According to the World Health Organization, in 2012 there were approximately 207 million cases of malaria that led to 627,000 deaths.2 The overwhelming majority, 90%, of these cases occur in Africa.1 Most of the deaths occur in children. In the United States, most of the cases of malaria are due to international travelers who contracted the disease while visiting an endemic country.2. Resistance occurs through various spontaneous mutations that reduce the sensitivity of the strains to the antimalarial medication.
Most of the mutations that cause resistance affect the erythrocyte stage of the Plasmodium, which affects the metabolism and action of the medication.4 This review will focus on the antimalarial pharmaceuticals available in the United States.
Background
By not finding the parasite in the air, water or wetland soil, Laveran was able to conclude that the parasite must live in the mosquito.6. Six years after the parasite was discovered in the blood of a patient with malaria, Camillo Golgi determined that there were multiple forms of the disease. He was able to link the fever to the rupture of the red blood cell due to the release of adult merozoites that had accumulated in the cell.
In 1899, Grassi, Amico Bignami and Guispeppe Bastianelli demonstrated that the sporogonic (sexual) cycle of the Plasmodium genus occurs in the Anopheles mosquito.
Life cycle of Malaria
This figure shows the life cycle of malaria in the Anopheles mosquito and the human host. In the mosquito, the male gametocytes, or microgametocytes, undergo ablation to form mature male gametes. The exoerythrocyte stage occurs first, as the sporozoites move to the liver of the human host and invade the hepatocytes.3 In the hepatocytes, the.
The merozoites in the dormant phase are called hypnozoites.8 The merozoites leave the hepatocytes and enter the bloodstream.
The Disease
A patient has severe malaria when he or she suffers from organ failure or abnormalities in the blood or metabolism. Severe malaria is associated with cerebral malaria, severe anemia, hemoglobinuria, acute respiratory distress syndrome (ARDS), abnormal blood coagulation, low blood pressure, acute renal failure, hyperparasitemia (more than 5% of erythrocytes are infected with parasites), metabolic acidosis, and hypoglycemia. The incubation period may be prolonged if the patient has received antimalarial drugs for prophylaxis.
Most of the complications and symptoms of malaria in the human host are associated with the erythrocyte stage of Plasmodium.8 Plasmodium destroys the interior of the erythrocyte, which causes debris and toxins to accumulate in the infected red blood cell. When merozoites cause red blood cells to rupture, toxins and waste products enter the bloodstream. Macrophages and other cytokine-producing cells are attracted to waste products, such as hemozoin, and toxins, such as
The resulting symptoms are fever and rigors.12 Moderate to severe tremors, chills, high fever, and profuse sweating occur in cycles. Cerebral malaria occurs when infected erythrocytes block the small vessels leading to the brain. Red blood cells with mature trophozoites adhere to the vascular walls of small blood vessels.
Heterozygotes for sickle genes show a lower number of erythrocytes infected with Plasmodium and a lower incidence of severe malaria complications such as cerebral malaria and severe anemia. However, homozygotes have no protective advantage and are highly susceptible to the lethal effects of malaria.
Blood Schizonticides
The common mechanism of action of this pharmaceutical class is inhibition of Plasmodium heme polymerase activity. Therefore, the activity of chloroquine to inhibit Plasmodium heme polymerase causes an increase in heme concentration in the red blood cell. The alkaline nature of chloroquine is important in the food vacuole because it increases the pH of the vacuole.
The increase in pH inhibits the digestion of amino acids that the parasite obtains from the degradation of the hemoglobin of the host's red blood cells. In fact, the K76T mutation is found in all the resistant strains isolated and not in the susceptible strains isolated in the study conducted by Djimde et al.4, 20 PfCRT, the gene product, is a transporter found in the membrane of the food vacuole that regulates drug flow and pH regulation. Seven other point mutations have been associated with chloroquine-resistant strains of Plasmodium: M74I, N75E, A220S, Q271E, N326S, I356T, and R371I.11 This mutation prevents chloroquine from accumulating in the parasite block in food. the heme polymerase mechanism of the drug.21 The rate of chloroquine expulsion in resistant strains is 30 to 40 times greater than strains that are susceptible to chloroquine.3.
Calcium channel blockers and other drugs allow the parasite's efflux mechanism to reverse P resistance. The destruction of gametocytes prevents further spread of the parasite to other mosquitoes and humans.27. It is taken weekly on the same day of the week in the malaria-endemic country and four weeks after the traveler returns home.
