Severe acute respiratory syndrome

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome

Severe acute respiratory syndrome (SARS)
Electron micrograph of SARS coronavirus virion
Pronunciation	SARS /sɑːrz/
Specialty	Infectious disease
Symptoms	Fever, dry cough, headache, muscle aches and difficulty breathing
Complications	Acute Respiratory Distress Syndrome (ARDS) with other comorbidities that eventually leads to death
Prevention	Hand washing, cough etiquette, avoiding close contact with affected people, avoiding travel to affected areas
Prognosis	9.5% chance of death (all countries)
Frequency	8,098 cases
Deaths	774

Severe acute respiratory syndrome (SARS) is a viral respiratory disease of zoonotic origin that surfaced in the early 2000s caused by severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-1), the first-identified strain of the SARS coronavirus species severe acute respiratory syndrome-related coronavirus (SARSr-CoV). The syndrome caused 2002–2004 SARS outbreak. In late 2017, Chinese scientists traced the virus through the intermediary of civets to cave-dwelling horseshoe bats in Yunnan province. No cases of the first SARS-CoV have been reported worldwide since 2004.

In 2019, a related virus strain, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was discovered. This new strain causes COVID-19, a disease which brought about the ongoing 2019–20 coronavirus pandemic.

Signs and symptoms

Symptoms are flu-like symptoms and may include fever, muscle pain, lethargy, cough, sore throat, and other nonspecific symptoms. The only symptom common to all patients appears to be a fever above 38 °C (100 °F). SARS may eventually lead to shortness of breath and pneumonia; either direct viral pneumonia or secondary bacterial pneumonia.

The average incubation period for SARS is 4–6 days, although rarely it could be as short as 1 day or as long as 14 days.

Transmission

The primary route of transmission for SARS-CoV is contact of the mucous membranes with respiratory droplets or fomites. While diarrhea is common in people with SARS, the fecal–oral route does not appear to be a common mode of transmission. The basic reproduction number of SARS-CoV, R₀, ranges from 2 to 4 depending on different analyses. Control measures introduced in April 2003 reduced the R to 0.4.

Diagnosis

A chest X-ray showing increased opacity in both lungs, indicative of pneumonia, in a patient with SARS

SARS-CoV may be suspected in a patient who has:

• Any of the symptoms, including a fever of 38 °C (100 °F) or higher, and
• Either a history of:
  • Contact (sexual or casual) with someone with a diagnosis of SARS within the last 10 days or
  • Travel to any of the regions identified by the World Health Organization (WHO) as areas with recent local transmission of SARS.

For a case to be considered probable, a chest X-ray must be positive for atypical pneumonia or respiratory distress syndrome.

The WHO has added the category of "laboratory confirmed SARS" for patients who would otherwise be considered "probable" but who have not yet had a positive chest X-ray changes, but have tested positive for SARS based on one of the approved tests (ELISA, immunofluorescence or PCR).

The appearance of SARS-CoV in chest X-rays is not always uniform but generally appears as an abnormality with patchy infiltrates.

Prevention

There is no vaccine for SARS, although doctor Anthony Fauci mentioned that the CDC developed one and placed it in the US national stockpile. Clinical isolation and quarantine remain the most effective means to prevent the spread of SARS. Other preventive measures include:

• Hand-washing with soap and water, or use of alcohol-based hand sanitizer
• Disinfection of surfaces of fomites to remove viruses
• Avoiding contact with bodily fluids
• Washing the personal items of someone with SARS in hot, soapy water (eating utensils, dishes, bedding, etc.)
• Keeping children with symptoms home from school
• Simple hygiene measures
• Isolating oneself as much as possible to minimize the chances of transmission of the virus

Many public health interventions were made to try to control the spread of the disease, which is mainly spread through respiratory droplets in the air. These interventions included earlier detection of the disease; isolation of people who are infected; droplet and contact precautions; and the use of personal protective equipment (PPE), including masks and isolation gowns. Studies done during the outbreak found that for medical professionals, wearing any type of mask compared to none could reduce the chances of getting sick by about 80%. A screening process was also put in place at airports to monitor air travel to and from affected countries.

SARS-CoV is most infectious in severely ill patients, which usually occurs during the second week of illness. This delayed infectious period meant that quarantine was highly effective; people who were isolated before day five of their illness rarely transmitted the disease to others.

Although no cases have been identified since 2004, the CDC was still working to make federal and local rapid response guidelines and recommendations in the event of a reappearance of the virus as of 2017.

Treatment

Award to the staff of the Hôpital Français de Hanoï for their dedication during the SARS crisis

As SARS is a viral disease, antibiotics do not have direct effect but may be used against bacterial secondary infection. Treatment of SARS is mainly supportive with antipyretics, supplemental oxygen and mechanical ventilation as needed. Antiviral medications are used as well as high doses of steroids to reduce swelling in the lungs.

People with SARS-CoV must be isolated, preferably in negative-pressure rooms, with complete barrier nursing precautions taken for any necessary contact with these patients, to limit the chances of medical personnel getting infected with SARS. In certain cases, natural ventilation by opening doors and windows are documented to help decreasing indoor concentration of virus particles.

Some of the more serious damage caused by SARS may be due to the body's own immune system reacting in what is known as cytokine storm.

As of 2020, there is no cure or protective vaccine for SARS that has been shown to be both safe and effective in humans. According to research papers published in 2005 and 2006, the identification and development of novel vaccines and medicines to treat SARS is a priority for governments and public health agencies around the world. In early 2004, an early clinical trial on volunteers was planned.

Prognosis

Several consequent reports from China on some recovered SARS patients showed severe long-time sequelae. The most typical diseases include, among other things, pulmonary fibrosis, osteoporosis, and femoral necrosis, which have led in some cases to the complete loss of working ability or even self-care ability of people who have recovered from SARS. As a result of quarantine procedures, some of the post-SARS patients have been documented as suffering from post-traumatic stress disorder (PTSD) and major depressive disorder.

Epidemiology

SARS was a relatively rare disease; at the end of the epidemic in June 2003, the incidence was 8,422 cases with a case fatality rate (CFR) of 11%.

