinine based on the Artemisia plant)

• atovaquone

• chloroquine (Nivaquine®, Aralen®, Damaral® etc.)

• fansidar (pyrimethamine, sulfadoxine)

• lumefatrine

• mefloquine (Lariam ®)

• quinine/quinidine (quinine is derived from the bark of the tropical cinchona

tree)

2. Antimalarial drugs currently used for prophylaxis

• chloroquine

• doxycycline

• hydroxychloroquine (Plaquenil)

• mefloquine

• proguanil


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• pyrimethamine (daraprim) -sulfadoxine (Fansidar®)

• Halofantrine (Halfan®)

3. New medicines

• Malarone

• DNA/MVA malaria vaccin (under development)

4. 4. Repellents

• DEET is available as lotion or DEET-spray

5. Mosquito nets

B.On the basis of chemical structure

Antimalarial drugs (P01B)

AminoquinolinesAmodiaquine, Chloroquine,

Hydroxychloroquine, Pamaquine, Primaquine

Biguanides Proguanil, Cycloguanil embolate

Methanolquinolines Mefloquine, Quinine

Diaminopyridines Pyrimethamine

Artemisinin{Herbal}

derivatives

Artemisinin, Artemether, Artesunate, Artemotil,

Artenimol

Others Halofantrine, Lumefantrine

Chloroquine: Many drugs were developed to protect the troops from malaria,

particularly during World War II. Chloroquine, Primaquine, Proguanil,

amodiaquine and Sulfadoxine/Pyrimethamine were all developed during this

time.


http://en.wikipedia.org/w/index.php?title=Lumefantrine&action=edit

http://en.wikipedia.org/wiki/Halofantrine

http://en.wikipedia.org/w/index.php?title=Artenimol&action=edit

http://en.wikipedia.org/w/index.php?title=Artemotil&action=edit

http://en.wikipedia.org/wiki/Artesunate

http://en.wikipedia.org/wiki/Artemether

http://en.wikipedia.org/wiki/Artemisinin

http://en.wikipedia.org/wiki/Artemisinin

http://en.wikipedia.org/wiki/Pyrimethamine

http://en.wikipedia.org/wiki/Mefloquine

http://en.wikipedia.org/w/index.php?title=Cycloguanil_embolate&action=edit

http://en.wikipedia.org/wiki/Proguanil

http://en.wikipedia.org/wiki/Biguanide

http://en.wikipedia.org/wiki/Primaquine

http://en.wikipedia.org/wiki/Pamaquine

http://en.wikipedia.org/wiki/Hydroxychloroquine

http://en.wikipedia.org/wiki/Chloroquine

http://en.wikipedia.org/wiki/Amodiaquine

http://en.wikipedia.org/wiki/8-Aminoquinoline

http://en.wikipedia.org/wiki/ATC_code_P01#P01B_Antimalarials

http://en.wikipedia.org/wiki/Antimalarial_drug

During World War I, Java and its valuable quinine stores fell into Japanese

forces. As a result, the German troops in East Africa suffered heavy casualties

from malaria. In a bid to have their own antimalarial drugs, the German

government initiated research into quinine substitutes and entrusted it to Bayer

Dye Works. Most of the work was done at Bayer Farbenindustrie A.G.

laboratories in Eberfeld, Germany. Several thousands of compounds were tested

and some were found to be useful. Plasmochin naphthoate (Pamaquine) in 1926

and quinacrine, mepacrine (Atabrine) in 1932 were the first to be found.

Plasmochin, an 8 amino quinoline, was quickly abandoned due to toxicity,

although its close structural analog primaquine is now used to treat latent liver

parasites of P. vivax and P. ovale. Atabrine, although found superior and

persisting in the blood for at least a week, had to be abandoned due to side

effects like yellowing of the skin and psychotic reactions. The breakthrough

came in 1934 with the synthesis of Resochin (chloroquine) by Hans

Andersag, followed by Sontochin or Sontoquine (3 methyl chloroquine). These

compounds belonged to a new class of antimalarials known as 4 amino

quinolines. But Farben scientists overestimated the compounds’ toxicity and

failed to explore them further. Moreover, they passed the formula for Resochin

to Winthrop Stearns, Farben’s U.S. sister company, in the late 1930s. Resochin

was then forgotten until the outbreak of World War II.

Other antimalaria drugs: 1.The formula of Atabrine (mepacrine, a 9-amino-

acridine), was also soon solved by Allied chemists and it was produced in large

scale in the U.S. It immediately gained widespread acceptance as an excellent

therapeutic agent. 2.The success of chloroquine led to the exploration of many

(nearly 15000) compounds in the United States and another 4-aminoquinoline

Camoquin (amodiaquin) was discovered. Studies on 8-aminoquinolines led to

the discovery of Primaquine by Elderfield in 1950. Meanwhile, British

investigators at ICI also carried out extensive studies on malaria drugs and


Curd, Davey and Rose synthesised antifolate drugs proguanil or Paludrine

(chlorguanide hydrochloride) in 1944 and Daraprim or Malocide

(pyrimethamine) was developed in 1952. However, resistance to proguanil was

observed within a year of introduction in Malaya in 1947. 3.Mefloquine was

jointly developed by the U.S. Army Medical Research and Development

Command, the World Health Organization (WHO/TDR), and Hoffman-La

Roche, Inc. After World War II, about 120 compounds were produced at the

Walter Reed Army Institute of Research and WR142490 (mefloquine), a 4-

quinoline methanol was developed. Its efficacy in preventing and treating

resistant P. falciparum was proved in 1974-75 and was useful for the US Army

in Southeast Asia and South America. By the time the drug became widely

available in 1985, evidence of resistance to mefloquine also began to appear in

Asia.4.Malarone: In 1998 a new drug combination was released in Australia

called Malarone. This is a combination of proguanil and atovaquone.

Atovaquone became available 1992 and was used with success for the treatment

of Pneumocystis carrinii. The synergistic combination with proguanil is found

to be an effective antimalarial treatment.


3. HERBAL ANTIMALARIAL DRUGS

Herbal medicines have been an important source of natural product drugs and

the root of modern pharmocology and drug develepment. Take digoxin as an

example. Digoxin is a modern drug used for congestive heart failure. It is a

natural molecule occurring in the herb foxglove.

Foxglove was originally used in folk herbal remedies consisting of a dozen of

herbs. Over 200 years ago it was found to be the active ingredient of the herbal

remedies. By 1906, different preparations of foxglove were included in US

pharmacopeia. No standard was there.

Then standard assays were developed to monitor the bioactivity of foxglove

preparations. Eventually, digoxin was identified and became a standard

chemical drug.

