ANTIMALARIAL THERAPY Presented By: Payal Mondal Priyadarshini. K. Prachi Gaikwad Pratik Gada Parvez Shaifi CRANFIELD BATCH No.8

CONTENTS INTRODUCTION VECTORS LIFECYCLE OF PLASMODIUM SIGNS AND SYMPTOMS DIAGNOSIS ANTIMALARIAL THERAPY RECENT ADVANCES CASE STUDY CLINICAL TRIAL OF ANTI MALARIAL DRUG

INTRODUCTION Malaria has been known since time immemorial, but previously it was thought that "miasma" (bad air or gas from swamps - "mal air ia") caused the disease. Systematic control of malaria started after the discovery malaria parasite by Laveran in 1889 (for which he received the Nobel Prize for medicine in 1907) The demonstration by Ross in 1897 that the mosquito was the vector of malaria.

MALARIA One of the most important infectious diseases in world. Caused by a parasite protozoan called Plasmodium. Four types:- Plasmodium vivax Plasmodium ovale Plasmodium malariae Plasmodium falciparum Plasmodium knowlesi is now established as the fifth Plasmodium species to cause malaria in humans (seen in Thailand and Sweden) electron micrograph of Plasmodium falciparum

VECTORS The parasite's primary (definitive) hosts and transmission vectors are female mosquitoes of the Anopheles genus, while humans and other vertebrates are secondary hosts. Plasmodium falciparum, a species most likely to be transmitted by the mosquito Anopheles gambiae. A. gambiae complex is the chief vector in Africa and A. freeborni in N. America.

LIFECYCLE OF PLASMODIUM

SIGNS AND SYMPTOMS Depends on : the parasitemia, the presence of the organism in different organs the parasite burden incubation period varies generally between 10-30 days headache, vague pains in the bones and joints, chilly sensations and fever. chill and fever follow a cyclic pattern (paroxysm) paroxysm is due to the rupture of infected erythrocytes and release of parasites.

patient experiences euphoria, and profuse perspiration and the temperature begins to drop. Fever is associated with severe headache, nausea (vomiting) and convulsions the body temperature begins to climb and reaches 103-106 degrees F (39- 41degrees C).. chilly sensation that progresses to teeth chattering, overtly shaking chill and peripheral vasoconstriction resulting in cyanotic lips and nails cold stage for about an hour PAROXYSM

CLASSIFICATION OF MALARIA According to severity of illness, malaria can be broadly classified into two types -  Uncomplicated (Benign) and Complicated (Malignant). UNCOMPLICATED MALARIA Relatively milder disease Generally caused by P. vivax Seldom fatal The chance of involvement of other organs (complications) is much less. Also referred to as Uncomplicated Malaria. COMPLICATED MALARIA Severe Rapid downhill course Caused mainly by P. falciparum and rarely by P. vivax. Poor prognosis (outcome) Nowadays "severe malaria" or "complicated malaria" are used more frequently to describe this type of malaria

DIAGNOSIS Diagnosis is based on symptoms and detection of parasite in Giemsa stained blood smears CBC Electrolytes "Think Mosquito bite"

DIAGNOSIS Plasmodium falciparum ring trophs in a single red blood cell from a human blood smear. Note the size of the infected cell RBC compared with the uninfected RBC.

NEWER DIAGNOSTIC TECHNIQUES

Objectives & Use of Antimalarials To prevent and treat clinical attack of malaria. To completely eradicate the parasite from the patients body. To reduce the human reservoir of infection- cut down transmission to mosquito. ANTIMALARIAL THERAPY: Causal prophylaxis (Pre-erythrocytic stage in liver) Suppressive prophylaxis(Erythrocytic phase) Clinical cure (Erythrocytic schizontocides ) Radical Cure.(Hypnozoites + Erythrocytic schizonts) Suppressive Cure Gametocidal.

Classification of Antimalarial drugs 4-Aminoquinolines– Chloroquine , Amodiaquine. Quinoline methanol –Mefloquine. Acridine –Mepacrine. (Atarbrine,Quinacrine) Cinchona alkaloid–Quinine. Biguanides –Proguanil. (chloroguanide) Diaminopyrimidines–Pyrimethamine.

