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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance Glossary acidosis. a disturbance of the body acid-base balance in which there is excessive acidity of the blood. metabolic acidosis results from excess acid due to abnormal metabolism (as in severe malaria), excessive acid intake, renal retention, or excessive loss of bicarbonate (as in severe diarrhea); respiratory acidosis results from inadequate elimination of carbon dioxide. agranulocytosis. a condition marked by a sharp drop in circulating white blood cells, often drug- or radiation-induced. anaphylaxis. an unusual or exaggerated allergic reaction, sometimes leading to shock and death, triggered by a foreign protein or other substance. anemia. decrease in number of red blood cells and/or quantity of hemoglobin. Malaria causes anemia through rupture of red blood cells during merozoite release as well as other mechanisms, e.g., suppressing red cell production by bone marrow. anopheline. referring to Anopheles mosquitoes. antenatal care. concerned with the care and treatment of a pregnant woman and her unborn child. anthropophilic. attracted to humans, especially as a source of food (e.g., malaria-carrying mosquitoes). antibody. a protein produced by the immune system in response to the introduction of a substance (an antigen) recognized as foreign. The chief purpose of an antibody is to interact with other components of the immune system and render the antigen harmless.
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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance antigen. a molecule capable of eliciting an immune response. antigenic diversity. the ability of an organism to vary its antigenic features. antigenic variation. same as antigenic diversity. antipyretic. an agent that reduces fever. arthralgia. pain in one or more joints. aspartate aminotransferase. an enzyme produced by the liver. When present in abnormally high levels in the blood, it may indicate inflammation or disease of the liver or another organ. ataxia. a staggering gait or other inability to coordinate voluntary muscular movements. This finding is symptomatic of certain nervous disorders especially involving the cerebellum. attenuate (as in vaccine). to reduce the virulence of a pathogenic agent. auditory evoked potential. electrical brain wave activity measured in response to acoustic stimulation (as sound). Evoked potentials are used as diagnostic tools to investigate potential damage to the central nervous system caused, for example, by a disease like multiple sclerosis or by a drug. brain stem. the part of the brain composed of the midbrain, pons, and medulla oblongata connecting the spinal cord with the forebrain and cerebrum. bioassay. a method of determining the relative strength of a substance (as a drug) by comparing its effect on a test organism with that of a standard preparation. blister pack. a form of medication packaging in which individual doses of one or more types of pill are encased in separate airtight plastic pockets, often accompanied by dosing instructions. Blister packs typically contain all of the doses needed for a single course of treatment. cardiotoxic. having a toxic effect on the heart. cell-mediated immunity. an immune process in which subpopulations of effector T cells defend against viruses and intracellular protozoal infections, such as malaria. centrifuge. a machine that uses centrifugal force to separate substances of different densities, remove moisture, or simulate gravitational effects. chemoprophylaxis. the use of drugs to prevent infection or progression of infection to illness. chromosome. any of the usually linear intracellular bodies that contain the genes or hereditary factors of eukaryotic organisms, bacteria, or certain DNA viruses (e.g., bacteriophages). cinchonism. side effects from quinine or quinidine, reversible with lower dosages or termination of the drugs. Effects include ringing in the ears,
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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance headache, nausea, diarrhea, altered auditory acuity, and blurred vision. The term derives from cinchona bark, the natural source of quinine. clinical cure. elimination of malaria symptoms, sometimes without eliminating all parasites. coformulation. a fixed-dose combination of two or more drugs, i.e., two (or more) drugs in one pill. This is distinguished from combinations of drugs in separate pills, either blister-packed together or from separate containers. coma. decreased state of consciousness from which a person cannot be aroused. cost effective. economical, based on the tangible benefits produced by the money spent. cost effectiveness. a measure of the value received (effectiveness) for the resources expended (cost). Usually considered as a ratio, the cost effectiveness of a drug or procedure, for example, relates the cost of that drug or procedure to the health benefits resulting from it. In health terms, it is often expressed as the cost per year of life saved or as the cost per quality-adjusted life-year saved. culicine. referring to mosquitoes of the genus Culex. cytoadherent [parasites]. red blood cells containing mature malaria schizonts that attach to endothelial cells lining small blood vessels. cytokine. a regulatory protein released by cells of the immune system that acts as an intercellular mediator in the generation of an immune response. Examples of cytokine classes include interleukins and lymphokines. cytotoxic. toxic to cells. DDT. 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane, or chlorophenothane, a pesticide. degedege. Swahili term for a febrile illness with convulsions (often cerebral malaria) sometimes perceived as a nonmalarial condition with supernatural causes. dipstick [test]. shorthand term for rapid diagnostic test (RDT), usually performed by immersing a commercially prepared strip into a body fluid. DNA. deoxyribonucleic acid, a carrier of genetic information (i.e., hereditary characteristics) found chiefly in the nucleus of cells. drug pressure. intense exposure of a population to a given drug, usually an antimicrobial agent. dysdiadochokinesis. the inability to halt one motor action and substitute its opposite action, usually the result of a neurologic disease.