Generally used herbal antimalarial plant are followings:-

3.1 CINCHONA [QUININE].

3.2 ARTEMISIA VULGARIS.

3.3 CRYPTOLEPIS.

3.4 YINGZHAOSU.


3.1 Cinchona Officinalis (Quinine)

A. Source and properties, and history of hurb

Family: Rubiaceae

Genus: Cinchona

Species: officinalis, ledgeriana, succirubra, calisaya

Synonyms: Quinaquina officinalis, Quinaquina lancifolia, Quinaquina coccinea

Common names: Quinine bark, quina, quinine, kinakina, China bark, cinchona

bark, yellow cinchona, red cinchona, Peruvian bark, Jesuit's bark, quina-quina,

calisaya bark, fever tree

Parts Used: Bark, wood


History of Cinchona

The cardiac effects of cinchona bark were noted in academic medicine at the

end of the 17th century.

1 Quinine was used sporadically through the first half of the 18th century for

cardiac problems and arrhythmia and it became a standard of cardiac therapy

in the second half of the 19th century.

2 Another alkaloid chemical called quinidine was discovered to be responsible

for this beneficial cardiac effect. Quinidine, a compound produced from

quinine, is still used in cardiology today, sold as a prescription drug for

arrhythmia. The sales demand for this drug still generates the need for

harvesting natural quinine bark today because scientists have been

unsuccessful in synthesizing this chemical without utilizing the natural

quinine found in cinchona bark.

In Brazilian herbal medicine quinine bark is considered tonic, stomachic, and

febrifuge. It is used for anemia, indigestion, gastrointestinal disorders, general

fatigue, fevers, malaria and as an appetite stimulant. Other folk remedies in

South America cite quinine bark as a natural remedy for cancer (breast, glands,

liver, mesentery, spleen), amoebiasis, cardidtis, colds, diarrhea, dysentery,

dyspepsia, fevers, flu, hangover, lumbago, malaria, neuralgia, pneumonia,

sciatica, typhoid, and varicose veins.


In European herbal medicine the bark is considered antiprotozoal,

antispasmodic, antimalarial, a bitter tonic, and febrifuge. There it is used as an

appetite stimulant, for hair loss, alcoholism, liver, spleen, and gallbladder

disorders; and to treat arrhythmia, anemia, leg cramps, and fevers of all kinds.

D. Chemical constituents:

Aricine, caffeic acid, cinchofulvic acid, cincholic acid, cinchonain,

cinchonidine, cinchonine, cinchophyllamine, cinchotannic acid, cinchotine,

conquinamine, cuscamidine, cuscamine, cusconidine, cusconine, epicatechin,

javanine, paricine, proanthocyanidins, quinacimine, quinamine, quinic acid,

quinicine, quinine, quininidine, quinovic acid, quinovin, sucirubine.

.

Table: Alkaloid Content Comparison by Cinchona species

Species Total Alkaloids

(%)

Quinine Content (%)

C. calisaya 3 - 7 0 - 4

C. pubescens 4.5 - 8.5 1 - 3

C. officinalis 5 - 8 2 - 7.5

C. ledgeriana 5 -14 3 - 13

C. succirubra 6 - 16 4 - 14


B. Property and Action

QUININE

HERBAL PROPERTIES AND ACTIONS

Main Actions Other Actions Standard Dosage

treats malaria relieves pain Bark

kills parasites kills bacteria Decoction: 1/2 to 1 cup

reduces fever kills fungi 3 times daily

regulated heartbeat dries secretions Capsules: 2 g twice daily

stimulates digestion calms nervesTincture: 1-2 ml twice

daily

kills germs

reduces spasms

kills insects

The genus Cinchona contains about forty species of trees. They grow 15-20

meters in height and produce white, pink, or yellow flowers. All cinchonas are

indigenous to the eastern slopes of the Amazonian area of the Andes, where

they grow from 1,500-3,000 meters in elevation on either side of the equator

(from Colombia to Bolivia). They can also be found in the northern part of the

Andes (on the eastern slopes of the central and western ranges). They are now

widely cultivated in many tropical countries for their commercial value,

although they are not indigenous to those areas.


C. Phytochemical Study :

Chemistry

Quinine sulfate is an antimalarial drug chemically described as cinchonan-9-ol,

6'- methoxy-, (8a, 9R)-, sulfate (2:1) (salt), dihydrate with a molecular formula

of (C20H24N2O2)2H2SO42H2O and a molecular weight of 782.96. The

structural formula of quinine sulfate is

: Quinine sulfate occurs as a white, crystalline powder that darkens on exposure

to light. It is odorless and has a persistent very bitter taste. It is only slightly

soluble in water, alcohol, chloroform

Mechanism of action:

Quinine acts as a blood schizonticide although it also has gametocytocidal

activity against P. vivax and P. malariae. Because it is a weak base, it is

concentrated in the food vacuoles of P. falciparum. It is said to act by inhibiting

heme polymerase, thereby allowing accumulation of its cytotoxic substrate,

heme.


http://www.rxlist.com/script/main/art.asp?articlekey=7796




Food VacuoleHeme

polymerase

HemoglobinToxic

Heme

Non Toxic Hemazoin

(Malarial Pigment)

Degradation? Inhibited by

Quinine

As a schizonticidal drug, it is less effective and more toxic than chloroquine.

However, it has a special place in the management of severe falciparum malaria

in areas with known resistance to chloroquine.

D. Pharmacological Study

Pharmacokinetics:

Quinine is readily absorbed when given orally or intramuscularly. Peak plasma

concentrations are achieved within 1 - 3 hours after oral dose and plasma half-

life is about 11 hours. In acute malaria, the volume of distribution of quinine

contracts and clearance is reduced, and the elimination half-life increases in

proportion to the severity of the illness. Therefore, maintenance dose of the drug

may have to be reduced if the treatment is continued for more than 48 hours.

The drug is extensively metabolised in the liver and only 10% is excreted

unchanged in the urine. There is no cumulative toxicity on continued

administration.


Side effect.

The most common adverse reaction to Cinchona alkaloids (quinine and

quinidine) in Australia[6] from November 1972 to March 1988 were

thrombocytopenia, anorexia, nausea, vomiting, diarrhoea, skin rash, fever,

rigors, disturbed liver function, arrhythmia, hypotension, arthralgia, and deaths.

The toxic effects of quinine are tinnitus, vertigo, visual impairment, rashes,

nausea, vomiting, diarrhoea, abdominal pain, fever, hypotension, convulsions,

respiratory depression, cardiac irregularities, weakness, drop in blood pressure,

and kidney failure with anuria.