Resistant strains are found in Southeast Asia and the Amazon region of South America.22 Mefloquine resistance has been associated with an increase in the number of copies of the pfmdr-1 gene.4 Figure 4 shows areas of known mefloquine resistance. Now quinine is only used for malaria caused by multiply resistant strains of Plasmodium.25. Plasmodium resistance to quinine has been reported in areas of South America, Southeast Asia, and Bangladesh.29 The first report of resistance was in Brazil about 100 years ago.
Resistance developed in Southeast Asia in the 1980s due to the increased use of quinine.23 As with chloroquine and mefloquine, pfmdr-1 mutations are associated with quinine resistance.4 A known pattern of resistance to quinine sulfate is shown in Figure 5.
Tissue Schizonticides
The mutations are point mutations that occur at five codons: the substitution of alanine or phenylalanine for serine at codon 436, glycine for alanine at codon 437, glutamic acid for lysine at codon 540, glycine for alanine at codon 581, and serine or threonine for alanine. at codon 613. These mutations occur at codon 16 (valine to alanine substitution), codon 51 (isoleucine to asparagine), codon 59 (arginine to cysteine), codon 108 (asparginine to serine), and codon 164 (leucine to isoleucine and threonine ). For doxycycline to be effective, it must be used in combination with other antimalarial drugs.32 The effectiveness of doxycycline as an antimalarial depends on patient adherence.32 Although doxycycline is an antibiotic, it can be used for malaria prophylaxis in travelers. . that visit areas with known strains of P.
For prophylaxis, it is recommended that a person traveling to countries with high malaria endemic rates begin administration at least one day before travel, then one dose for each day the traveler is in the country. The cases occurred as a result of insufficient serum concentration levels of doxycycline, which is most likely due to non-adherence.32. Atovaquone and proguanil hydrochloride are manufactured in combination as Malarone® for the prophylaxis and treatment of acute, uncomplicated malaria caused by P.
For prophylaxis, therapy with atovaquone and proguanil hydrochloride should be started one to two days before travel. Therapy should be taken during the stay in the malaria endemic country and seven days after leaving the endemic country. Common side effects of atovaquone and proguanil hydrochloride are blurred vision, insomnia, dizziness, headache, gastrointestinal upset, and pruritus.18.
Atovaquone selectively inhibits mitochondrial electron transport in the parasite's cytochrome bcl complex, which stops ATP synthesis.4, 34 Proguanil hydrochloride disrupts parasite deoxythymidylate synthesis by inhibiting dihydrofolate reductase inhibitor34. Resistance to atovaquone is caused by a point mutation in the cytochrome-b (cytB) gene.4 However, there is no known resistance to proguanil, which is thought to be the most important component of this combination.23.
Hypnozoitocides
It is suspected that primaquine may work by producing a reactive oxygen species or by interfering with the electron transport of Plasmodium. Primaquine prevents the parasite from converting heme into a non-toxic agent by disrupting the mitochondria. Primaquine's interference with the parasite's mitochondrion inhibits the production of ATP, which the parasite needs to generate the chemicals to detoxify the heme.
Primaquine also eliminates all forms of Plasmodia gametocytes which prevent the spread of malaria by the Anopheles. The resistance is mainly due to lower dosing of primaquine, a shorter duration of treatment and patient non-compliance.37. The resistance due to a lower dose than recommended mainly occurs due to the adverse effects of primaquine at higher doses and/or the incorrect calculation of dose for an individual patient.37 The normal dose given is 15 mg primaquine for 14 days to kill the exoerythrocyte stage of P.
If the duration of primaquine treatment is shorter than recommended, primaquine also becomes ineffective and allows the parasite to develop drug-resistant strategies.37. With the recommended 14-day treatment of primaquine, the patient can stop taking the medicine after the symptoms of the disease disappear, especially if the patient suffers from any adverse effects from the medicine.
Artemisinin
The Centers for Disease Control did not approve arthremether and lumenfantrine as first-line drugs for the treatment of uncomplicated malaria until 2004.
Future Resistance
The patient may be non-adherent due to common side effects associated with antimalarial drugs. One of the common side effects of the drug and a symptom of malaria is vomiting, which can also lower the concentration of the drug in the patient. The pharmacokinetics of drugs may be altered by the activity of drug-metabolizing enzymes.
If the patient is a poor metabolizer of one of these enzymes, the concentration of the active metabolite will be lowered. The CDC defines sub-standard antimalarial pharmaceuticals as "having no active ingredients, they may have less than the required amount of active ingredient, or they may contain ingredients other than what is described on the package label." In poor countries, counterfeit drugs are often found with a lower concentration of the active ingredients. The main cause of resistance is lower concentrations of the active ingredient of the antimalarial pharmaceuticals caused by lack of compliance, vomiting, sub-standard drugs and/or pharmacokinetics.
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