What Is Chloroquine Resistance?

Chloroquine has been used clinically since 1944; it was initially used to treat malaria, and its use has gradually expanded since then. In 1951, it was used to treat chloroquine rheumatoid arthritis with certain effects.

Chinese name: Chloroquine
Foreign name: Chloroquine

Molecular formula: C18H26ClN3
Molecular weight: 319.87
CAS no: 54-05-7

Chloroquine compounds

Chinese name: chloroquine

Chinese alias: chloroquinoline phosphate; chloroquinoline phosphate;

English name: chloroquine

English alias: Bemaco; [3H] -Chloroquine; N4- (7-chloroquinolin-4-yl) -N1, N1-diethylpentane-1,4-diamine; sn7618; Chloroquine;

CAS number: 54-05-7

Molecular formula: C ₁₈ H ₂₆ ClN ₃

Molecular weight: 319.87200

Exact mass: 319.18200

PSA: 28.16000

LogP: 4.88360

Physical and chemical properties

Appearance and properties: white powder

Density: 1.111 g / cm ³

Melting point: 87ºC

Boiling point: 460.6ºC at 760 mmHg

Flash point: 232.3ºC

Refractive index: 1.592

Stability: Stability is stable, but light sensitive. Incompatible with strong oxidants.

Security Information

Customs code: 2933499090 ^[1]

production method

It is obtained by condensing 4,7-dichloroquinoline ([86-98-6]) with 2-amino-5-diethylaminopentane ^[1] .

use

It is used to make salt with phosphoric acid to prepare chloroquine phosphate. It is a drug mainly used to control the symptoms of malaria and can also be used as an anti-amoeba drug. It also plays a role in certain autoimmune diseases, such as rheumatoid arthritis, lupus erythematosus, and nephrotic syndrome ^[1] .

Chloroquine Drug Description

Chloroquine

Tablets: Each tablet contains 0.075g of chloroquine phosphate; 0.25g.

Injection: 129 mg (80 mg base) (2 ml); 250 mg (155 mg base) (2 ml) each.

Compound chloroquine phosphate tablets (compound antimalarial tablets) each contain 110mg of chloroquine phosphate (66mg of base) and 8.8mg of primary aminoquinoline phosphate (5mg of base). Take 6 tablets orally once a day for 3 days.

Chloroquine indications

This product and other 4-aminoquinoline antimalarial drugs (such as piperazine, paracetamol, etc.) mainly affect the red stage of the Plasmodium and may interfere with the replication and transcription process of Plasmodium schizont DNA or Hindered its endocytosis, causing the body to die due to a lack of amino acids. This product can effectively control the onset of malaria symptoms. It has no effect on the infrared period and cannot prevent recurrence, but because the effect is longer-lasting, it can delay the recurrence (malignant malaria has no infrared period and can be cured). It is not effective for the primary infrared phase and has no direct effect on gametophyte, so it cannot be used for etiological prevention or to block transmission.

At present, it is clinically found that a considerable part of P. falciparum has developed resistance to this product, which reduces the efficacy of this product. Therefore, in many cases, it is necessary to switch to other antimalarial drugs or combined drugs.

After oral administration, the intestinal absorption is fast and sufficient, and only 8% is excreted through feces. After taking the drug, the blood concentration peaked at 1-2 hours, and t1 / 2 was 48 hours. Can be stored in visceral tissue, can be concentrated in red blood cells, most of the metabolism in the liver, slow excretion, so the effect is long-lasting ^[2] .

Chloroquine dosage

(1) Oral to control the onset of malaria, the first dose is 1g, and the daily dose is 0.5g. If combined with primary aminoquine, only need to take this on the first day

Chloroquine products Product 1g. 16mg / kg for the first time in children (decreased as appropriate in the high fever period, divided into doses), 6-8 hours later and 8mg / kg each on the 2nd to 3rd days. Intramuscular injection, once a day, 2 ~ 3mg / kg each time, intravenous drip: just before use, dilute with 5% glucose injection or 0.9% sodium chloride injection 500ml, and then instill slowly, 2 ~ 3mg each time / kg.

