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.

Mobile phone signal

From Wikipedia, the free encyclopedia

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

 

A display of bars on a mobile phone screen

A mobile phone signal (also known as reception and service) is the signal strength (measured in dBm) received by a mobile phone from a cellular network (on the downlink). Depending on various factors, such as proximity to a tower, any obstructions such as buildings or trees, etc. this signal strength will vary. Most mobile devices use a set of bars of increasing height to display the approximate strength of this received signal to the mobile phone user. Traditionally five bars are used.

Generally, a strong mobile phone signal is more likely in an urban area, though these areas can also have some "dead zones", where no reception can be obtained. Cellular signals are designed to be resistant to multipath reception, which is most likely to be caused by the blocking of a direct signal path by large buildings, such as high-rise towers. By contrast, many rural or sparsely inhabited areas lack any signal or have very weak fringe reception; many mobile phone providers are attempting to set up towers in those areas most likely to be occupied by users, such as along major highways. Even some national parks and other popular tourist destinations away from urban areas now have cell phone reception, though location of radio towers within these areas is normally prohibited or strictly regulated, and is often difficult to arrange.

In areas where signal reception would normally be strong, other factors can have an effect on reception or may cause complete failure (see RF interference). From inside a building with thick walls or of mostly metal construction (or with dense rebar in concrete), signal attenuation may prevent a mobile phone from being used. Underground areas, such as tunnels and subway stations, will lack reception unless they are wired for cell signals. There may also be gaps where the service contours of the individual base stations (Cell towers) of the mobile provider (and/or its roaming partners) do not completely overlap.

In addition, the weather may affect the strength of a signal, due to the changes in radio propagation caused by clouds (particularly tall and dense thunderclouds which cause signal reflection), precipitation, and temperature inversions. This phenomenon, which is also common in other VHF radio bands including FM broadcasting, may also cause other anomalies, such as a person in San Diego "roaming" on a Mexican tower from just over the border in Tijuana, or someone in Detroit "roaming" on a Canadian tower located within sight across the Detroit River in Windsor, Ontario.  These events may cause the user to be billed for "international" usage despite being in their own country, though mobile phone companies can program their billing systems to re-rate these as domestic usage when it occurs on a foreign cell site that is known to frequently cause such issues for their customers. 

The volume of network traffic can also cause calls to be blocked or dropped due to a disaster or other mass call event which overloads the number of available radio channels in an area, or the number of telephone circuits connecting to and from the general public switched telephone network.

Dead zones

Areas where mobile phones cannot transmit to a nearby mobile site, base station, or repeater are known as dead zones. In these areas, the mobile phone is said to be in a state of outage. Dead zones are usually areas where mobile phone service is not available because the signal between the handset and mobile site antennas is blocked or severely reduced, usually by hilly terrain, dense foliage, or physical distance. 

A number of factors can create dead zones, which may exist even in locations in which a wireless carrier offers coverage, due to limitations in cellular network architecture (the locations of antennas), limited network density, interference with other mobile sites, and topography. Since cell phones rely on radio waves, which travel through the air and are easily attenuated (particularly at higher frequencies), mobile phones may be unreliable at times. Like other radio transmissions, mobile phone calls can be interrupted by large buildings, terrain, trees, or other objects between the phone and the nearest base. Cellular network providers work continually to improve and upgrade their networks in order to minimize dropped calls, access failures, and dead zones (which they call "coverage holes" or "no-service areas"). For mobile virtual network operators, the network quality depends entirely on the host network for the particular handset in question. Some MVNOs use more than one host, which may even have different technologies (for example, different Tracfone handsets uses either CDMA and 1xRTT on Verizon Wireless, or GSM and UMTS on AT&T Mobility). 

Dead zones can be filled-in with microcells, while picocells can handle even smaller areas without causing interference to the larger network. Personal microcells, such as those for a home, are called femtocells, and generally have the range of a cordless phone, but may not be usable for an MVNO phone. A similar system can be set up to perform inmate call capture, which prevents cellphones smuggled into a prison from being used. These still complete calls to or from pre-authorized users such as prison staff, while not violating laws against jamming. These systems must be carefully designed so as to avoid capturing calls from outside the prison, which would in effect create a dead zone for any passersby outside.

In the event of a disaster causing temporary dead zones, a cell on wheels may be brought in until the local telecom infrastructure can be restored. These portable units are also used where large gatherings are expected, in order to handle the extra load.