The case fatality rate (CFR) ranges from 0% to 50% depending on the age group of the patient. Patients under 24 were least likely to die (less than 1%); those 65 and older were most likely to die (over 55%).

As with MERS and COVID-19, SARS resulted in significantly more deaths of males than females.

2003 Probable cases of SARS – worldwide

 

Probable cases of SARS by country or region,
1 November 2002 – 31 July 2003

Country or region	Cases	Deaths	Fatality (%)
China	5,327	349	6.6
Hong Kong	1,755	299	17.0
Taiwan	346	73	21.1
Canada	251	43	17.1
Singapore	238	33	13.9
Vietnam	63	5	7.9
United States	27	0	0
Philippines	14	2	14.3
Thailand	9	2	22.2
Germany	9	0	0
Mongolia	9	0	0
France	7	1	14.3
Australia	6	0	0
Malaysia	5	2	40.0
Sweden	5	0	0
United Kingdom	4	0	0
Italy	4	0	0
India	3	0	0
South Korea	3	0	0
Indonesia	2	0	0
South Africa	1	1	100.0
Kuwait	1	0	0
Ireland	1	0	0
Macau	1	0	0
New Zealand	1	0	0
Romania	1	0	0
Russia	1	0	0
Spain	1	0	0
Switzerland	1	0	0
Total excluding China	2,769	454	16.4
Total (29 territories)	8,096	774	9.6

Figures for China exclude Hong Kong and Macau, which are reported separately by the WHO.

After 11 July 2003, 325 Taiwanese cases were 'discarded'. Laboratory information was insufficient or incomplete for 135 of the discarded cases; 101 of these patients died.

Outbreak in South China

The viral outbreak can be genetically traced to a colony of cave-dwelling horseshoe bats in China's Yunnan province.

The SARS epidemic appears to have started in Guangdong Province, China, in November 2002 where the first case was reported that same month. The patient, a farmer from Shunde, Foshan, Guangdong, was treated in the First People's Hospital of Foshan. The patient died soon after, and no definite diagnosis was made on his cause of death. Despite taking some action to control it, Chinese government officials did not inform the World Health Organization of the outbreak until February 2003. This lack of openness caused delays in efforts to control the epidemic, resulting in criticism of the People's Republic of China from the international community. China officially apologized for early slowness in dealing with the SARS epidemic.

The outbreak first appeared on 27 November 2002, when Canada's Global Public Health Intelligence Network (GPHIN), an electronic warning system that is part of the World Health Organization's Global Outbreak Alert and Response Network (GOARN), picked up reports of a "flu outbreak" in China through Internet media monitoring and analysis and sent them to the WHO. While GPHIN's capability had recently been upgraded to enable Arabic, Chinese, English, French, Russian, and Spanish translation, the system was limited to English or French in presenting this information. Thus, while the first reports of an unusual outbreak were in Chinese, an English report was not generated until 21 January 2003. The first super-spreader was admitted to the Sun Yat-sen Memorial Hospital in Guangzhou on 31 January, which soon spread the disease to nearby hospitals.

Subsequent to this, the WHO requested information from Chinese authorities on 5 and 11 December. Despite the successes of the network in previous outbreaks of diseases, it did not receive intelligence until the media reports from China several months after the outbreak of SARS. Along with the second alert, WHO released the name, definition, as well as an activation of a coordinated global outbreak response network that brought sensitive attention and containment procedures. By the time the WHO took action, over 500 deaths and an additional 2,000 cases had already occurred worldwide.

In early April 2003, after Jiang Yanyong pushed to report the danger to China, there appeared to be a change in official policy when SARS began to receive a much greater prominence in the official media. Some have directly attributed this to the death of American James Earl Salisbury. It was around this same time that Jiang Yanyong made accusations regarding the undercounting of cases in Beijing military hospitals. After intense pressure, Chinese officials allowed international officials to investigate the situation there. This revealed problems plaguing the aging mainland Chinese healthcare system, including increasing decentralization, red tape, and inadequate communication.

Many healthcare workers in the affected nations risked and lost their lives by treating patients, and trying to contain the infection before ways to prevent infection were known.

Spread to other regions

The epidemic reached the public spotlight in February 2003, when an American businessman traveling from China, Johnny Chen, became afflicted with pneumonia-like symptoms while on a flight to Singapore. The plane stopped in Hanoi, Vietnam, where the victim died in Hanoi French Hospital. Several of the medical staff who treated him soon developed the same disease despite basic hospital procedures. Italian doctor Carlo Urbani identified the threat and communicated it to WHO and the Vietnamese government; he later succumbed to the disease.

The severity of the symptoms and the infection among hospital staff alarmed global health authorities, who were fearful of another emergent pneumonia epidemic. On 12 March 2003, the WHO issued a global alert, followed by a health alert by the United States Centers for Disease Control and Prevention (CDC). Local transmission of SARS took place in Toronto, Ottawa, San Francisco, Ulaanbaatar, Manila, Singapore, Taiwan, Hanoi and Hong Kong whereas within China it spread to Guangdong, Jilin, Hebei, Hubei, Shaanxi, Jiangsu, Shanxi, Tianjin, and Inner Mongolia.

Hong Kong

9th-floor layout of the Hotel Metropole in Hong Kong, showing where a super-spreading event of severe acute respiratory syndrome (SARS) occurred

 

The disease spread in Hong Kong from Liu Jianlun, a Guangdong doctor who was treating patients at Sun Yat-Sen Memorial Hospital. He arrived in February and stayed on the ninth floor of the Metropole Hotel in Kowloon, infecting 16 of the hotel visitors. Those visitors traveled to Canada, Singapore, Taiwan, and Vietnam, spreading SARS to those locations.

Another larger cluster of cases in Hong Kong centred on the Amoy Gardens housing estate. Its spread is suspected to have been facilitated by defects in its bathroom drainage system that allowed sewer gases including virus particles to vent into the room. Bathroom fans exhausted the gases and wind carried the contagion to adjacent downwind complexes. Concerned citizens in Hong Kong worried that information was not reaching people quickly enough and created a website called sosick.org, which eventually forced the Hong Kong government to provide information related to SARS in a timely manner. The first cohort of affected people were discharged from hospital on 29 March 2003.