(2) Suppressive prevention of malaria symptoms, taking once a week, 0.5g each time. Children 8mg / kg per week.

(3) Anti-amoebic liver abscesses take 2-3 times a day for 1 or 2 days, 0.5g each time, and 0.5g daily for 2 to 3 weeks.

(4) For the treatment of connective tissue disease for discoid lupus erythematosus and rheumatoid arthritis, the starting dose is 1 to 2 times a day, 0.25 g each time. After 2 to 3 weeks, if the symptoms are controlled, change to 1 day 2 3 times, each amount should not exceed 0.25g, long-term maintenance. For systemic lupus erythematosus, chloroquine can be added to reduce the amount of corticosteroids after the symptoms are treated with corticosteroids.

Chloroquine precautions

(1) After taking the medicine, there may be reactions such as loss of appetite, nausea and vomiting, diarrhea; itching, purpura, hair loss, whitening of the hair, eczema and exfoliative dermatitis, psoriasis; head weight, headache, dizziness, tinnitus, dizziness , Burnout, sleep disturbance, insanity, reduced vision, corneal and retinal degeneration, etc.

(2) Leucopenia is sometimes seen. If it drops below 4000, the drug should be discontinued.

(3) This product does not have the effect of contracting the uterus, but it may cause fetal deafness, hydrocephalus, and limb defects, so pregnant women should not use it.

(4) For a small number of patients, it can cause arrhythmia, and severe cases can cause Alzheimer's syndrome, which is worthy of attention. If not rescued in time, it may cause death.

(5) Long-term use can produce drug resistance (more common in P. falciparum). If the dosage is insufficient, malaria falciparum often re-ignites within 2 to 4 weeks and easily causes drug resistance.

(6) This product has damage to the cornea and retina, so before long-term treatment with this product, a detailed eye examination should be performed to eliminate the original lesions. Patients over 60 years of age should be checked regularly to prevent visual impairment. The long-term maintenance dose is preferably 0.25 g or less per day, and the course of treatment does not exceed 1 year ^[2] .

Chloroquine pharmacological action

After the action of chloroquine, the nucleus of the Plasmodium flakes, vacuoles appear in the cytoplasm, and malarial pigments aggregate into clumps. It is known that chloroquine cannot directly kill Plasmodium, but it can interfere with its reproduction. This product has a strong binding force to nucleoproteins, through the negatively charged 7-chloro group on the quinoline ring and DNA

Plasmodium The proximity of the 2-amino group on guanine caused chloroquine to be inserted between the double strands of the DNA. Chloroquine forms a complex with DNA, preventing DNA replication and RNA transcription. Chloroquine also inhibits the incorporation of phosphate into the Plasmodium's DNA and RNA, which interferes with the reproduction of the Plasmodium due to reduced synthesis of nucleic acids. Experiments using isotopes to label chloroquine have shown that infected red blood cells can cause chloroquine to accumulate in it, and the food vesicles and lysosomes of the protozoa are the concentrated sites.