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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance electrocardiogram (ECG). a graphic tracing of the electrical current produced during the contraction of heart muscle. electrocardiograph. an instrument for recording the changes of electrical activity occurring during heart contraction, often used to diagnose abnormalities of cardiac conduction. Emax. maximum effect exerted by a drug. In the case of antimalarial drugs, it usually represents the log decrease in total plasmodial burden following exposure to a given agent. endemic. describing the presence of a disease in a community. holoendemic. affecting essentially all the inhabitants of an area. hyperendemic. causing a high but steady rate of infection over time. hypoendemic. causing a low but steady rate of infection over time. endothelial cells. cells that line the cavities of the heart, blood and lymph vessels. entomological inoculation rate (EIR). the measurement of frequency with which a human is bitten by an infectious mosquito; or the average number of infective bites a resident of a malarious area receives over a year or other time period. enzyme. any of numerous complex proteins that are produced by living cells and catalyze specific biochemical reactions. eosinophilia. abnormal increase in the number of eosinophils (a type of white blood cell) in the blood, characteristic of allergic states and various parasitic infections. epidemic. rapid and/or widespread outbreak of a disease through a community in which the disease is normally absent or present at a low level. epidemiology. study of the distribution and determinants of a disease in populations. erythrocyte. a red blood cell. erythrocytic. relating to red blood cells. erythrocytic stage. stage of the malaria parasite’s life cycle infecting and developing within red blood cells. exoerythrocytic stage. stage of the malaria parasite’s life cycle infecting, developing, or remaining latent in liver cells (hepatocytes). essential drug (or medicine). one of a group of drugs which together comprise safe, effective treatment for the majority of communicable and non-communicable diseases currently affecting the world’s population. The 12th Model List of Essential Drugs, prepared by a WHO expert committee in 2002, contains 325 individual drugs. externality. an economic side-effect: externalities are costs (“negative externalities”) or benefits (“positive externalities”) arising from an economic activity that affect somebody other than the people engaged in the economic activity and are not reflected fully in prices. Relating to malaria, when a large proportion of people in a community purchase and
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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance use insecticide-treated nets (ITNs), even those who do not purchase them gain some protection, a positive externality. falciparum malaria. malaria caused by the species Plasmodium falciparum febrile. describing an elevated body temperature. first-line treatment. initial treatment for a specific disease or condition. gamete. a mature male or female germ cell usually possessing a single set of chromosomes and capable of initiating formation of a new diploid individual by fusion with a gamete of the opposite sex. gametocytocidal. capable of killing gametocytes. gametocyte. sexual stage of malaria parasite that forms in red blood cells. Macrogametocytes (female) and microgametocytes (male) form in individual erythrocytes, are ingested by female mosquitoes, and unite in the mosquito’s stomach. gene amplification. a process in response to certain cell development signals or environmental stresses that leads to an increased number of gene copies. In humans, this process is seen most often in malignant cells. genetically modified mosquito. a mosquito with added or altered genes that either destroy developing malaria parasites or render the mosquito an inhospitable or refractory host for malaria. genotype. the genetic makeup, as distinguished from the physical appearance, of an organism or a group of organisms; the combination of alleles located on homologous chromosomes that determines a specific characteristic or trait. glucose-6-phosphate dehydrogenase (G6PD) deficiency. a common enzyme deficiency within the human red cell, affecting an estimated 400 million people worldwide. The deficiency confers some resistance to malaria, but also can lead to hemolytic anemia of varying severiy, especially following exposure to certain drugs including the antimalarial drug primaquine. half-life. the time required for half of the amount of a substance (as a drug or radioactive tracer) in a physiologic or ecologic system to be eliminated or disintegrated by natural processes. hematocrit. the ratio of the volume of packed red blood cells to the volume of whole blood as determined by a centrifugation instrument: a measure of possible anemia. heme dimerization. the stage in the biochemical breakdown of human hemoglobin within the malaria parasite that yields malaria pigment (hemozoin). hemoglobin. the protein in red blood cells which carries oxygen.