Contra indications:

Hypersensitivity in the form of rashes, angioedema, visual and auditory

symptoms are indications for stopping the treatment. It is contraindicated in

patients with tinnitus and optic neuritis. It should be used with caution in

patients with atrial fibrillation. Hemolysis is indication for immediately

stopping the drug.

Availability:

It is available as tablets and capsules containing 300 or 600 mg of the base. It is

also available as injections, containing 300mg /ml.

E. Uses and applications of Quinine

Analgesic, anesthetic, antiarrhythmic, antibacterial, antimalarial, antimicrobial,

antiparasitic, antipyretic, antiseptic, antispasmodic, antiviral, astringent,

bactericide, cytotoxic, febrifuge, fungicide, insecticide, nervine, stomachic,

tonic.


Main Uses:

1. for malaria

2. as a bitter digestive aid to stimulate digestive juices

3. for nocturnal leg cramps

4. for intestinal parasites and protozoa

5. for arrhythmia and other heart conditions

WORLDWIDE ETHNOMEDICAL USES

Brazil for anemia, anorexia, debility, digestive sluggishness,

dyspepsia, fatigue, fevers, gastrointestinal disorders,

indigestion, malaria

Europe for alcoholism, anemia, antimalarial, appetite stimulant,

cramps, debility, diarrhea, enlarged spleen, fevers,

flatulence, gallbladder disorders, hair loss, irregular

heartbeat, leg cramps, liver disorders, malaria, muscle pain,

protozoal infections, and as a antiseptic

Mexico malaria, and as an antiseptic, astringent, and tonic

US for bacterial infections, colds, digestive disorders, dyspepsia,

fevers, flu, headaches, heart palpitations, hemorrhoids, leg

cramps, malaria, pain, varicose veins, viral infections, and as

an appetite stimulant, astringent and cardiotonic

Venezuela for cancer and malaria

Elsewhere for amebic infections, bacterial infections, carditis, colds,

contraceptive, cough, dandruff, diarrhea, digestive

sluggishness, dysentery, dyspepsia, fever, flu, glandular

disorders, hangovers, hemorrhoids, lumbago, malaria,

neuralgia, pain, pinworms, pneumonia, sciatica, septic

infections, sore throat, stomatitis, tumor (glands), typhoid,

varicose veins, and as a insecticide, insect repellent,


stimulant, and uterine tonic

F. Biological Activities And Clinical Research

Interestingly enough, natural quinine extracted from quinine bark and the use of

natural bark tea and/or bark extracts are making a comeback in the management

and treatment of malaria. Malaria strains have evolved which have developed a

resistance to the synthesized quinine drugs. It was shown in early studies that an

effective dose of natural quinine bark extract elicited the same antimalarial

activity as an effective dose of the synthesized quinine drug. Scientists are now

finding that these new strains of drug-resistant malaria can be treated effectively

with natural quinine and/or quinine bark extracts. As evolving pathogens

develop widespread resistance to our standard antibiotics, antivirals, and

antimalarial drugs, it is of little wonder that the use of the natural medicine in

quinine bark is being revisited, even by such giants as the World Health

Organization.

A recent use for quinine drugs has been for the treatment of muscle spasms and

leg cramps. A 1998 study documented the beneficial effects of quinine for leg

cramps, with tinnitus being the only documented side effect. In 2002, a double-

blind placebo study was undertaken in which 98 people with nocturnal leg

cramps were given 400 mg of quinine daily for 2 weeks. The results stated that

quinine administered at this dose effectively reduced the frequency, intensity,

and pain of leg cramps without relevant side-effects. This use has fueled the

natural product market and more people are looking for natural quinine bark as

an alternative to the synthesized prescription drugs for this purpose.


G. Formulation

A.Quinine

Tablets of quinine hydrochloride, quinine dihydrochloride or quinine sulfate

containing 82%, 82% and 82.6% quinine base respectively. Quinine bisulfate

formulations, containing 59.2% base are less widely available.

Injectable solutions of quinine hydrochloride, quinine dihydrochloride or

quinine sulfate containing 82%, 82% and 82.6% quinine base respectively.

Efficacy

Quinine is normally effective against falciparum infections that are resistant to

chloroquine and sulfa drug-pyrimethamine combinations. Decreasing sensitivity

to quinine has been detected in areas of South-East Asia where it has been

extensively used for malaria therapy. This has occurred particularly when

therapy was given in an unsupervised and ambulatory setting with regimens

longer than 3 days. In these settings, patient adherence to therapy is low, leading

to incomplete treatment; this may have led to the selection of resistant parasites.

There is some cross-resistance between quinine and mefloquine, suggesting that

the wide use of quinine in Thailand might have influenced the development of

resistance to mefloquine in that country (31). Strains of P. falciparum from

Africa are generally highly sensitive to quinine.

Recommended treatment : Quinine can be given by the oral, intravenous or

intramuscular routes. Quinine or quinine-containing compounds such as

Quinimax should not be given alone for the treatment of malaria as short

courses, e.g. 3 days, owing to the possibility of recrudescence (200).

When administered to patients with uncomplicated malaria, quinine should be

given orally if possible, by one of the following regimens:

Areas where parasites are sensitive to quinine:>


Sulfadoxine 1 500 mg or sulfalene 1500 mg plus pyrimethamine 75 mg given

on the first day of quinine treatment.

Areas with marked decrease in susceptibility of P. falciparum to quinine

Quinine 8 mg of base per kg three times daily for 7 days

plus

Doxycycline 100 mg of salt daily for 7 days (not in children under 8 years of

age and not during pregnancy); a pharmacologically superior regimen would

include a loading dose of 200 mg of doxycycline followed by 100 mg daily for

6 days.

or

Tetracycline 250 mg four times daily for 7 days (not in children under 8 years

of age and not in pregnancy).

Use in pregnancy

Quinine is safe in pregnancy. Studies have shown that therapeutic doses of

quinine do not induce labour and that the stimulation of contractions and

evidence of fetal distress associated with the use of quinine may be attributable

to fever and other effects of malarial disease (110). The risk of quinine-induced

hypoglycaemia is, however, greater than in non-pregnant women, particularly in

severe disease. Special vigilance is therefore required.