The amount of chloroquine concentration is related to the pH in the food bubble. The pH in the food is acidic (the optimal pH for decomposing hemoglobin is 4), which can lead to the concentration of the basic drug chloroquine. This concentration of the drug consumes the food bubble. Therefore, the pH value in the food bubble is increased, the hemoglobin digestion of hemoglobin is lost, the hemoglobin ingested by the malaria parasite cannot be digested, resulting in the lack of amino enzymes necessary for the growth and development of the malaria parasite, and causing ribonucleic acid solution. In addition, chloroquine can interfere with the entry of fatty acids into phospholipids and control glutamate dehydrogenase hexokinase. In recent years, some people think that the early effect of chloroquine on Plasmodium is to cause agglutination of malarial pigment. The main component of malarial pigment is iron protoporphyrin tincture (FP), which can damage red blood cells and form a complex with chloroquine to mediate the chemotherapeutic effect of chloroquine. It is speculated that the protozoa has one or more receptors, that is, "FP conjugates", which may be an albumin that can bind to FP to form a non-toxic complex, which protects the protozoan biofilm from damage by FP. The mechanism of action of chloroquine may be to separate the "FP conjugate" from FP and form a toxic chloroquine-FP complex, thereby exerting its antimalarial effect. Due to receptor changes, chloroquine loses its due effect, which may be one of the reasons for the resistance of chloroquine to Plasmodium. Chloroquine mainly acts on erythrozoic schizonts. After 48 to 72 hours, schizonts in blood are killed. This product is not effective for the P. vivax malaria phase, so it cannot be cured. Malaria is curable. Chloroquine has no effect on the pre-red period and has no direct effect on gametophyte, so it cannot be used for the prevention of pathogens and interruption of transmission ^[3-4] .

Chloroquine pharmacokinetics

Chloroquine is quickly and fully absorbed after oral administration, and the highest blood concentration is 1-2 hours after taking the drug. About 55% of the drug binds to plasma components in the blood. The blood drug concentration was maintained for a long time, and T1 / 2 was 2.5 to 10 days. The concentration of chloroquine in red blood cells is 10-20 times that in plasma, and the concentration of chloroquine in red blood cells invaded by Plasmodium is about 25 times higher than normal. Chloroquine binds more to tissue proteins, and its concentration in liver, spleen, kidney, and lung is 200-700 times higher than plasma concentration. The concentration in brain tissue and spinal cord tissue is 10 to 30 times the plasma concentration. The metabolic conversion of chloroquine in the body is carried out in the liver. Its main metabolite is desethylchloroquine, which still has antimalarial effects. A small part (10-15%) of chloroquine is excreted through the kidneys in its original form, and its excretion rate can be accelerated by urine acidification and decreased by alkalization. About 8% is excreted with feces, and chloroquine is also excreted from milk.

Chloroquine indications

For the treatment of falciparum, vivax and malaria. Can also be used for the treatment of parenteral amebiasis, connective tissue disease, light-sensitive diseases (such as sun erythema) and so on. This product is mainly used to treat acute malaria attacks and control malaria symptoms. Can not prevent recurrence, but because the effect is longer, it can delay recurrence. Nor can it be used to prevent and block transmission of malaria. It has a curative effect on falciparum malaria, but in recent years, it has been found that some malaria has resistance to this product and reduces the efficacy. Therefore, it is necessary to switch to other antimalarial drugs or use a combination of drugs. It can also be used to treat liver amoebiasis, clonorchiasis, lung fluke disease, and connective tissue disease. It can also be used to treat photosensitivity disorders, such as erythema erythematosus.

Adverse reactions of chloroquine

1. When this product is used to treat malaria, there are fewer adverse reactions, and the general reactions that may occur are: dizziness, headache, dizziness, loss of appetite, nausea, vomiting, abdominal pain, diarrhea, itching, rash, tinnitus, irritability . Most of the reactions are mild and disappear by themselves after stopping the drug.

2. In the treatment of pulmonary trematodes, clonorchiasis and connective tissue diseases, large doses and long treatment periods may cause severe reactions. The most common is toxic to the eyes, because chloroquine can be secreted by the lacrimal glands and caused by Corneal absorption, diffuse white particles appear on the cornea, and disappear after stopping the drug.

Clonorchiasis sinensis

3. This product can accumulate on the retina, and long-term service can cause mild retinal edema and pigment accumulation, dark spots appear, and affect vision, often irreversible.

4. Chloroquine can also damage hearing. A large number of pregnant women can cause congenital deafness and mental retardation in children.

5. Chloroquine can cause inhibition of the sinoatrial node, leading to arrhythmia, shock, and asthma syndrome can occur in severe cases, leading to death.