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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance hemolysis. a condition in which red blood cells prematurely rupture. Examples of hemolytic conditions include sickle cell anemia and malaria. Hemolytic anemia occurs when the bone marrow is unable to compensate for the premature destruction by increasing production of new red cells. hemozoin. malaria pigment; an iron-containing breakdown product of hemoglobin which accumulates as cytoplasmic granules in malaria parasites and tissues of infected individuals. hepatocyte. a liver cell. hyperparasitemia. parasite count in excess of 250,000 per microliter, or a state in which more than 5% of circulating red blood cells are parasitized. Hyperparasitemic patients have an increased risk of death from microvascular disease as well as metabolic effects from the high parasite load. hypoglycemia. blood glucose less than the lower value of normal (70-110 mg/dL [3.9-6.1 mmol/L in SI reference units]). Glucose levels of 40 and below constitute severe hypoglycemia, a life-threatening emergency. Hypoglycemia is common in malaria, as malaria parasitized red blood cells utilize glucose 75 times faster than uninfected cells. Treatment with quinine also lowers blood glucose by stimulating insulin secretion. hyponatremia. serum sodium less than the normal lower limit, which is 135-147 mEq/L (135-147 mmol/L in SI reference units). Serum sodium levels approaching 120 and below constitute severe hyponatremia, a medical emergency. Hyponatremia can be seen in malaria, and is indicative of complicated malaria. hypnozoite. a stage of malaria parasites found in liver cells. After sporozoites invade liver cells, some develop into latent forms called hypnozoites. They become active months or years later, producing a recurrent malaria attack. Only P. vivax and P. ovale produce hypnozoites in humans. immune system. a natural defense mechanism of the body, in which specialized cells and proteins in the blood and other body elements interact to eliminate or neutralize infectious microorganisms and other foreign substances. immunity. the body’s ability to control or lessen a malaria attack with antibodies and other protective reactions developed in response to previous malaria attacks. Semi-immune individuals live in malaria endemic areas and are repeatedly infected. Immunity minimizes their symptoms and decreases parasitemia. immunochromatography. an antibody-based process that uses capillary flow through an absorbent membrane to separate components; used in research and as a basis for diagnostic tests.
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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance incidence. as used in epidemiology, the number of new cases of a disease occurring within a specified period. An incidence rate is a measure of the frequency with which new cases occur in a population over a period of time. The denominator is the population at risk and the numerator is the number of new cases occurring during a given time period. indoor residual spraying (IRS). spraying long-lasting insecticide on indoor walls or rafters in order to kill resting insects, specifically female malaria vectors that rest indoors following blood meals. integrated control. disease control that involves more than one type of intervention. For malaria, this could involve the combination of drug treatment for symptomatic cases, prevention through ITNs, and environmental measures to reduce mosquito breeding. insecticide-treated bednet (ITN). a fine meshed net that has either been treated with a long-lasting insecticide or manufactured with insecticide directly incorporated into its fibers, hung over a bed to protect sleepers from insect bites. Insecticide-treated curtains (ITC) are hung in windows and doorways. intermittent preventive treatment (IPT). antimalarial drug treatment during pregnancy to prevent clinical disease. This approach is now being extended to infants and may also be incorporated into childhood immunization schedules in malaria-endemic regions. intraerythrocytic. situated within red blood cells. intramuscular. situated within or administered into a muscle. intrauterine growth restriction (IUGR). failure of appropriate fetal growth, usually defined as a baby weighing below the 10th percentile of expected weight for gestational age. Malaria during pregnancy can cause IUGR. intravascular. situated within a blood vessel. intravenous. administered into a vein, as in intravenous fluids for treatment of dehydration. in vitro. biological processes that occur in isolation from the whole organism, such as in a test tube or in cell culture. in vivo. biological processes that occur within the body of a living organism. jaundice. yellowish discoloration of the whites of the eyes, skin, and mucous membranes caused by deposition of bile salts in these tissues. It may be seen in various liver diseases, such as hepatitis, that affect the processing of bile as well as hemolysis (excessive destruction of red blood cells). Also called icterus. knock down resistance (kdr). a form of resistance to pyrethroid insecticides