8-Aminoquinolines–Primaquine, Bulaquine. Sulfonamides & sulfones–Sulfadoxine, Sulfamethopyrazine, Dapsone. Tetracyclines –Tetracycline, Doxycycline. Sesquiterpine lactones–Artesunate, Artemether , Arteether. Phenanthrene methanol–Halofantrine. Naphthoquinone –Atovaquone.

Chloroquine Rapidly acting erythrocytic schizonticide Acts on all species of Plasmodium MOA: Actively concentrated by sensitive intraerythrocytic plasmodia: higher concentration in infected RBC  increase vesicular pH  degradation of Hb by parasitic lysosomes  Inhibition of conversion of heme to hemozoin by formation of Chloroquin heme complex  damage of plasmodial membrane. Quinine, mefloquine, mepacrine acts in an same manner.

Aritimisinin derivatives Active principle of plant Artemisia annua. Used in chinese traditional medicines. Active against P. falciparum. Rapidly acting blood schizontocide MOA: Endoperoxide bridge in molecule interacts with heme in parasite  cleavage release highly free radical species binds to membrane protein causes lipid peroxidation, damage endoplasmic reticulum, inhibit protein synthesis and causes lysis of the parasite.

Adverse effects: Uses: nausea, vomiting, itching, abdominal pain, and drug fever. Abnormal bleeding, first degree AV block, transient reticulopenia and leucopenia. Drug interactions. Uses: Chloroquine resistant malaria Severe and complicated malaria

ARTIMISININ COMBINATION THERAPY ( ACT) Artesunate-mefloquine Artesunate -sulfadoxine-pyrimethamine Artesunate -amodiaquine Artesunate -chloroquine Artemether-lumefantrine Dihydroartemisinin-piperaquine

THE MAIN CAUSE OF THE RESURGENCE IS DRUG RESISTANCE. Rising resistance to antimalarial drugs Universal Chloroquine resistance to Plasmodium falciparum Development of resistance not only compromises the efficacy of existing antimalarial drugs but also threatens to pre-maturely terminate the useful therapeutic life of new antimalarial drugs Lack of effective, affordable and appropriate treatment options

CHALLENGES IN DEVELOPMENT OF NEW TREATMENT FOR MALARIA Between 1975 and 1999, only four of the almost 1,400 new drugs developed worldwide were antimalarial, and all were at least in part the products of publicly funded research Significant R & D effort and funding required to develop new treatments Distribution of the treatment is difficult due to the remoteness of the areas in which the disease is most prevalent and poor health systems in malaria endemic countries

RECENT ADVANCES Malaria Drug Through Genetic Engineering Artemisinin is the most effective treatment for malaria and the best drug for treating resistant forms Artemisinin is made from the sweet wormwood plant found in China and Vietnam.  But supplies of the plant are limited. And it takes a lot of plant material to get enough of the drug to treat one patient Placed genes from the wormwood plant into a yeast organism and got it to produce large amounts of artemisinic acid.  This acid can be made into the drug artemisinin in just a few chemical steps.

GENETICALLY MODIFIED MOSQUITO Mosquitoes genetically engineered for malaria resistance can outcompete their wild counterparts By producing a peptide called SM1 that blocks Plasmodium from invading the mosquito's gut, thus interrupting the parasite's development. Since it is not a naturally occurring peptide, SM1 doesn't activate the mosquito's immune system

REVERSING ANTIMALARIAL RESISTANCE A malaria parasite gene called “pfcrt”, already confirmed as the culprit behind resistance to the drug chloroquine in the malaria species Plasmodium falciparum, may be responsible for resistance to several other antimalarial drugs In chloroquine-resistant malaria, mutations in “pfcrt” may encourage chloroquine to "leak" out of the vacuole before it has a chance to stop the heme detoxification process By modifyng this gene resistance to chloroquine can be reversed

VACCINES FOR MALARIA Immunization with irradiated sporozoite will confer protection against infection Antigens can be used for immunization in order to create antibody against the sporozoite.