6. This product can still cause drug-induced psychosis, leukopenia, purpura, rash, dermatitis, photosensitive dermatitis and even exfoliative dermatitis, psoriasis, whitening of hair, hair loss, neuromuscular pain, etc.

7. Hemolysis, aplastic anemia, reversible agranulocytosis, thrombocytopenia, etc. are relatively rare.

Chloroquine poisoning Can cause gastrointestinal reactions: nausea and vomiting, loss of appetite, bloating, diarrhea. Itching, exfoliative dermatitis, headache, dizziness, tinnitus, drowsiness. Leukopenia, purpura, hair loss. Individual cases of muscle weakness, convulsions, arrhythmias, mental disorders or disorders, depression. Excessive doses cause retinopathy, blindness, convulsions, cardiogenic collapse, cardiac arrest, atrioventricular block, respiratory arrest and even death. Peripheral neuritis, symptoms disappeared after discontinuation. Have spastic cone syndrome in the lower extremities. Extrapyramidal symptoms can be seen in children or young people, manifested by involuntary movements, such as abnormal eye movements, closed teeth, torticollis, and torsional dystonia, which often appear within hours after taking the usual dose. Soft palate mucosa pigmentation (part of the pigmentation around the body) is visible, stomatitis, and sometimes oral buccal mucosal ulcers. Some people have aplastic anemia. Retinopathy is an important adverse reaction. The typical clinical manifestation is "Bull'seye", that is, the foveal retina is intact, surrounded by a depigmented ring, and scattered pigments increase.

Retinopathy

Surrounded by districts. At this time, the retinal blood vessels contract, the surrounding retinal pigment epithelial cells change and the optic nerve atrophy. Macular pigment epithelial cells in the retina can be seen early, and peripheral retinopathy may be the first manifestation. Another sign is unilateral macular edema. Difficulties in reading, dark spots, fear of light, flashes, and reduced visual acuity can also occur. The prognosis of retinopathy caused by chloroquine is severe, which can be improved by stopping the drug early, worsening with continued medication, and progressive vision loss. There were ruptured retinal detachment and bilateral temporal blindness. Long-term medication may cause diplopia and loss of regulation, but it is reversible. Chloroquine and similar drugs can cause corneal lesions because corneal epithelial cells have a high concentration of drug accumulation. Slit-lamp examination revealed diffuse, point-like turbidity in the cornea, sometimes strip-like turbidity in the lower part of the corneal center, and thick yellow-green lines on the stroma. After stopping treatment, corneal lesions are often reversible. Ear complications are rare, and tinnitus or neurological deafness can occur at high doses, which are often irreversible, and deafness is apparent only after a few weeks of treatment.

skin

This medicine can cause skin damage and various types of rashes. It is sensitive to sunlight and photoallergic dermatitis. This drug can induce transient peritonal reactions in patients with delayed-onset skin porphyria with elevated porphyrinuria and elevated AST. Rarely, soft palate, blue and black pigmentation with retinopathy on the skin of the face and anterior tibia, brown nail beds with blue-gray stripes, dark gray pigmentation on the shoulders, neck, and around the eyes. Sometimes, skin discoloration, hair, eyebrows, and eyebrows fall off, erythema of the oral mucosa with blisters and ulcers.

Chloroquine contraindications

1. Patients with liver and kidney dysfunction, heart disease, severe polyerythema, hematoporphyria, psoriasis and psychosis should be used with caution.

2. This product can cause fetal hydrocephalus, limb deformities and deafness, so pregnant women are prohibited. Teratogenicity can be used in early pregnancy, pregnant women should avoid it. Because chloroquine and similar drugs accumulate in the liver, those with liver disease should be careful when using it. This medicine is particularly dangerous for patients with porphyria. The risk of hemolysis is extremely high in patients lacking glucose 6-phosphate dehydrogenase. Children are particularly sensitive to the toxicity of this medicine. This medicine can aggravate the onset of psoriasis or promote recurrence in those with a history of psoriasis.