Toronto

The first case of SARS in Toronto was identified on 23 February 2003. Beginning with an elderly woman, Kwan Sui-Chu, returning from a trip to Hong Kong; the virus killed her on 5 March and eventually infected 257 individuals in the province of Ontario. The trajectory of this outbreak is typically divided into two phases, the first centring around her son Tse Chi Kwai, who infected other patients at the Scarborough Grace Hospital and died on 13 March. The second major wave of cases was clustered around accidental exposure among patients, visitors, and staff within the North York General Hospital. The WHO officially removed Toronto from its list of infected areas by the end of June 2003.

The official response by the Ontario provincial government and Canadian federal government has been widely criticized in the years following the outbreak. Brian Schwartz, vice-chair of Ontario's SARS Scientific Advisory Committee, described public health officials' preparedness and emergency response at the time of the outbreak as "very, very basic and minimal at best". Critics of the response often cite poorly outlined and enforced protocol for protecting healthcare workers and identifying infected patients as a major contributing factor to the continued spread of the virus. The atmosphere of fear and uncertainty surrounding the outbreak resulted in staffing issues in area hospitals when healthcare workers elected to resign rather than risk exposure to SARS.

Identification of virus

In late February 2003, Italian doctor Carlo Urbani was called into The French Hospital of Hanoi to look at Johnny Chen, an American businessman who had fallen ill with what doctors thought was a bad case of influenza. Urbani realized that Chen's ailment was probably a new and highly contagious disease. He immediately notified the WHO. He also persuaded the Vietnamese Health Ministry to begin isolating patients and screening travelers, thus slowing the early pace of the epidemic. He subsequently contracted the disease himself, and died in March 2003.

The CDC and Canada's National Microbiology Laboratory identified the SARS genome in April 2003. Scientists at Erasmus University in Rotterdam, the Netherlands demonstrated that the SARS coronavirus fulfilled Koch's postulates thereby confirming it as the causative agent. In the experiments, macaques infected with the virus developed the same symptoms as human SARS victims.

In late May 2003, studies were conducted using samples of wild animals sold as food in the local market in Guangdong, China. The results found that the SARS coronavirus could be isolated from masked palm civets (Paguma sp.), even if the animals did not show clinical signs of the virus. The preliminary conclusion was the SARS virus crossed the xenographic barrier from asian palm civet to humans, and more than 10,000 masked palm civets were killed in Guangdong Province. The virus was also later found in raccoon dogs (Nyctereuteus sp.), ferret badgers (Melogale spp.), and domestic cats. In 2005, two studies identified a number of SARS-like coronaviruses in Chinese bats.

Phylogenetic analysis of these viruses indicated a high probability that SARS coronavirus originated in bats and spread to humans either directly or through animals held in Chinese markets. The bats did not show any visible signs of disease but are the likely natural reservoirs of SARS-like coronaviruses. In late 2006, scientists from the Chinese Centre for Disease Control and Prevention of Hong Kong University and the Guangzhou Centre for Disease Control and Prevention established a genetic link between the SARS coronavirus appearing in civets and humans, bearing out claims that the disease had jumped across species.

In December 2017, "after years of searching across China, where the disease first emerged, researchers reported ... that they had found a remote cave in Yunnan province, which is home to horseshoe bats that carry a strain of a particular virus known as a coronavirus. This strain has all the genetic building blocks of the type that triggered the global outbreak of SARS in 2002." The research was performed by Shi Zheng-Li, Cui Jie and coworkers at the Wuhan Institute of Virology, China, and published in PLOS Pathogens. The authors are quoted as stating that "another deadly outbreak of SARS could emerge at any time. As they point out, the cave where they discovered their strain is only a kilometre from the nearest village."

Date of containment

The World Health Organization declared severe acute respiratory syndrome contained on 5 July 2003. In the following years, four SARS cases were reported in China between December 2003 and January 2004. There were also three separate laboratory accidents that resulted in infection. In one of these cases, an ill lab worker spread the virus to several other people. Study of live SARS specimens requires a biosafety level 3 (BSL-3) facility; some studies of inactivated SARS specimens can be done at biosafety level 2 facilities.

Animals

A small number of cats and dogs tested positive for the virus during the outbreak. However, these animals did not transmit the virus to other animals of the same species or to humans.

Society and culture

Fear of contracting the virus from consuming infected wild animals resulted in public bans and reduced business for meat markets in southern China and Hong Kong.

Chloroquine

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Chloroquine

Chloroquine

Clinical data
Pronunciation	/ˈklɔːrəkwiːn/
Trade names	Aralen, other
Other names	Chloroquine phosphate
AHFS/Drugs.com	Monograph
License data	US DailyMed: Chloroquine US FDA: Chloroquine
ATC code	P01BA01 (WHO)
Legal status
Legal status	UK: P (Pharmacy medicines) US: ℞-only
Pharmacokinetic data
Metabolism	Liver
Elimination half-life	1-2 months
Identifiers
IUPAC name[show]
CAS Number	54-05-7
PubChem CID	2719
IUPHAR/BPS	5535
DrugBank	DB00608
ChemSpider	2618
UNII	886U3H6UFF
KEGG	D02366
ChEBI	CHEBI:3638
ChEMBL	ChEMBL76
NIAID ChemDB	000733
CompTox Dashboard (EPA)	DTXSID2040446
ECHA InfoCard	100.000.175
Chemical and physical data
Formula	C18H26ClN3
Molar mass	319.872 g·mol−1
3D model (JSmol)	Interactive image
SMILES[show]
InChI[show]
(verify)

Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medication. Chloroquine is also occasionally used for amebiasis that is occurring outside the intestines, rheumatoid arthritis, and lupus erythematosus. While it has not been formally studied in pregnancy, it appears safe. It is also being studied to treat COVID-19 as of 2020. It is taken by mouth.