Dropped calls

A dropped call is a common term used and expressed by wireless mobile phone call subscribers when a call is abruptly cut-off (disconnected) during midconversation. This happens less often today than it would have in the early 1990s. The termination occurs unexpected and is influenced by a number of different reasons such as "Dead Zones." In technical circles, it is called an abnormal release. 

One reason for a call to be "dropped" is if the mobile phone subscriber travels outside the coverage area—the cellular network radio tower(s). After a telephone connection between two subscribers has been completed, it must remain within range of that subscribers network provider or that connection will lost (dropped). Not all cellular telephone radio towers are owned by the same telephone company (though this is not true to all locations) be maintained across a different company's network (as calls cannot be re-routed over the traditional phone network while in progress), also resulting in the termination of the call once a signal cannot be maintained between the phone and the original network.

Another common reason is when a phone is taken into an area where wireless communication is unavailable, interrupted, interfered with, or jammed. From the network's perspective, this is the same as the mobile moving out of the coverage area. 

Occasionally, calls are dropped upon handoff between cells within the same provider's network. This may be due to an imbalance of traffic between the two cell sites' areas of coverage. If the new cell site is at capacity, it cannot accept the additional traffic of the call trying to "hand in." It may also be due to the network configuration not being set up properly, such that one cell site is not "aware" of the cell to which the phone is trying to handoff. If the phone cannot find an alternative cell to which to move that can take over the call, the call is lost. 

Co-channel and adjacent-channel interference can also be responsible for dropped calls in a wireless network. Neighbouring cells with the same frequencies interfere with each other, deteriorating the quality of service and producing dropped calls. Transmission problems are also a common cause of dropped calls. Another problem may be a faulty transceiver inside the base station.

Calls can also be dropped if a mobile phone at the other end of the call loses battery power and stops transmitting abruptly.

Sunspots and solar flares are rarely blamed for causing interference leading to dropped calls, as it would take a major geomagnetic storm to cause such a disruption (except for satellite phones). 

Experiencing too many dropped calls is one of the most common customer complaints received by wireless service providers. They have attempted to address the complaint in various ways, including expansion of their home network coverage, increased cell capacity, and offering refunds for individual dropped calls. 

Various signal booster systems are manufactured to reduce problems due to dropped calls and dead zones. Many options, such as wireless units and antennas, are intended to aid in strengthening weak signals.

ASU

Arbitrary Strength Unit (ASU) is an integer value proportional to the received signal strength measured by the mobile phone. 

It is possible to calculate the real signal strength measured in dBm (and thereby power in Watts) by a formula. However, there are different formulas for 2G, 3G and 4G networks. 

In GSM networks, ASU maps to RSSI (received signal strength indicator, see TS 27.007 sub clause 8.5).

dBm = 2 × ASU - 113, ASU in the range of 0.31 and 99 (for not known or not detectable).

In UMTS networks, ASU maps to RSCP level (received signal code power, see TS 27.007 sub clause 8.69 and TS 25.133 sub clause 9.1.1.3).

dBm = ASU - 115, ASU in the range of 0.90 and 255 (for not known or not detectable).

In LTE networks, ASU maps to RSRP (reference signal received power, see TS 36.133, sub-clause 9.1.4). The valid range of ASU is from 0 to 97. For the range 1 to 96, ASU maps to

(ASU - 143) < dBm ≤ (ASU - 140).

The value of 0 maps to RSRP below -140 dBm and the value of 97 maps to RSRP above -44 dBm.

On Android devices however, the original GSM formula may prevail for UMTS. Tools like Network Signal Info can directly show the signal strength (in dBm), as well as the underlying ASU. 

ASU shouldn't be confused with "Active Set Update". The Active Set Update is a signalling message used in handover procedures of UMTS and CDMA mobile telephony standards. On Android phones, the acronym ASU has nothing to do with Active Set Update. It has not been declared precisely by Google developers.

The Global Fund to Fight AIDS, Tuberculosis and Malaria

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/The_Global_Fund_to_Fight_AIDS,_Tuberculosis_and_Malaria

The Global Fund to Fight AIDS, Tuberculosis and Malaria

Founded	January 28, 2002 (first Board of Directors meeting)
Focus	Accelerating the end of AIDS, tuberculosis and malaria as epidemics
Location	Geneva, Switzerland
Key people	Peter Sands, (Executive Director, March 2018 -)
Website	www.theglobalfund.org

The Global Fund to Fight AIDS, Tuberculosis and Malaria (or simply the Global Fund) is an international financing and partnership organization that aims to “attract, leverage and invest additional resources to end the epidemics of HIV/AIDS, tuberculosis and malaria to support attainment of the Sustainable Development Goals established by the United Nations.” The international organization maintains its secretariat in Geneva, Switzerland. The organization began operations in January 2002. Microsoft founder Bill Gates was one of the first private foundations among many bilateral donors to provide seed money for the partnership.