Chloroquine drug interactions

This product is used together with Baotai Song, which can easily cause allergic dermatitis;

Combined with chlorpromazine, it is easy to aggravate liver damage;

Penicillamine

This product has a direct inhibitory effect on neuromuscular junctions, streptomycin can aggravate this side effect;

Application of this product after digitalis is likely to cause cardiac block;

The combination of this product with heparin or penicillamine can increase the chance of bleeding;

Combining this product with primary aminoquine can cure vivax malaria. The combination of chloroquine, primary aminoquine, and dapsone can prevent hemolytic anemia in patients lacking glucose 6-phosphate dehydrogenase.

1. When combined with primaquine, some patients may have serious adverse cardiovascular reactions. If they are taken sequentially, the effects are not reduced and the adverse reactions are reduced.

2. Combined with chlorpromazine and other drugs that have damage to the liver can increase the burden on the liver; combined with Baotaisong, it can easily cause allergic dermatitis; combined with ammonium chloride can accelerate excretion and reduce blood concentration; attention must be paid.

Information about chloroquine

"science" According to an online report in the journal Science, in Malawi, Africa, scientists have recently confirmed that an antimalarial drug, chloroquine, is still effective in antiparasitic treatment. Prior to this, studies have shown that the parasite causing malaria, Plasmodium falciparum, has become resistant to chloroquine because of its resistance to chloroquine.

Researchers recently published an article in the New England Journal of Medicine saying that chloroquine had cured 79 patients in the treatment of 80 uncomplicated malaria cases in Blantyre, the commercial centre of Malawi.

Chloroquine was once a miracle drug against malaria; it has played an important role in eradicating disease in southern Europe and the southern United States due to its cheapness, ease of use, and low side effects. However, people also paid a high price for the widespread application of chloroquine. In the 1970s and 1980s, malaria spread in South America, Asia, and quickly spread throughout Africa, and drug resistance was developed. Soon, people had nothing to do with malaria.

Malawi was one of the first countries to officially change its malaria treatment approach-1993

Hydroxychloroquine sulfate tablets

Deprecated in Malawi. No one thinks that chloroquine will work on malaria any more, but a few years ago, scientists' analysis of the molecular mechanism of malaria drug resistance changed the situation, and in many countries, malaria resistance has disappeared. After conducting drug treatment experiments on adult malaria patients, the drug was found to clear the parasites. The new study was done by MiriamLaufer and Christopher Plowe, experts in malaria research at the University of Maryland School of Medicine in Baltimore and their colleagues. Preliminary drug trials were performed in patients with acute childhood malaria infection who needed the most medication. Experts divided these children with malaria into two groups and treated them with chloroquine and Malawi's main antimalarial drug, weekly sulfamethoxazole. Chloroquine played a role in treating 79 of the 80 children with the disease. It took an average of 2.6 days to remove the parasites in the blood of these children; as a control, weekly sulfamethamine did not treat 71 of the 80 children in the other group (of course, these children He eventually received follow-up treatment and recovered.)

"This does not mean that chloroquine should be resumed in Malawi," Plowe emphasized. "Under the threat of resistance, Malawi is like a very sensitive island surrounded by the sea. If chloroquine is widely used, these parasites Resistance will re-emerge. Malawi should follow world standards and adopt the latest and more effective artemisinin-based combination therapy before these parasites develop resistance. If this cycle can be broken out, chloroquine can The reappearance of glory also inspired researchers to use the same principle to study other drug-resistant plagues and drug development.

"The results have led to another debate-how to apply chloroquine to the African fight against malaria," said Thomas Wellems, a malaria genetics expert at the National Institute of Infectious Diseases and Allergies in Bethesda, Maryland. "The best way is to widely apply the latest combination therapy based on artemisinin at a reasonable price," said Plowe.