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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance caused by a genetic point mutation. kdr is found in anopheline malaria vectors as well as other mosquitoes and some other insects. larvicide. an agent for killing insect larvae (in the case of malaria, mosquito larvae). ligand. an attachment site or a molecule that binds to a complementary site on another molecule. light microscope. a conventional laboratory microscope that uses ordinary light (as opposed to parallel beams of electrons, for example, in an electron microscope) to illuminate an object. lysis. a process of disintegration or dissolution (as of cells). meningitis. inflammation of the meninges of the brain and the spinal cord, most often caused by a bacterial or viral infection and characterized by fever, vomiting, intense headache, and stiff neck. merozoite. the stage of the malaria parasite, in the human host, that infects red blood cells. metabolic acidosis. resulting from excess acid due to abnormal metabolism (as in severe malaria), excessive acid intake, or renal retention or from excessive loss of bicarbonate (as in severe diarrhea). microhematocrit (tube). a procedure for determining the ratio of the volume of packed red blood cells to the volume of whole blood by centrifuging a minute quantity of blood in a capillary tube coated with heparin. monotherapy. use of a single drug to treat a disease. molecular markers. genetic markers, usually proteins or DNA sequences, detected by biochemical methods. multigravidae. women who have had several previous pregnancies. mutagenicity. the capacity to induce mutations in DNA. myalgia. muscle pain. neutropenia. a decrease in white blood cells chiefly affecting neutrophils. oocyst. cyst located in the outer stomach wall of a female anopheline mosquito where sporozoite development takes place. When mature, the oocysts rupture and release sporozoites. Sporozoites subsequently migrate to salivary glands to be injected into the host when mosquitoes feed. ookinete. the fertilized form of the malaria parasite in the mosquito’s body. outbreeding. increasing in numbers faster than a competing population. parasitemia. condition in which parasites are present in the blood with or without clinical symptoms.
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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance paroxysm. a sudden attack or increase in intensity of a symptom, usually occurring in intervals. Malaria is classically described as producing fever paroxysms—sudden severe temperature elevations preceded by chills and followed by profuse sweating. perennial transmission. year-round (as opposed to seasonal) transmission. peripartum. occurring before, during or following birth. pharmacodynamics. a branch of pharmacology dealing with the reactions between drugs and living systems. pharmacokinetics. the interactions of drugs with people who take them—how the compounds are absorbed, metabolized, distributed and excreted. phenotype. the visible properties of an organism that are produced by the interaction of the genotype (genetic make-up) and the environment. Plasmodium. the genus of protozoans that includes all of the malaria parasites affecting humans and other animals; any individual malaria parasite. point mutation. a gene mutation specifically involving the substitution, addition, or deletion of a single nucleotide base. polymerase chain reaction (PCR). A method of amplifying low levels of specific DNA sequences, allowing detection of very low levels of antigen in the sample. polymorphism. the existence of a gene in several allelic forms. polypharmacy. prescribing of multiple drugs. premunition. imperfect immunity. presumptive treatment. administration of anti-malarial drugs in suspected cases before results of laboratory tests are available to confirm diagnosis. prevalence. the proportion of a population that is affected with a particular disease at a given time. primigravidae. women who are pregnant for the first time. prophylaxis. measures designed to prevent disease and preserve health: protective or preventive treatment. protozoan. a single-celled animal. public goods. Things that are either consumed by everybody in a society or by nobody at all. They have three characteristics. Public goods are: 1) non-rival—one person consuming them does not stop another person consuming them; 2) nonexcludable—if one person can consume them, it is impossible to stop another person consuming them; and 3) non-rejectable—people cannot choose not to consume them even if they want to. Examples include clean air, a national defense system, and the judiciary. Global public goods cannot be provided by one country acting alone, but only by the joint efforts of many (strictly, all) countries. The univer-