Common side effects include muscle problems, loss of appetite, diarrhea, and skin rash. Serious side effects include problems with vision, muscle damage, seizures, and low blood cell levels. Chloroquine is a member of the drug class 4-aminoquinoline. As an antimalarial, it works against the asexual form of the malaria parasite in the stage of its life cycle within the red blood cell. How it works in rheumatoid arthritis and lupus erythematosus is unclear.

Chloroquine was discovered in 1934 by Hans Andersag. It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system. It is available as a generic medication. The wholesale cost in the developing world is about US$0.04. In the United States, it costs about US$5.30 per dose.

Medical uses

Malaria

Distribution of malaria in the world:
♦ Elevated occurrence of chloroquine- or multi-resistant malaria
♦ Occurrence of chloroquine-resistant malaria
♦ No Plasmodium falciparum or chloroquine-resistance
♦ No malaria

Chloroquine has been used in the treatment and prevention of malaria from Plasmodium vivax, P. ovale, and P. malariae. It is generally not used for Plasmodium falciparum as there is widespread resistance to it.

Chloroquine has been extensively used in mass drug administrations, which may have contributed to the emergence and spread of resistance. It is recommended to check if chloroquine is still effective in the region prior to using it. In areas where resistance is present, other antimalarials, such as mefloquine or atovaquone, may be used instead. The Centers for Disease Control and Prevention recommend against treatment of malaria with chloroquine alone due to more effective combinations.

Amebiasis

In treatment of amoebic liver abscess, chloroquine may be used instead of or in addition to other medications in the event of failure of improvement with metronidazole or another nitroimidazole within 5 days or intolerance to metronidazole or a nitroimidazole.

Rheumatic disease

As it mildly suppresses the immune system, chloroquine is used in some autoimmune disorders, such as rheumatoid arthritis and lupus erythematosus.

Side effects

Side effects include blurred vision, nausea, vomiting, abdominal cramps, headache, diarrhea, swelling legs/ankles, shortness of breath, pale lips/nails/skin, muscle weakness, easy bruising/bleeding, hearing and mental problems.

• Unwanted/uncontrolled movements (including tongue and face twitching) 
• Deafness or tinnitus
• Nausea, vomiting, diarrhea, abdominal cramps
• Headache
• Mental/mood changes (such as confusion, personality changes, unusual thoughts/behavior, depression, feeling being watched, hallucinating)
• Signs of serious infection (such as high fever, severe chills, persistent sore throat)
• Skin itchiness, skin color changes, hair loss, and skin rashes
  • Chloroquine-induced itching is very common among black Africans (70%), but much less common in other races. It increases with age, and is so severe as to stop compliance with drug therapy. It is increased during malaria fever; its severity is correlated to the malaria parasite load in blood. Some evidence indicates it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally
• Unpleasant metallic taste
  • This could be avoided by "taste-masked and controlled release" formulations such as multiple emulsions
• Chloroquine retinopathy
• Electrocardiographic changes
  • This manifests itself as either conduction disturbances (bundle-branch block, atrioventricular block) or Cardiomyopathy – often with hypertrophy, restrictive physiology, and congestive heart failure. The changes may be irreversible. Only two cases have been reported requiring heart transplantation, suggesting this particular risk is very low. Electron microscopy of cardiac biopsies show pathognomonic cytoplasmic inclusion bodies.
• Pancytopenia, aplastic anemia, reversible agranulocytosis, low blood platelets, neutropenia

Pregnancy

Chloroquine has not been shown to have any harmful effects on the fetus when used in the recommended doses for malarial prophylaxis. Small amounts of chloroquine are excreted in the breast milk of lactating women. However, this drug can be safely prescribed to infants, the effects are not harmful. Studies with mice show that radioactively tagged chloroquine passed through the placenta rapidly and accumulated in the fetal eyes which remained present five months after the drug was cleared from the rest of the body. Women who are pregnant or planning on getting pregnant are still advised against traveling to malaria-risk regions.

Elderly

There is not enough evidence to determine whether chloroquine is safe to be given to people aged 65 and older. Since it is cleared by the kidneys, toxicity should be monitored carefully in people with poor kidney functions.

Drug interactions

Chloroquine has a number of drug–drug interactions that might be of clinical concern:

• Ampicillin- levels may be reduced by chloroquine;
• Antacids- may reduce absorption of chloroquine;
• Cimetidine- may inhibit metabolism of chloroquine; increasing levels of chloroquine in the body;
• Cyclosporine- levels may be increased by chloroquine; and
• Mefloquine- may increase risk of convulsions.

Overdose

Chloroquine, in overdose, has a risk of death of about 20%. It is rapidly absorbed from the gut with an onset of symptoms generally within an hour. Symptoms of overdose may include sleepiness, vision changes, seizures, stopping of breathing, and heart problems such as ventricular fibrillation and low blood pressure. Low blood potassium may also occur.

While the usual dose of chloroquine used in treatment is 10 mg/kg, toxicity begins to occur at 20 mg/kg, and death may occur at 30 mg/kg. In children as little as a single tablet can cause problems.

Treatment recommendations include early mechanical ventilation, cardiac monitoring, and activated charcoal. Intravenous fluids and vasopressors may be required with epinephrine being the vasopressor of choice. Seizures may be treated with benzodiazepines. Intravenous potassium chloride may be required, however this may result in high blood potassium later in the course of the disease. Dialysis has not been found to be useful.

Pharmacology

Chloroquine's absorption of the drug is rapid. It is widely distributed in body tissues. Its protein binding is 55%. Its metabolism is partially hepatic, giving rise to its main metabolite, desethylchloroquine. Its excretion is ≥50% as unchanged drug in urine, where acidification of urine increases its elimination. It has a very high volume of distribution, as it diffuses into the body's adipose tissue.

Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. It and related quinines have been associated with cases of retinal toxicity, particularly when provided at higher doses for longer times. With long-term doses, routine visits to an ophthalmologist are recommended.

Chloroquine is also a lysosomotropic agent, meaning it accumulates preferentially in the lysosomes of cells in the body. The pK_a for the quinoline nitrogen of chloroquine is 8.5, meaning it is about 10% deprotonated at physiological pH (per the Henderson-Hasselbalch equation). This decreases to about 0.2% at a lysosomal pH of 4.6. Because the deprotonated form is more membrane-permeable than the protonated form, a quantitative "trapping" of the compound in lysosomes results.