B. QUINIMAX

Quinimax is an association of four cinchona alkaloids: quinine, quinidine,

cinchonine and cinchonidine. It was formerly available as tablets of 100 mg,

ampoules of 500 mg, 200 mg and 400 mg and suppositories. Each 100 mg tablet

contained 96.10 mg of quinine-resorcine bichlorohydrate (59.3 mg of quinine

base), 2.55 mg of quinidine-resorcine bichlorohydrate (1.6 mg of quinidine

base), 0.68 mg of cinchonine-resorcine bichlorohydrate (0.4 mg of cinchonine

base) and 0.67 mg of cinchonidine-resorcine bichlorohydrate (0.4 mg of


cinchonidine base). These have been re-formulated and the preparations now

available include tablets of 100 mg and 125 mg of base of all the four

components, and ampoules of 125 mg, 250 mg and 500 mg of base of all the

four components. Suppositories are no longer available.

Quinimax has been shown to be somewhat more effective than quinine in vitro

and in animal models, as well as producing somewhat higher plasma levels in

humans. A synergistic effect of the association has been claimed but is doubtful.

Limited studies show no significant difference between the therapeutic efficacy

of Quinimax and that of quinine (205). Intramuscular injection of Quinimax is

better tolerated than intramuscular injection of quinine dihydrochloride.

Quinimax is used more widely than generic quinine salts in many countries,

especially in francophone Africa.

C. QUINIDINE

Quinidine is a distereoisomer of quinine, with similar antimalarial properties. It

is available as tablets of 200 mg of quinidine base as the sulfate and as a slow-

release formulation (Quinidine SR ®). It is slightly more effective than quinine

but has a greater cardiosuppressant effect (110). In other respects the toxicity

and drug interactions of quinidine are similar to those of quinine


3.2 Artemisias

The genus Artemisia spp, includes the herb Tarragon. The plants are herbaceous

or suffruticose (woody in the lower part of the stem, but with yearly branches

herbaceous) perennials and are rarely shrubs or annual herbs. They posses

alternate pinnasect or palmatisect leaves. Racemes or racemose panicles bear

numerous small flowerheads. The plants range in height depending on the

species, from 30 - 120 cm high.

Chemical Constitunets of Artemisias

Bitter principals: wormwood

coumarins: cronewort, tarragon

essential oils (complex, variety specific, with hundreds of components per

plant): cronewort (high in camphor, thujone), tarragon, wormwood (high in

camphor, thujone)

flavonoids: cronewort, tarragon

glycosides: cronewort, tarragon

hormones: cronewort (sitosterol, stigmasterol)

sesquiterpene lactones: cronewort

.

Species of Artemisias

Some of the many Artemisia species that herbalists and gardeners use:

A. abrotanum (southernwood)

A. absinthium (wormwood)

A. afra (African wormwood)

A. annua (sweet Annie, qing hao)

A. camphorata (camphor-scented sothernwood)


A. drancuncula (tarragon, estragon, little dragon)

A. frigida (fringed sagebrush)

A. lactiflora (ghost plant)

A. ludoviciana (silver queen)

A. pontica (Roman wormwood)

A. schmidtiana (silver mound)

A. stellerana (old woman, dusty miller)

A. tridentata (sagebrush; three-toothed sagebrush)

A. vulgaris (cronewort, mugwort)


3.2 Artemisia vulgaris:

Scientific classification

Kingdom:Plantae

Division:Magnoliophyta

Class:Magnoliopsida

Order:Asterales

Family:Asteraceae

Genus:Artemisia

Species:A. vulgaris

Binomial name

Artemisia vulgarisL.

Common Name: Artemisia Oil ( Armoise Oil )

Botanical Name: Artemisia vulgaris L.


http://en.wikipedia.org/wiki/Carolus_Linnaeus

http://en.wikipedia.org/wiki/Binomial_nomenclature

http://en.wikipedia.org/wiki/Artemisia_(plant)

http://en.wikipedia.org/wiki/Asteraceae

http://en.wikipedia.org/wiki/Asterales

http://en.wikipedia.org/wiki/Magnoliopsida

http://en.wikipedia.org/wiki/Flowering_plant

http://en.wikipedia.org/wiki/Plant

http://en.wikipedia.org/wiki/Scientific_classification

http://en.wikipedia.org/wiki/Scientific_classification

A. Source and Property

Geographic origin of the

plant:

Western Nepal

Method of growing: Wild

Introduction / Varity of plant /

Method of extraction / Distilled

organ:

The essential oil is obtained by steam

distillation of the aerial part of Artemisia

vulgaris L.

1. Organoleptic Properties

Appearance Fluid liquid.

Color Pale yellow or slightly greenish.

Aroma Powerful, fresh-camphoraceous, somewhat green &

bitter-sweet.

2. Physico-chemical Properties

Specific gravity 0.8786 to 0.9265 at 25º C

Optical rotation [-] 13.25º to [-] 29.35º at 25º C

Refractive index 1.350 to 1.49 at 25º C

Acid number 2.49 to 6.5

Ester number 25.05 to 55

Ester number after

acetylation

65 to 90

Solubility Insoluble in alcohol

3. Uses

(a) In perfumes and as a flavoring agent


Synonyms : ARMOISE OIL (ARTEMISIA VULGARIS); MUGWORT OIL

(ARTEMISIA VULGARIS); YOMUGI OIL (ARTEMISIA VULGARIS);

ARTEMISIA VULGARIS OIL; COMMON MUGWORT OIL;

A. vulgaris seems to have originated in Eastern Europe and Western Asia. Most

of these species are found growing wild and abundantly all over the temperate

and cold temperate zones of the world. It is a very common weed in Central

Europe, Southeastern Europe, India, China and Japan. This perennial aromatic

herb, 60 - 120cm high, has a branching root stock, dark green deeply indented

leaves with reddish, grooved and angled, glabrescent or sparsely pubescent

stems. The plant's florets are wind pollinated. 28,30,42

B. Morphological Study and Cultivation

Morphology

It is a tall herbaceous perennial plant growing 1-2 m (rarely 2.5 m) tall, with a

woody root. The leaves are 5-20 cm long, dark green, pinnate, with dense white

tomentose hairs on the underside. The erect stem often has a red-purplish tinge.

The rather small flowers (5 mm long) are radially symmetrical with many

yellow or dark red petals. The narrow and numerous capitula (flower heads)

spread out in racemose panicles. It flowers from July to September.

Characterstics:

Odor Description : Powerful Fresh Cedarleaf Minty Camphor Sage Herbal

Bitter-sweet

Appearence : Pale Yellow Amber To Almost Colorless Liquid

Blends Well With : Patchouli; Rosemary; Clary Sage; 3,3-dimethyl-1,5-

dioxaspiro[5.5]undecane; 3,3-dimethyl-2-(3-butenyl)norbornanol;

Insoluble in : Water;


http://en.wikipedia.org/wiki/Leaf

http://en.wikipedia.org/wiki/Perennial_plant

http://en.wikipedia.org/wiki/Herbaceous

Some Perfumery Uses : Cedarleaf; Balsam; Lavandin; Fern; Aftershave

Fragrances;

Traditional use: emollient, soothing agent, muscle relaxant,antimalarial.