The Global Fund is the world's largest financier of AIDS, TB, and malaria prevention, treatment, and care programs. As of June 2019, the organization had disbursed more than US$41.6 billion to support these programs. According to the organization, in 2018 it helped finance the distribution of 131 million insecticide-treated nets to combat malaria, provided anti-tuberculosis treatment for 5.3 million people, supported 18.9 million people on antiretroviral therapy for AIDS, and since its founding saved 32 million lives worldwide.

The Global Fund is a financing mechanism rather than an implementing agency. Programs are implemented by in-country partners such as ministries of health, while the Global Fund secretariat, whose staff only have an office in Geneva, monitor the programs. Implementation is overseen by Country Coordinating Mechanisms, country-level committees consisting of in-country stakeholders that need to include, according to Global Fund requirements, a broad spectrum of representatives from government, NGOs, faith-based organizations, the private sector, and people living with the diseases. This system has kept the Global Fund secretariat smaller than other international bureaucracies. The model has also raised concerns about conflict of interest, as some of the stakeholders represented on the Country Coordinating Mechanisms may also receive money from the Global Fund, either as grant recipients, sub-recipients, private persons (e.g. for travel or participation at seminars) or contractors.

Creation

At the end of the 20th century, international political will to improve coordinated efforts to fight the world's deadliest infectious diseases began to materialize. Through various multilateral fora, consensus around creating a new international financial vehicle to combat these diseases emerged. In this context the World Health Organization called for a "Massive Attack on Diseases of Poverty" in December 1999. The original concept suggested tackling “malaria, tuberculosis, unsafe pregnancy, AIDS, diarrheal diseases, acute respiratory infections and measles.” This list would steadily narrow to only include the three diseases the Global Fund fights today: HIV/AIDS, TB, and malaria.

In April 2001, in Abuja, Nigeria at a summit of African leaders, United Nations Secretary General Kofi Annan made the first explicit public call by a highly visible global leader for this new funding mechanism, proposing "the creation of a Global Fund, dedicated to the battle against HIV/AIDS and other infectious diseases." Secretary General Annan made the first contribution to the Global Fund in 2001. Having just been named the recipient of the 2001 Philadelphia Liberty Medal, Annan announced he would donate his US$100,000 award to the Global Fund "war chest" he had just proposed creating. In June 2001 the United Nations General Assembly endorsed the creation of a global fund to fight HIV/AIDS.

The G8 formally endorsed the call for the creation of the Global Fund at its summit in July 2001 in Genoa, Italy, although pledges were significantly lower than the US$7 billion to US$10 billion annually Kofi Annan insisted was needed. According to the G8's final communique, “At Okinawa last year, we pledged to make a quantum leap in the fight against infectious diseases and to break the vicious cycle between disease and poverty. To meet that commitment and to respond to the appeal of the UN General Assembly, we have launched with the UN Secretary-General a new Global Fund to fight HIV/AIDS, malaria and tuberculosis. We are determined to make the Fund operational before the end of the year. We have committed $1.3 billion. The Fund will be a public-private partnership and we call on other countries, the private sector, foundations, and academic institutions to join with their own contributions - financially, in kind and through shared expertise.”

The Global Fund's initial 18-member policy-setting board held its first meeting in January 2002, and issued its first call for proposals. The first secretariat was established in January 2002 with Paul Ehmer serving as team leader, soon replaced by Anders Nordstrom of Sweden who became the organization's interim executive director. By the time the Global Fund Secretariat became operational, the organization had received US$1.9 billion in pledges. 

In March 2002, a panel of international public health experts was named to begin reviewing project proposals that same month. In April 2002, the Global Fund awarded its first batch of grants – worth US$378 million – to fight the three diseases in 31 countries.

Fundraising

Since the Global Fund was created in 2002, public sector contributions have constituted 95 percent of all financing raised; the remaining 5 percent comes from the private sector or other financing initiatives such as Product Red. The Global Fund states that from 2002 to July 2019, more than 60 donor governments pledged a total of US$51.2 billion and paid US$45.8 billion. From 2001 through 2018, the largest contributor by far has been the United States, followed by France, the United Kingdom, Germany, and Japan. The donor nations with the largest percent of gross national income contributed to the fund from 2008 through 2010 were Sweden, Norway, France, the United Kingdom, the Netherlands, and Spain.