Mechanism of action

Medical quinolines

Malaria

Hemozoin formation in P. falciparum: many antimalarials are strong inhibitors of hemozoin crystal growth.

 

The lysosomotropic character of chloroquine is believed to account for much of its antimalarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its lysosomotropic properties further allow for its use for in vitro experiments pertaining to intracellular lipid related diseases, autophagy, and apoptosis.

Inside red blood cells, the malarial parasite, which is then in its asexual lifecycle stage, must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasitic cell.

Hemoglobin is composed of a protein unit (digested by the parasite) and a heme unit (not used by the parasite). During this process, the parasite releases the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a nontoxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.

Chloroquine enters the red blood cell by simple diffusion, inhibiting the parasite cell and digestive vacuole. Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form the FP-chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. Parasites that do not form hemozoin are therefore resistant to chloroquine.

Resistance in malaria

Since the first documentation of P. falciparum chloroquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast Asia, and South America. The effectiveness of chloroquine against P. falciparum has declined as resistant strains of the parasite evolved. They effectively neutralize the drug via a mechanism that drains chloroquine away from the digestive vacuole. Chloroquine-resistant cells efflux chloroquine at 40 times the rate of chloroquine-sensitive cells; the related mutations trace back to transmembrane proteins of the digestive vacuole, including sets of critical mutations in the P. falciparum chloroquine resistance transporter (PfCRT) gene. The mutated protein, but not the wild-type transporter, transports chloroquine when expressed in Xenopus oocytes (frog's eggs) and is thought to mediate chloroquine leak from its site of action in the digestive vacuole. Resistant parasites also frequently have mutated products of the ABC transporter P. falciparum multidrug resistance (PfMDR1) gene, although these mutations are thought to be of secondary importance compared to Pfcrt. Verapamil, a Ca²⁺ channel blocker, has been found to restore both the chloroquine concentration ability and sensitivity to this drug. Recently, an altered chloroquine-transporter protein CG2 of the parasite has been related to chloroquine resistance, but other mechanisms of resistance also appear to be involved. Research on the mechanism of chloroquine and how the parasite has acquired chloroquine resistance is still ongoing, as other mechanisms of resistance are likely.

Other agents which have been shown to reverse chloroquine resistance in malaria are chlorpheniramine, gefitinib, imatinib, tariquidar and zosuquidar.

Antiviral

Chloroquine has antiviral effects. It increases late endosomal and lysosomal pH, resulting in impaired release of the virus from the endosome or lysosome – release of the virus requires a low pH. The virus is therefore unable to release its genetic material into the cell and replicate.

Chloroquine also seems to act as a zinc ionophore, that allows extracellular zinc to enter the cell and inhibit viral RNA-dependent RNA polymerase.

Other

Chloroquine inhibits thiamine uptake. It acts specifically on the transporter SLC19A3. 

Against rheumatoid arthritis, it operates by inhibiting lymphocyte proliferation, phospholipase A2, antigen presentation in dendritic cells, release of enzymes from lysosomes, release of reactive oxygen species from macrophages, and production of IL-1.

History

In Peru, the indigenous people extracted the bark of the Cinchona tree (Cinchona officinalis) and used the extract to fight chills and fever in the seventeenth century. In 1633 this herbal medicine was introduced in Europe, where it was given the same use and also began to be used against malaria. The quinoline antimalarial drug quinine was isolated from the extract in 1820, and chloroquine is an analogue of this. 

Chloroquine was discovered in 1934, by Hans Andersag and coworkers at the Bayer laboratories, who named it Resochin. It was ignored for a decade, because it was considered too toxic for human use. Instead, the DAK used the chloroquine analogue 3-methyl-chloroquine, known as Sontochin. After Allied forces arrived in Tunis, Sontochin fell into the hands of Americans, who sent the material back to the United States for analysis, leading to renewed interest in chloroquine. United States government-sponsored clinical trials for antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.

Society and culture

Resochin tablet package

Formulations

Chloroquine comes in tablet form as the phosphate, sulfate, and hydrochloride salts. Chloroquine is usually dispensed as the phosphate.

Names

Brand names include Chloroquine FNA, Resochin, Dawaquin, and Lariago.

Other animals

Chloroquine, in various chemical forms, is used to treat and control surface growth of anemones and algae, and many protozoan infections in aquariums, e.g. the fish parasite Amyloodinium ocellatum.

Research

COVID-19

As of 8 April 2020, there is limited evidence to support the use of chloroquine in treating COVID-19. In January 2020, during the 2019–20 coronavirus pandemic, Chinese medical researchers stated that exploratory research into chloroquine seemed to have "fairly good inhibitory effects" on the SARS-CoV-2 virus. Requests to start clinical testing were submitted. Use, however, is only recommended in the setting of an approved trial or under the details outlined by Monitored Emergency Use of Unregistered Interventions.

Chloroquine has been approved by Chinese, South Korean and Italian health authorities for the experimental treatment of COVID-19. These agencies noted contraindications for people with heart disease or diabetes.

Health experts warned against the misuse of the non-pharmaceutical versions of chloroquine phosphate after a husband and wife consumed a fish tank antiparasitic containing chloroquine phosphate on March 24, with the intention of it being prophylaxis against COVID-19. One of them died and the other was hospitalized. Chloroquine has a relatively narrow therapeutic index and it can be toxic at levels not much higher than those used for treatment—which raises the risk of inadvertent overdose. On 27 March 2020, the US Food and Drug Administration (FDA) issued guidance, "do not use chloroquine phosphate intended for fish as treatment for COVID-19 in humans".

On March 28, 2020 the FDA authorized the use of hydroxychloroquine and chloroquine under an Emergency Use Authorization (EUA). The treatment has not been approved by the FDA. The experimental treatment is authorized only for emergency use for people who are hospitalized but not able to receive treatment in a clinical trial.

On 1 April 2020, the European Medicines Agency (EMA) issued guidance that chloroquine and hydroxychloroquine are only to be used in clinical trials or emergency use programs.