Geographical source: Perennial herb native to Africa, temperate Asia, and

Europe, widely naturalized in most parts of the world. Found growing on

hedgebanks and waysides, uncultivated and waste land. .

Cultivation aspects:-

Cultivation is fairly easy Mugwort prefers slightly alkaline, well-drained loamy

soil, in a a sunny position. A tall-growing shrubby plant, with angular stems,

which are and often purplish, growing 3 feet or more in height. The leaves are

smooth and dark green above and covered with a cottony down beneath. They

are alternate, pinnately lobed, and segmented. The small greenish yellow

flowers are panicled spikes with a cottony appearance. Blooming is from July to

October. Mugwort is closely related to Common Wormwood (Absinthe). Gather

leaves and stems when in bloom, dry for later herb use. complaints, and diseases

of the brain. As a gargle for sore throat, a wash for sores and a poultice for

infections, tumors and to stop bleeding. These actions and uses are now backed

by scientific studies The leaves have an antibacterial action, inhibiting the

growth of Staphococcus aureus, Bacillus typhi, B. dysenteriae, streptococci, E.

coli, B. subtilis, and pseudomonas. A weak tea made from the infused plant is a

good all-purpose insecticide. The fresh or the dried plant repels insects. 54,56

Chemical constituents:-

main constituents volatile oils containing 1,8-cineole, artemisin, azulenes

sesquiterpene lactones, flavonoids, coumarin derivatives, tannins, thujone and


triterpenes. The plant contains ethereal oils (such as cineole, or wormwood oil,

and thujone), flavonoids, triterpenes, and coumarin derivatives. 38,42,45

Use

Chewing some leaves will kill the fatigue and stimulate the nervous system. It

was also used as an anthelminthic, so it is sometimes confused with wormwood

(Artemisia absinthium).

C. Production Profile

Current Production and Yields :-

EU-15 countries currently showing an interest in Artemisia are Austria, Finland,

France, Italy Sweden and the UK. Of these France and Sweden are currently

running pilot studies on Artemisia.

Oil yields - world market tonnage:-

PlantWorld market

TonnageAvailable oil yield kg/ha

Artemisia

(Wormwood)7 25

Tarragon 10 12


http://en.wikipedia.org/wiki/Absinth_Wormwood

http://en.wikipedia.org/wiki/Anthelminthic

http://en.wikipedia.org/wiki/Coumarin

http://en.wikipedia.org/wiki/Terpene

http://en.wikipedia.org/wiki/Flavonoid

http://en.wikipedia.org/wiki/Thujone

http://en.wikipedia.org/wiki/Cineole

Constraints upon Production

Southernwood is native to western Asia and has naturalised in Spain, Italy and

other Mediterranean countries. It will not set seed and rarely flowers in the UK

or in northern Europe. In southern Europe it is rare in the wild, but is cultivated

for the perfumeindustry.

The plant is extremely aggressive and invasive and will inhibit the growth of

nearby plants by the means of root secretions. The plant is spread both by seeds

and vegetation; dispersal occurs in most cases by seeds coming from plants in

hedges. The severity of mugwort as a weed causes problems in some farming

systems as it is so difficult to eradicate once established. The occurrence of

volunteers is becoming an increasing worry in such farming systems.

D. Markets and Market Potential

The leaves and roots of the plant provide a digestive and tonic herb which has a

wide variety of traditional uses. It can be taken over the long term at a low dose

to improve appetite, digestive function and absorption of nutrients. It can also

be taken to eliminate worms. A. vulgaris has traditionally been taken to aid

childbirth and its after effects. Mugwort contains a volatile oil, a sequiterpene

lactone, flavonoids, coumarin

derivatives and triterpenes. Sesquiterpene lactones have many properties which

include: Bitter tasting, antibiotic, anthelmintic, anti-inflammatory and

phytotoxic. The cytotoxic activities have also been extensively researched (D.

Frohne and J. Pfänder, 1984).An essential oil known as Artemisia oil or

Armoise oil is obtained by steam distillation of the aerial part of Artemisia

vulgaris and is used in perfumes .


3.3 Cryptolepis:

A. History :

The root of the plant cryptolepis (Cryptolepis sanguinolenta (Lindl.) Schlecter,

Asclepiadaceae or Periplocaceae) is used in traditional African medicine to treat

a variety of diseases, including malaria.Scientific investigations have indicated

a number of biological/pharmacological effects of compounds isolated from the

plant material, including anti-bacterial, anti-hyperglycemic, anti-inflammatory,

anti-plasmodial/anti-malarial, and anti-viral effects Some of these effects have

been demonstrated in the crude extract as well as its fractions, including a dose-

dependent inhibitory effect on the classical pathway of complement fixation.

During the past few years, cryptolepis has received additional attention by the

phytomedicine division of a pharmaceutical company in Ghana, which

developed an herbal tea based on this traditional medicinal herb and recently

demonstrated the clinical efficacy of a tea-bag formulation in the treatment of

malaria. A preliminary clinical study in 1989 conducted with an aqueous extract

of cryptolepis, prepared by boiling powdered cryptolepis roots in water, also

suggested the efficacy of the plant material against malaria.

B. Nomenclature and Taxonomy:-

Cryptolepis is derived from the root of Cryptolepis sanguinolenta; syn. C.

triangularis N.E. Br., and Pergularia sanguinolenta Lindl. Its common name

among the various tribes of Ghana include nibima (among the Twi speaking

people), kadze (among the Ewe), and g ngamau (among the Hausa). It is also

known as Ghana quinine or yellow-dye root. Although the aqueous extract has a

bitter taste, this name is probably based on the common use of the plant as a

substitute for the anti-malarial alkaloid quinine, and should not be confused

with it. Some decades ago, quinine was the drug of choice for the treatment of


malaria, and is still in use in areas where there is resistance to chloroquine

malaria drugs.

In keeping with common practice with popular medicinal botanicals that do not

have accepted common names in English, the common name cryptolepis, based

on its Latin generic name, will be used throughout this paper.

Common Name : Yellow dye Root (Ghane quinine)

Botanical Name : Cryptolepis Sanguinolenata

Plant Part Used : Root

C. Morphological Study :

Morphology :-

Cryptolepis is a thin-stemmed twining and scrambling shrub. The leaves are

petiolate, glabrous, elliptic or oblong-elliptic, up to 7 cm long and 3 cm wide.

