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ANA00003 - SOME EFFECTS OF SUB- ACUTE ADMINISTRATION OF ARTESUNATE ON CEREBELLUM OF ADULT WISTAR RATS


CHAPTER ONE

1.0       INTRODUCTION

Artesunate (AS) is an Artemisinin Anti-Malarial drug used as a single drug or in combination with other Anti-Malarial. (Klayman, 2002).

Artesunate the drug of study is a water soluble derivative of artemisinin which was extracted from the leaves of the Chinese herbal plant Artemisia sannua and sweet worm-wood. Archeological finding indicates that this herb has been in use as a traditional remedy for the treatment of malaria fever in china as back as 340A.D. Artesunate is an effective, potent and rapidly acting blood schizonticide, a parasitidal of the asexual stage and has maintained activity even in patient with multi-drug resistance to malaria parasite(Kumar, 1999).

Human have always co-exited with parasites. Even in medieval times it was believed that using large amount of herb, spices, perfumery material e.g sandal wood incense etc afforded protection from mosquitoes and subsequently malaria, the infectious disease cause by these mosquitoes (Mann, 2000).

Malaria is cause be the protozoan parasite of genus plasmodium, it is one of the widest disease affecting human populations especially in the torpics. Approximately 300-500millions people are infected each day and 15-2.7million lives are lost annually due to malaria. (Klayman, 2002).

Malaria has been known since time immemorial but it was centuries later that the causative agent was known. Drugs such as miasma drugs became less effective following malaria resistance to their usage, coupled with undesirable side effect. Thereafter chloroquine first line usage as a treatment became limited following evolution of plasmodium vivax resistance recorded in 1989 (Ridley, 2002) and some side effect which includes blurred vision, seizures and polyneutitis.

Also the use of antifolate drugs like pyrimethamine sulphadoxine combination under the brand names fasidar, malariech etc. also became discourage because of such effects like skin rashes, neuromyopathy etc. couple with plasmodium falciparum resistance to the drug recorded in places like Amazon basins of South America and parts of Ethiopia in Africa (Ridley, 2002).


Figure :1 Chemical structure of Artesunate

1.1       HISTORY

Malaria is a disease that is caused in humans by parasites of the Plasmodium species through the bite of infected anopheles mosquitoes. About 3.3 billion people—half of the world’s population—are at risk of malaria. Every year, this leads to about 250 million malaria cases and nearly one million deaths. Nigeria is known for high prevalence of malaria and it is a leading cause of morbidity and mortality in the country. WHO recently listed Nigeria among high burden countries with limited evidence of decrease in malaria cases. Cinchona bark is one of the most naturally occurring drugs. This natural product was used by the inhabitants of Peru to control malaria, and the Jesuits introduced this practice to Europe during the 1640s where it was rapidly accepted. However, it was not until 1820s that the active ingredient quinine was extracted from the bark and isolated. It was named by the French chemists Pierre Joseph Pelletier and Joseph Bienaim´e Caventou. (Mann, 2000).

Treatment of malaria involves supportive measures as well as specific antimalarial drugs. With early diagnosis and effective treatment, someone with malaria can expect a complete recovery. There are several families of drugs used to treat malaria. In the face of this challenge facing chemotherapy of malaria, Artemisinin and its derivatives (Artesunate, Artemether, Arteether, and dihydroartemisinin) have given renewed hope for combating resistant malaria.(Klayman, 2002) .

Artesunate (ART) is part of the Artemisinin group of drugs that treat malaria. It is a semisynthetic derivative of Artemisinin. Clinical evidence of drug resistance to Artesunate was first reported in Western Cambodia, where Artemisinin Monotherapy is common. Over the past decade, a new group of Anti-Malarials known as (Artemisinin-based combination therapies) has brought new hope in the fight against malaria. In malaria endemic areas such as Nigeria, self-medication is quite common and purchase of antimalarial sin the open market is rampant. (Klayman, 2002).

Artesunate is a water-soluble, semi-synthetic derivative of the sesquiterpine lactone artemisinin with anti-malarial, anti-shistosomiasis, antiviral, and potential anti-neoplastic activities. Upon hydrolysis of artesunate's active endoperoxide bridge moiety by liberated heme in parasite-infected red blood cells, reactive oxygen species and carbon-centered radicals form, which have been shown to damage and kill parasitic organisms. Additionally, in vitro studies demonstrate that this agent induces DNA breakage in a dose-dependent manner. Artesunate has also been shown to stimulate cell differentiation, arrest the cell cycle in the G1 and G2/M phases, inhibit cell proliferation, and induce apoptosis through mitochondrial and caspase signaling pathways. Artemisinin is isolated from the plant Artemisia annua. (Klayman, 2002)

Artesunate is part of the Artemisinin group of drugs that treat malaria. It is a semi-synthetic derivative of Artemisinin that is water-soluble and may therefore be given by injection. It is on the World Health Organization's List of Essential Medicines. It has been made available in the US under the investigational new drug protocol [L890]. Artesunate is provided by the Centers for Disease Control and Prevention on an emergency basis. (Klayman, 2002).

1.2       CHEMICAL PROPERTIES.

Artesunate is a water soluble, semi-synthetic derivative of the sesquiterpine lactone artemisinin with anti-malaria, anti-shistosomiasis, antiviral and potential anti-neoplastic activities.

Molecular Formula: C19H2808

Chemical Names: Artesunate; Succinyl dihydroartemisinin;88495-63-0;

Molecular Weight: 384.425 g/mol

1.3       ABSORPTION AND DISTRIBUTION:

A sensitive bioassay was used to measure the antimalarial activity in plasma which results from Artesunate and its principal metabolite, dihydroartemisinin.

            The absorption and elimination of oral artesunate were rapid, with a mean elimination half-life of antimalarial activity of 43 min (95% CI, 33 to 53 min).

 

1.4       INDICATIONS AND USES

Artesunate is an effective anti-malarial medicine. It is used to treat severe malaria caused by plasmodium falciparum strains when other medicines are not effective. (Kumar, 1999)

1.5       AIMS AND OBJECTIVES OF STUDY

The present study is designed to invest the possible changes which may occur to the morphology, physiology and histology of the spleen following varied dosage and time duration of the drug through oral route.

The result obtained is aimed at determining the toxic effect if any kind that may be associated with the use of this drug and the consequent affect that is obtained over dosage or abuse of this drug.

1.6       SCOPE OF THE STUDY

The scope of this study is limited to the histology of the cerebellum of adult wistar rats under light microspe following administration of Artesunate.