A study of chloroquine in 81 hospitalized people in Brazil was halted. About 40 people with coronavirus got a 600 milligram dose over 10 days. By the sixth day of treatment, 11 of them had died, leading to an immediate end to the high-dose segment of the trial. About 40 other people received a dose of 450 milligrams of chloroquine twice daily for five days.

In anticipation of product shortages, the FDA issued product-specific guidance for chloroquine phosphate and for hydroxychloroquine sulfate for generic drug manufacturers.

Other viruses

Chloroquine had been also proposed as a treatment for SARS, with in vitro tests inhibiting the SARS-CoV virus. In October 2004, a group of researchers at the Rega Institute for Medical Research published a report on chloroquine, stating that chloroquine acts as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro.

Chloroquine was being considered in 2003, in pre-clinical models as a potential agent against chikungunya fever.

Other

The radiosensitizing and chemosensitizing properties of chloroquine are beginning to be exploited in anticancer strategies in humans. In biomedicinal science, chloroquine is used for in vitro experiments to inhibit lysosomal degradation of protein products.

Wireless device radiation and health

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Wireless_device_radiation_and_health 

 

The antennas contained in mobile phones, including smartphones, emit radiofrequency (RF) radiation (non-ionizing "radio waves" such as microwaves); the parts of the head or body nearest to the antenna can absorb this energy and convert it to heat. Since at least the 1990s, scientists have researched whether the now-ubiquitous radiation associated with mobile phone antennas or cell phone towers is affecting human health. Mobile phone networks use various bands of RF frequency, some of which overlap with the microwave range. Other digital wireless systems, such as data communication networks, produce similar radiation.

In response to public concern, the World Health Organization established the International EMF Project in 1996 to assess the scientific evidence of possible health effects of EMF in the frequency range from 0 to 300 GHz. They have stated that although extensive research has been conducted into possible health effects of exposure to many parts of the frequency spectrum, all reviews conducted so far have indicated that, as long as exposures are below the limits recommended in the ICNIRP (1998) EMF guidelines, which cover the full frequency range from 0–300 GHz, such exposures do not produce any known adverse health effect. The WHO states that "A large number of studies have been performed over the last two decades to assess whether mobile phones pose a potential health risk. To date, no adverse health effects have been established as being caused by mobile phone use."

International guidelines on exposure levels to microwave frequency EMFs such as ICNIRP limit the power levels of wireless devices and it is uncommon for wireless devices to exceed the guidelines. These guidelines only take into account thermal effects, as non-thermal effects have not been conclusively demonstrated. The official stance of the British Health Protection Agency (HPA) is that "[T]here is no consistent evidence to date that WiFi and WLANs adversely affect the health of the general population", but also that "... it is a sensible precautionary approach ... to keep the situation under ongoing review ...". In a 2018 statement, the FDA said that "the current safety limits are set to include a 50-fold safety margin from observed effects of Radio-frequency energy exposure".

In 2011, International Agency for Research on Cancer (IARC), an agency of the World Health Organization, classified wireless radiation as Group 2B – possibly carcinogenic. That means that there "could be some risk" of carcinogenicity, so additional research into the long-term, heavy use of wireless devices needs to be conducted.

Exposure

Mobile phones

A mobile phone connects to the telephone network by radio waves exchanged with a local antenna and automated transceiver called a cellular base station (cell site or cell tower). The service area served by each provider is divided into small geographical areas called cells, and all the phones in a cell communicate with that cell's antenna. Both the phone and the tower have radio transmitters which communicate with each other. Since in a cellular network the same radio channels are reused every few cells, cellular networks use low power transmitters to avoid radio waves from one cell spilling over and interfering with a nearby cell using the same frequencies. 

Mobile phones are limited to an equivalent isotropic radiated power (EIRP) output of 3 watts, and the network continuously adjusts the phone transmitter to the lowest power consistent with good signal quality, reducing it to as low as one milliwatt when near the cell tower. Tower channel transmitters usually have an EIRP power output of around 50 watts. Even when it is not being used, unless it is turned off, a mobile phone periodically emits radio signals on its control channel, to keep contact with its cell tower and for functions like handing off the phone to another tower if the user crosses into another cell. When the user is making a call, the phone transmits a signal on a second channel which carries the user's voice. Existing 2G, 3G, and 4G networks use frequencies in the UHF or low microwave bands, 600 MHz to 3.5 GHz. Many household wireless devices such as WiFi networks, garage door openers, and baby monitors use other frequencies in this same frequency range. 

Radio waves decrease rapidly in intensity by the inverse square of distance as they spread out from a transmitting antenna. So the phone transmitter, which is held close to the user's face when talking, is a much greater source of human exposure than the tower transmitter, which is typically at least hundreds of metres away from the user. A user can reduce their exposure by using a headset and keeping the phone itself further away from their body.

Next generation 5G cellular networks, which began deploying in 2019, use higher frequencies in or near the millimetre wave band, 24 to 52 GHz. Millimetre waves are absorbed by atmospheric gases so 5G networks will use smaller cells than previous cellular networks, about the size of a city block. Instead of a cell tower, each cell will use an array of multiple small antennas mounted on existing buildings and utility poles. In general, millimeter waves penetrate less deeply into biological tissue than microwaves, and are mainly absorbed within the first centimeter of the body surface.

Cordless phones

The HPA also says that due to the mobile phone's adaptive power ability, a DECT cordless phone's radiation could actually exceed the radiation of a mobile phone. The HPA explains that while the DECT cordless phone's radiation has an average output power of 10 mW, it is actually in the form of 100 bursts per second of 250 mW, a strength comparable to some mobile phones.

Wireless networking

Most wireless LAN equipment is designed to work within predefined standards. Wireless access points are also often close to people, but the drop off in power over distance is fast, following the inverse-square law. However, wireless laptops are typically used close to people. WiFi had been anecdotally linked to electromagnetic hypersensitivity but research into electromagnetic hypersensitivity has found no systematic evidence supporting claims made by sufferers.