The blades have an acute apex and a symmetrical base. The inflorescence

cymes, lateral on branch shoots, are few flowered, with a yellow corolla tube up

to 5 mm long. The fruits are paired in linear follicles and are horn-like. The

seeds are oblong in shape, small (averaging, 7.4 mm in length and 1.8 mm in

the middle), and pinkish, embedded in long silky hairs. Photos on these pages

show the root and other plant parts of cryptolepis.

Dried cryptolepis has a sweet fragrance. The root, the plant part used for the

treatment of malaria, varies from 0.4—6.6. cm long and 0.31—1.4 cm wide and

has a bitter taste. The root surface is light to medium brown in color. The

texture is hard and brittle, longitudinally rigid with occasional cracks and

striations. Rootlets are not present. Cut roots show a bright yellow surface, as

seen in the photo on this page.


D. Pharmacological Study

Biology and Pharmacology

Numerous biological/pharmacological activities have been demonstrated in

extracts from the roots of C. sanguinolenta, as well as for the alkaloids isolated

from these extracts. They include anti-plasmodial (both chloroquine-sensitive

and chloroquine-resistant strains of the malaria parasite), anti-bacterial, anti-

viral, anti-inflammatory, anti-diabetic and hypotensive effects.

Clinical Trials

In a preliminary study aimed at comparing efficacy of an aqueous extract of

cryptolepis with that of chloroquine, G.L. Boye, of the University of Ghana,

used the WHO extended seven-day in vivo test43 to measure P. falciparum

response in a number of patients attending the outpatient clinic of the Centre for

Scientific Research into Plant Medicine, a facility in Ghana where orthodox

medical practitioners collaborate with traditional medical practitioners. Malarial

patients with parasitemia of 1,000 to 100,000 P. falciparum parasites per 8,000

white blood cells, and negative for urinary chloroquine and sulphonamide were

recruited into the study. The patients were given either aqueous extract of

cryptolepis roots obtained by boiling root powder of the plant in hot water, in a

dose as that prescribed by the local herbalist, or chloroquine according to the

prescribed dose. After 7 days, the subjects were observed weekly for 3 weeks.

The results of this open, randomized, comparative study indicated that the

efficacy of cryptolepis in the treatment of malaria was comparable to that of

chloroquine1 All 22 patients in the study responded clinically and asexual

parasitemia was cleared within 7 days. There was no recurrence of parasitemia

during the follow-up period. The mean parasite clearance time in the 12 patients

on cryptolepis extract was 3.3 days compared to 2.3 days in the 10 patients on


chloroquine. Of significance in this trial is that the author states that the efficacy

of the extract in this study was similar to that of chloroquine. The mean fever

clearance time in the cryptolepis extract-treated group was 36 hours, compared

to 48 hours for the chloroquine-treated group. Unlike patients in the chloroquine

group, patients in the cryptolepis group did not require anti-pyretics (fever-

reducing drugs).

More recently, another open label, uncontrolled clinical trial was conducted by

Boye, which demonstrated the clinical efficacy of Phyto-laria®, a product of

cryptolepis roots formulated as a tea for use in the treatment of acute

uncomplicated malaria (Phyto-Riker Pharmaceuticals, Phytomedicine Division,

Accra, Ghana).20 Phyto-laria is approved by Ghana’s drug regulatory agency,

the Food and Drugs Board, and is packaged with instructions on the volume of

boiling water to use per tea bag. 59,63

Each patient was given one tea bag, for consumption 3 times a day for 5 days

of treatment. The dose administered was based on that calculated from the

decoctions prescribed by traditional healers. The results of this study indicated a

mean parasite clearance time of 82.3 hours (24—144 hours). The mean fever

clearance time was 25.4 hours (12—96 hours). These figures are comparable to

those obtained with chloroquine in Ghana and elsewhere in West Africa.

Safety

Safety is one of the most important considerations for the assessment of any

agent administered for treatment of a disease. Assessment of toxicity is

therefore critical in research and development of phytomedicines. Cryptolepine

is believed to interact with DNA13 and this could result in toxicity.

Evidence of DNA being the direct target of cryptolepine has been provided by

Bonjean and his co-workers. Their work has shown that cryptolepine binds

tightly to DNA. As is well known, DNA in the nucleus of living organisms


exists as a double helix, two intertwined coils or helices. Some chemical

compounds can insert themselves, or intercalate, between the two helices,

thereby interfering with the functions of the DNA that depend on this unique

double helical structure. One such function is cell division, preceded by

replication of the nuclear material and separation of the two sets of nuclear

material resulting from the replication. DNA replication occurs through nucleic

acid synthesis, using one uncoiled strand of DNA as a template. The reactions

responsible for replicating the nuclear material, must therefore involve

uncoiling and recoiling of DNA, and are catalyzed by a set of enzymes

including those responsible for the unwinding and relaxation of the DNA to

remove the tightly coiled helices. One of these enzymes is known as

topoisomerase, responsible for the interconversion between the relaxed and

coiled forms of DNA. For this interconversion to take place, the DNA must be

cut and then rejoined. Topoisomerase I cuts only one strand of the double-

stranded DNA and topoisomerase II cuts both strands. When topoisomerases are

inhibited, DNA replication ceases to occur.

Cryptolepine has been shown to be a potent inhibitor of topoisomerase II. Its

effect is to stop the cell from dividing and is probably the basis for its effect on

microorganisms, including the malaria parasite. It is also the basis for it being

regarded as a promising anti-tumor agent.

There have been reports of toxicity of the aqueous extracts of cryptolepis and

compounds isolated from the plant material when cell lines usually used to

assess anti-tumor activity or in vitro methods of risk assessment were used.43

Cytotoxicity in anti-viral test systems has also been reported. In one study,

cytotoxicity, measured as anti-tumor activity (against B16 melanoma cells) did

not correlate with toxicity in the in vivo mouse model for malaria used in the

same study. Phyto-laria, the cryptolepis product formulated as a tea, was

evaluated in vivo by administering it orally to mice, rats, and rabbits and using


the conventional acute toxicity and clinical chemistry tests. This tea bag

formulation, which represents an aqueous preparation, was shown to be safe.

The LD50 (lethal dose in which 50 percent of test animals died) obtained was

above 2,000mg/kg, more than two orders of magnitude higher than the effective

dose. It is noteworthy that Luo et al. report the use of cryptolepis extract as a

tonic, often taken daily for years without evidence of side effects or toxicity.