CASE STUDY One Traveler's Ordeal with Severe Malaria Mr. Ver Wys suffered from malaria at Haiti Neglected Anti malarial Illness in Lake Charles Diagnosis Treatment Malaria Visits a Child in Africa Ramadhani Shida Mashaka* was only 8 months old when he got seriously ill Home treatment Seeking treatment outside the home A happy ending

CLINICAL TRIAL OF ANTI MALARIAL DRUG Phase 1 Studies of AQ-13, a Candidate Aminoquinoline Antimalarial, in Comparison With Chloroquine. Efficacy, Safety and Pharmacokinetic of Artequin TM P. Falciparum Malaria. Effectiveness of Artemisinin Combination Regimens in Falciparum Malaria (ACT).

Phase 1 Studies of AQ-13, a Candidate Aminoquinoline Antimalarial, in Comparison With Chloroquine. Sponsor: Tulane University Health Sciences Center. Collaborator: National Institutes of Health (NIH). Phase 1. Study Type: Interventional. Ages Eligible for Study. Genders Eligible for Study. Inclusion Criteria: Healthy adult volunteers. Exclusion Criteria: Chronic medications with the exception of oral contraceptives, Pregnancy, Breast-feeding.

Efficacy, Safety and Pharmacokinetic of Artequin TM P Efficacy, Safety and Pharmacokinetic of Artequin TM P. Falciparum Malaria. Sponsor: Albert Schweitzer Hospital. Collaborator: Mepha Ltd. Phase II. Study Type: Interventional. Genders Eligible for Study. Accepts Healthy Volunteers. Inclusion Criteria. Exclusion Criteria.

Effectiveness of Artemisinin Combination Regimens in Falciparum Malaria (ACT). Sponsor: Medecins Sans Frontieres. Collaborators: Mahidol University University of Oxford Disease Control, Department of Health, Myanmar. Phase IV. Study Type: Interventional. Ages Eligible for Study: Genders Eligible for Study: Inclusion criteria. Exclusion criteria.

Key Figures WHAT HAS TO BE DONE:  More than 700 million insecticide-treated bednets – half of those in Africa More than 200 million of doses of effective treatment Indoor spraying for around 200 million homes annually Approximately 1.5 billion diagnostic tests annually

WHAT IT WILL COST In 2010, $6.2 billion will be needed From 2011 to 2020, roughly $5 billion per year will be need to sustain the gains of control measures In addition, about $1 billion per year will be needed for research and development of new prevention and treatment tools

REFRENCES www.malaria.org World Health Organization – Article http://www.who.int/en/ "Engineering a mevalonate pathway in Escherichia coli for production of terpenoids," by Vincent J. J. Martin, Douglas J. Pitera, Sydnor T. Withers, Jack D. Newman, and Jay D. Keasling, appeared in Nature Biotechnology, 1 July 2003. ANTIIMALARIALS By- K D Tripathi, Essentials of medical pharmacology, 5th edition Jaypee publications. www.anopheles.com

THANK YOU

TIME HAS COME TO COUNT MALARIA OUT World Malaria day (25 April)- A Day to Act Blue Ribbon Campaign Launched by Malaria Foundation International

Back up slides

Do NOT be fooled into thinking white blood cells are Plasmodium parasites! White blood cells are larger in size than the red blood cells, and have a large, darkly staining, bi-lobed nucleus.

A mature Plasmodium falciparum gametocyte.

According to severity of illness, malaria can be broadly classified into two types -  Uncomplicated (Benign) and Complicated (Malignant). UNCOMPLICATED MALARIA Relatively milder disease Generally caused by P. vivax Seldom fatal The chance of involvement of other organs (complications) is much less. Also referred to as Uncomplicated Malaria. COMPLICATED MALARIA Severe Rapid downhill course Caused mainly by P. falciparum and rarely by P. vivax. Poor prognosis (outcome) Nowadays "severe malaria" or "complicated malaria" are used more frequently to describe this type of malaria