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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance sal use of combination drug treatment (as opposed to monotherapy) for malaria would reduce the likelihood that resistant plasmodia will develop, and would benefit all. pulmonary edema. abnormal accumulation of fluid in the lungs. pyrethrin. either of two oily liquid esters—C21H28O3 and C22H28O5—extracted from dried chrysanthemum flowers (the oldest effective insecticide known) that have insecticidal properties and are the active components of pyrethrum. pyrethroids. any of various synthetic compounds that are related to the pyrethrins and resemble them in insecticidal properties. quartan malaria. malaria caused by Plasmodium malariae and marked by recurrence of bouts of chills and fever at 72-hour intervals. rapid diagnostic test (RDT). a rapid, convenient and/or inexpensive method of determining whether a patient has a certain disease. RBC. red blood cell. reagent. a substance used to detect, measure or synthesize a product because of its chemical or biological activity; a reactor. recombinant vaccine. a vaccine prepared by recombinant DNA technology in which a host organism (expression vector) is directed to synthesize specific molecules after DNA segments from another organism (such as the malaria parasite) are inserted. In this manner, vaccines that are directed against specific antigens on or within the parasites can be made. recrudescence. a repeated attack of malaria due to the survival of malaria parasites in red blood cells. relapse. a repeat attack of malaria specific to P. vivax and P. ovale, in which the repeat attack represents re-seeding of the bloodstream by latent hypnozoites in the liver. reticular. of, relating to, or forming a network. reticulocyte. an immature red blood cell that appears especially during regeneration of lost blood and that has a fine basophilic reticulum formed of the remains of ribosomes. P. vivax exclusively parasitizes reticulocytes. rigor. severe chill, characterized by shaking of the body. schizont. a multinucleate parasite that represents a mature stage of the asexual malaria parasite. schizogony. the asexual cycle of sporozoa, particularly the life cycle of the malaria parasite in the red blood cells of man. sensitivity. the property of a test or case definition defined by the degree to
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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance which it correctly identifies those having the disease or condition of interest. specificity. the property of a test or case definition defined by the degree to which it correctly identifies those not having the disease or condition of interest. splenomegaly. an enlarged spleen. A common finding in malaria patients that can sometimes be detected by physical examination of the abdomen. sporogony. the portion of the sexual reproduction of the malaria parasite that takes place in the mosquito. sporozoite. stage of malaria parasites injected into the bloodstream by biting infective mosquitoes. Sporozoites infect liver cells, disappearing from the bloodstream within 30 minutes of entry. sterile insect technique (SIT). the mass release of sterile male insects to displace the normal male population, thus reducing the number of females who reproduce. Radiation is most often used to sterilize male insects, but genetic techniques have also been developed. SIT has not yet played a role in malaria control, but research is ongoing. tachycardia. increased heart rate, greater than 100 beats per minute. tachypnea. increased respiratory rate, greater than 20 breaths per minute. teratogenic. capable of causing structural abnormalites (i.e., birth defects) during fetal development. tertian malaria. malaria caused by Plasmodium vivax or Plasmodium ovale, marked by recurrence of bouts of chills and fever at 48-hour intervals. thrombocytopenia. low platelet count, defined as less than 150,000 per mL. Low platelet counts can lead to impaired blood clotting, and counts below 50,000 per mL increase the risk of spontaneous bleeding. tiered pricing. a mechanism for segmenting the global market, used in the case of medicines, so that poor countries pay lower prices than richer ones; also called equitable, or differential, pricing. trophozoite. the asexual growing stage of the malaria parasite in the human red blood cell, leading to the mature schizont. vector. an agent that transmits disease from one host to another, e.g., the mosquito that transmits the malaria parasite. vivax malaria. malaria caused by the malaria parasite Plasmodium vivax. wild type [genes]. phenotype, genotype, or gene that predominates in a natural population of organisms or strain of organisms in contrast to that of natural or laboratory mutant forms; also an organism or strain displaying the wild type.
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Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance zoophilic/zoophagic. preferring lower animals to humans as a source of food. zooprophylaxis. the diversion of disease carrying insects from humans to animals.
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