IN VITRO:-

In vitro anti-plasmodial activities, which are indicative of anti-malarial activity,

have been carried out using inhibition of the incorporation of the malaria

parasite into red blood cells. In one study in which both the chloroquine-

sensitive D6 strain and the chloroquine-resistant K-1 and W-2 strains of the

malaria parasite were used, the anti-plasmodial activity was measured using the

incorporation of H-hypoxanthine into red blood cells infected with P.

falciparum, the standard anti-plasmodial assay. Aqueous, alcoholic, and total

alkaloidal extracts, and compounds isolated from the plant material were found

to be effective against all three strains of parasite to varying degrees. Of the

extracts, the total alkaloid was the most active with mean IC50 values of 47, 42,

and 54 micromolar for the three strains, respectively, compared to values of 2.3,

72, and 68 micromolar, for chloroquine. The aqueous extract was the least

active. Of the isolated compounds, cryptolepine was the most effective, with

mean IC50 values of 27, 33 and 41 micromolar for the D6 chloroquine-sensitive

and K-1 and W-2 chloroquine-resistant strains, respectively. Hydroxy-

cryptolepine was the next best compound with IC50 values of 31, 45, and 59

micromolar, respectively, followed by neocryptolepine. Quindoline, or nor-

cryptolepine, without the methyl group, was the least active anti-plasmodial of

the isolated compounds. This is an indication that the methyl group contributes

to anti-malarial activity, at least in part. The result of this study with respect to

the K-1 strain is in agreement with the work of Noamesi and coworkers, as well


as Kirby and coworkers,who reported the anti-plasmodial activity of

cryptolepine against the multi-drug resistant K-1 strain of P. falciparum.

In another study, Wright et al., using multi-drug resistant K1 strain of P.

falciparum and a method of assessing inhibition of parasite growth based on

measurement of lactate dehydrogenase activity, showed that among a number of

anhydronium bases, only cryptolepine, the major alkaloid in cryptolepis, had

anti-plasmodial activity similar to that of chloroquine.

The mean IC50 value, determined from linear regression analysis of dose-

response curves, was 0.114 micromolar for cryptolepine, compared to a mean

value of 0.2 micromolar for chloroquine diphosphate.

Inhibition of beta-hematin formation in a cell-free system is another in vitro test

for anti-plasmodial activity. Reduction or elimination of the characteristic peaks

of beta-hematin at 1663 and 1210 cm-1 in an infrared spectrum indicates

efficacy. Cryptolepine has been shown to be effective in this model, the peaks

disappearing when the reaction mixture was pre-incubated with the alkaloid

suggesting that cryptolepine’s anti-plasmodial effect depended, at least in part,

on a quinine-like mode of action. A relatively simple method of measuring beta-

hematin, using absorbance in a simple spectrophotometer, is currently being

used in the Department of Biochemistry of the University of Ghana, and could

be adopted for assessing the efficacy of extracts of cryptolepis and compounds

isolated from them in a research and development effort to develop this

particular phytomedicine.Studies have been carried out to evaluate the anti-

microbial properties of cryptolepis extracts and compounds isolated from them.

In a program of biological evaluation to justify traditional uses of herbal

remedies, cryptolepis was studied because of its successful use in treating

diarrhea caused by intestinal amoebiasis, and found to be effective in vitro

against Entamoeba histolytica. Diarrheal diseases are very common in West


Africa and therefore, any anti-diarrheal remedy is of great interest. Over 100

strains of Campylobacter species, which are causative agents for gastroenteritis,

have been used to study the effect of cryptolepis and compounds isolated from

it on diarrheal bacteria The finding that cryptolepine was more effective than

co-trimoxazole and sulfamethoxazole, just as effective as ampicillin and less

effective than erythromycin and streptomycin, the antibiotics usually used

against diarrheal diseases, indicates that cryptolepis may be a potential remedy

for diarrhea. The ethanolic extract, not the aqueous one, had activity but not as

good as that of the isolated alkaloid.

The effect of the plant material was not so dramatic when Vibrio cholerae, the

causative agent for enteric infections, was used as the test organism. Obviously,

cryptolepis could be used as therapy for gastroenteritis although it is not known

as such in the region where it is used to manage a number of infections.

Some pharmacological effects of cryptolepis, quite unrelated to the use of the

plant in folkloric medicine, are its anti-inflammatory and anti-hyperglycemic

properties. It has been more than two decades since the anti-inflammatory

properties were established, as indicated by inhibition of carageenan-induced

edema and that of platelet aggregation (Carageenan-induced edema is a typical

pharmacological test for antiinflammatory drugs; carageenan, a gelatinous

preparation made from seaweed, is injected into parts, often the paw, of test

animals to produce a localized inflammation – usually, the type characterized by

accumulated fluids, i.e., edema. The tested agent is then measured for its ability

to inhibit the resulting inflammation.) The anti-hyperglycemic property has

been shown as enhanced insulin-mediated glucose disposal in a mouse model of

diabetes and in an in vitro system using the 3T3-L1 glucose transport assay,

indicating an effect on Type 2 diabetes Hypotensive properties have also been

reported, including effects on cholinergic nerve transmission, alpha-

adrenoceptors, and muscarinic receptors. Malaria and other infectious diseases


are more prevalent in the West African sub-region and therefore the anti-

plasmodial and anti-bacterial properties of cryptolepis are more exciting.

However, one should not underestimate the potential of cryptolepis in treating

some of these other diseases.

E. Traditional Ethnobotanical Use

The plant has been shown to be important in West African traditional medicine.

Aqueous extract of cryptolepis is used by the Fulani traditional healers in

Guinea-Bissau to treat jaundice and hepatitis.1 In Zaire and the Casamance

district of Senegal, infusions of the roots are used in the treatment of stomach

and intestinal disorders.2,27 In Ghana, dried root decoctions of the herb, prepared

by boiling the powdered roots in water, are used in traditional medicine to treat

various forms of fevers, including malaria, urinary and upper respiratory tract

infections, rheumatism, and venereal diseases. Cryptolepis is used in Congolese

traditional medicine for the treatment of amoebiasis. An aqueous decoction of

the root bark of cryptolepis is used in Congo for this treatment.