Users of wireless networking devices are typically exposed for much longer periods than for mobile phones and the strength of wireless devices is not significantly less. Whereas a Universal Mobile Telecommunications System (UMTS) phone can range from 21 dBm (125 mW) for Power Class 4 to 33 dBm (2W) for Power class 1, a wireless router can range from a typical 15 dBm (30 mW) strength to 27 dBm (500 mW) on the high end. 

However, wireless routers are typically located significantly farther away from users' heads than a phone the user is handling, resulting in far less exposure overall. The Health Protection Agency (HPA) says that if a person spends one year in a location with a WiFi hot spot, they will receive the same dose of radio waves as if they had made a 20-minute call on a mobile phone.

The HPA's position is that "... radio frequency (RF) exposures from WiFi are likely to be lower than those from mobile phones." It also saw "... no reason why schools and others should not use WiFi equipment." In October 2007, the HPA launched a new "systematic" study into the effects of WiFi networks on behalf of the UK government, in order to calm fears that had appeared in the media in a recent period up to that time". Michael Clark of the HPA says published research on mobile phones and masts does not add up to an indictment of WiFi.

Effects studied

Blood–brain barrier

A 2010 review stated that "The balance of experimental evidence does not support an effect of 'non-thermal' radio frequency fields" on the permeability of the blood-brain barrier, but noted that research on low frequency effects and effects in humans was sparse. A 2012 study of low-frequency radiation on humans found "no evidence for acute effects of short-term mobile phone radiation on cerebral blood flow".

Cancer

There is no strong or consistent evidence that mobile phone use increases the risk of getting brain cancer or other head tumors. The United States National Cancer Institute points out that "Radiofrequency energy, unlike ionizing radiation, does not cause DNA damage that can lead to cancer. Its only consistently observed biological effect in humans is tissue heating. In animal studies, it has not been found to cause cancer or to enhance the cancer-causing effects of known chemical carcinogens." The majority of human studies have failed to find a link between mobile phone use and cancer. In 2011 the IARC, a World Health Organization working group, classified mobile phone use as "possibly carcinogenic to humans". The IARC summed up their conclusion with: "The human epidemiological evidence was mixed. Several small early case–control studies were considered to be largely uninformative. A large cohort study showed no increase in risk of relevant tumours, but it lacked information on level of mobile-phone use and there were several potential sources of misclassification of exposure. The bulk of evidence came from reports of the INTERPHONE study, a very large international, multicentre case–control study and a separate large case–control study from Sweden on gliomas and meningiomas of the brain and acoustic neuromas. While affected by selection bias and information bias to varying degrees, these studies showed an association between glioma and acoustic neuroma and mobile-phone use; specifically in people with highest cumulative use of mobile phones, in people who had used mobile phones on the same side of the head as that on which their tumour developed, and in people whose tumour was in the temporal lobe of the brain (the area of the brain that is most exposed to RF radiation when a wireless phone is used at the ear)" The CDC states that no scientific evidence definitively answers whether mobile phone use causes cancer.

In a 2018 statement, the US Food and Drug Administration said that "the current safety limits are set to include a 50-fold safety margin from observed effects of radiofrequency energy exposure".

On 1 November 2018, the US National Toxicology Program published the final version (after peer review that was performed through March 2018) of its "eagerly anticipated" study using rats and mice, conducted over some ten years. This report concludes after the review with an updated statement that "there is clear evidence that male rats exposed to high levels of radio frequency radiation (RFR) like that used in 2G and 3G cell phones developed cancerous heart tumors.... There was also some evidence of tumors in the brain and adrenal gland of exposed male rats. For female rats, and male and female mice, the evidence was equivocal as to whether cancers observed were associated with exposure to RFR".

An early analysis of preliminary results issued by the National Toxicology Program had indicated that due to such issues as the inconsistent appearances of "signals for harm" within and across species and the increased chances of false positives due to the multiplicity of tests, the positive results seen are more likely due to random chance. The full results of the study were released for peer review in February 2018.

Male fertility

A decline in male sperm quality has been observed over several decades. Studies on the impact of mobile radiation on male fertility are conflicting, and the effects of the radio frequency electromagnetic radiation (RF-EMR) emitted by these devices on the reproductive systems are currently under active debate. A 2012 review concluded that "together, the results of these studies have shown that RF-EMR decreases sperm count and motility and increases oxidative stress". A 2017 study of 153 men that attended an academic fertility clinic in Boston, Massachusetts found that self-reported mobile phone use was not related to semen quality, and that carrying a mobile phone in the pants pocket was not related to semen quality.

Electromagnetic hypersensitivity

Some users of mobile phones and similar devices have reported feeling various non-specific symptoms during and after use. Studies have failed to link any of these symptoms to electromagnetic exposure. In addition, EHS is not a recognized medical diagnosis.

Glucose metabolism

According to the National Cancer Institute, two small studies exploring whether and how mobile phone radiation affects brain glucose metabolism showed inconsistent results.

Effects on children

A report from the Australian Government's Radiation Protection and Nuclear Safety Agency (ARPANSA) in June 2017 noted that:

The 2010 WHO Research Agenda identified a lack of sufficient evidence relating to children and this is still the case. ... Given that no long-term prospective study has looked at this issue to date this research need remains a high priority. For cancer in particular only one completed case-control study involving four European countries has investigated mobile phone use among children or adolescents and risk of brain tumour; showing no association between the two (Aydin et al. 2011). ... Given this paucity of information regarding children using mobile phones and cancer ... more epidemiological studies are needed.

Base stations

Cellular Mobile and UHF Antenna Tower with multiple Antennas

Experts consulted by France considered it was mandatory that the main antenna axis should not to be directly in front of a living place at a distance shorter than 100 metres. This recommendation was modified in 2003 to say that antennas located within a 100-metre radius of primary schools or childcare facilities should be better integrated into the city scape and was not included in a 2005 expert report. The Agence française de sécurité sanitaire environnementale as of 2009, says that there is no demonstrated short-term effect of electromagnetic fields on health, but that there are open questions for long-term effects, and that it is easy to reduce exposure via technological improvements. A 2020 study in Environmental Research found that "Although direct causation of negative human health effects from (radio frequency radiation) from cellular phone base stations has not been finalized, there is already enough medical and scientific evidence to warrant long-term liability concerns for companies deploying cellular phone towers" and thus recommended voluntary setbacks from schools and hospitals.

Safety standards and licensing

To protect the population living around base stations and users of mobile handsets, governments and regulatory bodies adopt safety standards, which translate to limits on exposure levels below a certain value. There are many proposed national and international standards, but that of the International Commission on Non-Ionizing Radiation Protection (ICNIRP) is the most respected one, and has been adopted so far by more than 80 countries. For radio stations, ICNIRP proposes two safety levels: one for occupational exposure, another one for the general population. Currently there are efforts underway to harmonize the different standards in existence.

Radio base licensing procedures have been established in the majority of urban spaces regulated either at municipal/county, provincial/state or national level. Mobile telephone service providers are, in many regions, required to obtain construction licenses, provide certification of antenna emission levels and assure compliance to ICNIRP standards and/or to other environmental legislation.

Many governmental bodies also require that competing telecommunication companies try to achieve sharing of towers so as to decrease environmental and cosmetic impact. This issue is an influential factor of rejection of installation of new antennas and towers in communities.

The safety standards in the US are set by the Federal Communications Commission (FCC). The FCC has based its standards primarily on those standards established by the National Council on Radiation Protection and Measurements (NCRP) a Congressionally chartered scientific organization located in the WDC area and the Institute of Electrical and Electronics Engineers (IEEE), specifically Subcommittee 4 of the "International Committee on Electromagnetic Safety".

Switzerland has set safety limits lower than the ICNIRP limits for certain "sensitive areas" (classrooms, for example).

In March 2020, for the first time since 1998, ICNIRP updated radiation requirements for mobile phones using 5G. Admitting that the network is generally safe, the Commission, at the same time, restricted the exposure of the whole body and greater exposure of small parts of the body to frequencies above 6 GHz.

Lawsuits

In the US, personal injury lawsuits have been filed by individuals against manufacturers (including Motorola, NEC, Siemens, and Nokia) on the basis of allegations of causation of brain cancer and death. In US federal courts, expert testimony relating to science must be first evaluated by a judge, in a Daubert hearing, to be relevant and valid before it is admissible as evidence. In a 2002 case against Motorola, the plaintiffs alleged that the use of wireless handheld telephones could cause brain cancer and that the use of Motorola phones caused one plaintiff's cancer. The judge ruled that no sufficiently reliable and relevant scientific evidence in support of either general or specific causation was proffered by the plaintiffs, accepted a motion to exclude the testimony of the plaintiffs' experts, and denied a motion to exclude the testimony of the defendants' experts.

Two separate cases in Italy, in 2009 and 2017, resulted in pensions being awarded to plaintiffs who had claimed their benign brain tumors were the result of prolonged mobile phone use in professional tasks, for 5–6 hours a day, which they ruled different from non-professional use.

Precautions

Precautionary principle

In 2000, the World Health Organization (WHO) recommended that the precautionary principle could be voluntarily adopted in this case. It follows the recommendations of the European Community for environmental risks. 

According to the WHO, the "precautionary principle" is "a risk management policy applied in circumstances with a high degree of scientific uncertainty, reflecting the need to take action for a potentially serious risk without awaiting the results of scientific research." Other less stringent recommended approaches are prudent avoidance principle and as low as reasonably practicable. Although all of these are problematic in application, due to the widespread use and economic importance of wireless telecommunication systems in modern civilization, there is an increased popularity of such measures in the general public, though also evidence that such approaches may increase concern. They involve recommendations such as the minimization of usage, the limitation of use by at-risk population (e.g., children), the adoption of phones and microcells with as low as reasonably practicable levels of radiation, the wider use of hands-free and earphone technologies such as Bluetooth headsets, the adoption of maximal standards of exposure, RF field intensity and distance of base stations antennas from human habitations, and so forth. Overall, public information remains a challenge as various health consequences are evoked in the literature and by the media, putting populations under chronic exposure to potentially worrying information.

Precautionary measures and health advisories

In May 2011, the World Health Organization's International Agency for Research on Cancer announced it was classifying electromagnetic fields from mobile phones and other sources as "possibly carcinogenic to humans" and advised the public to adopt safety measures to reduce exposure, like use of hands-free devices or texting.

Some national radiation advisory authorities, including those of Austria, France, Germany, and Sweden, have recommended measures to minimize exposure to their citizens. Examples of the recommendations are:

• Use hands-free to decrease the radiation to the head.
• Keep the mobile phone away from the body.
• Do not use telephone in a car without an external antenna.

The use of "hands-free" was not recommended by the British Consumers' Association in a statement in November 2000, as they believed that exposure was increased. However, measurements for the (then) UK Department of Trade and Industry and others for the French Agence française de sécurité sanitaire environnementale [fr] showed substantial reductions. In 2005, Professor Lawrie Challis and others said clipping a ferrite bead onto hands-free kits stops the radio waves travelling up the wire and into the head.

Several nations have advised moderate use of mobile phones for children. A journal by Gandhi et al. in 2006 states that children receive higher levels of Specific Absorption Rate (SAR). When 5- and 10-year olds are compared to adults, they receive about 153% higher SAR levels. Also, with the permittivity of the brain decreasing as one gets older and the higher relative volume of the exposed growing brain in children, radiation penetrates far beyond the mid-brain.

5G

In the beginning of the year 2020 Slovenia stopped the deployment of the 5G technology as a precaution due to health concerns.

During the 2019–20 coronavirus pandemic, misinformation circulated claiming that 5G networks contribute to the spread of COVID-19.

Bogus products

Products have been advertised that claim to shield people from EM radiation from mobile phones; in the US the Federal Trade Commission published a warning that "Scam artists follow the headlines to promote products that play off the news – and prey on concerned people."

According to the FTC, "there is no scientific proof that so-called shields significantly reduce exposure from electromagnetic emissions. Products that block only the earpiece – or another small portion of the phone – are totally ineffective because the entire phone emits electromagnetic waves." Such shields "may interfere with the phone's signal, cause it to draw even more power to communicate with the base station, and possibly emit more radiation." The FTC has enforced false advertising claims against companies that sell such products.