The major alkaloid, cryptolepine, was first isolated from C. sanguinolenta in

Nigeria and later in Ghana by Dwuma-Badu and his co-workers. According to

Ablordeppey et al.,and Tackie et al. this indoloquinoline alkaloid was isolated

from the roots of C. triangularis, a plant native to the Belgian Congo and

synonymous with C. sanguinolenta. Curiously, cryptolepine was first artificially

synthesized in 1906 by Fichter et al., but naturally-occurring cryptolepine from

C. triangularis isolated by Clinquart was reported 23 years later in 1929.

In addition to cryptolepine, several related minor alkaloids and their salts have

been isolated from C. sanguinolenta. These include the hydrochloride (although

the hydrochloride salt of a chemical compound is usually not considered a

distinct compound) and the 11-hydroxy derivatives of cryptolepine,


cryptoheptine, iso- and neo-cryptolepine, quindoline, and the dimers

biscryptolepine, cryptoquindoline, and cryptospirolepine. The dimers have been

found to be less active than the monomers, and they include

cryptosanguinolentine, cryptotakienine, and cryptomisrine.

Cryptolepine of the ma, the major alkaloid in cryptolepis, is not the only

alkaloid with biological/pharmacological activity. Almost all the minor

alkaloids also have anti-plasmodial activity. However, the activities of these,

based on the inhibition of the chloroquine-sensitive strain laria parasite

Plasmodium falciparum, are less than the activity of cryptolepine. Samples of

cryptolepis contain cryptolepine at varying concentrations, and since the minor

alkaloids also have biological activity, using the content of cryptolepine alone

for standardization is questionable. Total alkaloidal content or high performance

thin-layer chromatography (HPTLC) with densitometry would be the preferred

analytical methods for standardization. 69, 70

Concluding Remarks :-

In new drug discovery from medicinal botanical preparations, most

pharmaceutical companies would use an approach that relies on random, mostly

in vitro, mechanism-based, high throughput screening, especially in the initial

phases. This approach leads to the formulation of a drug based on a pure

chemical compound isolated from a medicinal plant or a derivative of such a

compound. An alternative pathway is based on ethnomedical information

obtained mainly from traditional medical practitioners (TMPs) and unequivocal

biological/pharmacological research results of a number of scientists and

clinicians working on the products used by these TMPs. The latter approach is

the one used by the Phytomedicine Division of Phyto-Riker, coupled with

toxicity as well as clinical confirmatory tests.


The scientific research that ought to be an important part of this alternative

pathway is not merely to inject science into the art of healing that is practiced

by indigenous people using medicinal plants, but also to make this art better

serve the indigenous and other people.

As demonstrated in some of the research work on the biology/pharmacology of

cryptolepis, the alcoholic extract is more effective compared to the aqueous

extract that the people normally use. It would be worthwhile to carry out

appropriate toxicity tests to ensure that the more effective ethanolic extract is

just as safe as the aqueous extract, and that it does not extract from the plant

compounds that are toxic to humans in addition to extracting more of the

effective and safe compounds. When this has been done and the safety of the

ethanolic extract assured, a better product could be formulated.

As shown in the accompanying Pharmacology article, cryptolepis, or

compounds extracted from it, has antimicrobial properties, affecting a number

of different microorganisms. In West Africa, where the plant originates,

infections from microorganisms are rampant. Malaria is endemic in the sub-

region as well. A phytomedicine that is capable of treating malarial and other

infections could provide an excellent remedy for a whole host of diseases which

afflict the majority of the people. It is for this reason that many local health

professionals are keen on promoting scientific research efforts required for the

development of such a remedy. Quality, safety, and efficacy are obviously key

issues. Evaluation of these parameters should be conducted on the plant extract

so that standardized remedies of plant materials can be produced without

requiring processes that would make the remedy extremely expensive and

unaffordable to a large number of people.


3.4 Yingzhaosu

{Naturally Occurring Antimalarial Endoperoxide}

The evolution of malaria strains resistant to standard quinine based drugs has

led to a renewed interest in novel antimalarial drugs with a divergent mode of

action. Compounds containing an endoperoxide functionality constitute a

promising class of antimalarial drugs. Yingzhaosu A (1) was isolated from a

herbal extract used in China as a folk remedy against malaria1 and was

subsequently obtained by total synthesis. While many analogues of Yingzhaosu

A are known to exhibit antimalarial activity in the low-nanomolar range,3a,b little

is known about the antimalarial properties of Yingzhaosu A itself. This is partly

due to the problematic isolation of the compound from natural sources. Also,

the only published total synthesis of Yingzhaosu A (1) is long, (15 steps) and

lacking in efficiency.

Recently, methodology for the synthesis of highly active antimalarial

compounds of type 2 and 3 was developed in our laboratory. We now report an

extension of this methodology for a new and efficient total synthesis of

Yingzhaosu A (1). Thiol-oxygen-co-oxidation of (S)-limonene was used to

introduce the peroxide moiety with concomitant formation of the bicyclic ring

in the initial step.3c Special attention was given to the sensitive peroxide

functionality, in selecting the reaction conditions for the subsequent steps.

These included a high yielding Pummerer reaction, a Mukaiyama-type aldol

condensation and a diastereoselective hydrogenation.


4. CONCLUSION

The pace at which research on quinine is progressing would certainly lead us to

a benefiting drug regime for the treatment of malaria. Even through the use of

quinine and its salts is not yet prevalent in India, active research on tissue

culture, activity and formulation of potent derivatives like quinine sulfate are

being carried out. The introduction of comparatively more potent artemisinin

and its derivatives, than chloroquin, mefloquin, quinine etc. is an encouraging

aspect in this area of increased drug resistant in Plasmodium vivax in Mathura

(U.P.) and studies as such would necessitate the use of these drugs. A thorough

study on multi drug therapy with quinine and artemisinin oil and other drugs

may decrease the incidence of development of quinine resistant strain. Clinical

studies on the more potent artemisinin derivatives with low recrudescence rates

toxic effects and their formulation would lead to a better therapeutic use of

these compounds.

The presently available evidence suggest that the supporitory formulation of

quinine sulfate and cryptoles is effective and safe in the treatment of

uncomplicated and complicated falciparum malaria in adults and children. It is

also effective and safe in treating children's as out patients when given as a

single dose in combination with mefloquine where is possibility that this

treatment regimen, if used for adults and children early in the course of the

diseases at the hamletor home level, could improve the physical and economical

health of a community and reduce costs to the health care system by decreasing

referrals to secondary and tertiary care hospital.

Thus, with the emergence of drug resistance in treatment regimens, a new

concepts has evolved to combact malaria today. Artemisinin oil and its

derivatives have been shown to be effective in the management of chloroquin

resistant faciparum malaria. Its therapeutic utility is also greater as it can used


effectively in combination to improve efficacy e.g. with mefloquine. This

current drug therapy along with vectory control strategies and other preventive

aspects may provide an effective means of management of cerebral malaria. 73


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herbal antimalerial

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