The Global Fund typically raises and spends funds during three-year "replenishment" fund-raising periods. Its first replenishment was launched in 2005, the second in 2007, the third in 2010, the fourth in 2013, and the fifth in 2016.

Alarms were raised prior to the third replenishment meeting in October 2010 about a looming deficit in funding, which would have led to people undergoing ARV treatment losing access, increasing the chance of them becoming resistant to treatment. UNAIDS Executive Director Michel Sidibé dubbed the scenario of a funding deficit an "HIV Nightmare". The Global Fund stated it needed at least US$20 billion for the third replenishment (covering programs 2011-2013), and US$13 billion just to "allow for the continuation of funding of existing programs." Ultimately, US$11.8 billion was mobilized at the third replenishment meeting, with the United States being the largest contributor - followed by France, Germany, and Japan. The Global Fund stated the US$1.2 billion lack in funding would "lead to difficult decisions in the next three years that could slow down the effort to beat the three diseases."

In November 2011, the organization's board cancelled all new grants for 2012, only having enough money to support existing grants. However, following the Global Fund's May 2012 board meeting, it announced that an additional US$1.6 billion would be available in the 2012-2014 period for investment in programs.

In December 2013, the fourth replenishment meeting was held in Washington D.C. USD 12 billion was pledged in contributions from 25 countries, as well as the European Commission, private foundations, corporations, and faith-based organizations for the 2014–2016 period. It was the largest amount ever committed to fighting the three diseases.

The fifth replenishment meeting took place September 2016 in Montreal, Canada, and was hosted by Canadian Prime Minister Justin Trudeau. Donors pledged US$12.9 billion (at 2016 exchange rates) for the 2017-2019 period.

France hosted the sixth replenishment meeting in 2019 in Lyon, raising US$14 billion for 2020–2022.

Leadership

Richard Feachem was named the Global Fund's first executive director in April 2002 and faced early criticism from activists for stating the Global Fund has "plenty" of money to start.

Feachem served from July 2002 through March 2007. Dr. Michel Kazatchkine was then selected as executive director over the Global Fund's architect, David Nabarro, even though Nabarro was “considered the strongest of three shortlisted candidates to head the Global Fund ... A selection committee has evaluated the three nominees' qualifications and ranked ‘Nabarro first, Kazatchkine second and (Alex) Cotinho third,’ according to a Fund source.”

In September 2011, the AIDS Healthcare Foundation called for Kazatchkine's resignation in the wake of isolated yet unprecedented reports of "waste, fraud, and corruption" in order that "reforms may begin in earnest". In January 2012, Kazatchkine ultimately declared his resignation, following the decision made by the Global Fund board in November 2011 to appoint a general manager, leaving Kazatchkine's role to that of chief fund-raiser and public advocate. Communications later disclosed by the United States government stated that Kazatchkine's performance was deemed unsatisfactory by the Global Fund board, notably in relation to the funding of activities related to the First Lady of France at the time, Carla Bruni-Sarkozy.

Following Kazatchkine's resignation, the Global Fund announced the appointment of Gabriel Jaramillo, the former chairman and chief executive officer of Sovereign Bank, to the newly created position of general manager. Jaramillo, who had retired one year earlier, had since served as a Special Advisor to the Office of the Special Envoy for Malaria of the Secretary General of the United Nations, and was a member of the high-level independent panel that looked at the Global Fund's fiduciary controls and oversight mechanisms. Jaramillo reorganized and reduced Global Fund staff in response to the previous year's critics of the Global Fund.

Dr. Mark R. Dybul was appointed executive director in November 2012. He previously served as the United States Global AIDS Coordinator, leading the implementation of the President's Emergency Plan for AIDS Relief (PEPFAR) from 2006 to 2009. Dybul ended his appointment in 2017. 

A nominating process to find a successor to Dybul ran into trouble in 2017 because nominees had spoken out against Donald Trump as a candidate for president of the United States. The Global Fund board named Global Fund Chief of Staff Marijke Wijnroks of the Netherlands as interim executive director while the nominating process restarted.

The Global Fund board selected banker Peter Sands as executive director in 2017. He assumed the role in 2018.

Operations

The Global Fund was formed as an independent, non-profit foundation under Swiss law and hosted by the World Health Organization in January 2002. In January 2009, the organization became an administratively autonomous organization, terminating its administrative services agreement with the World Health Organization.

The initial objective of the Global Fund — to provide funding to countries on the basis of performance — was supposed to make it different from other international agencies at the time of its inception. Other organizations may have staff that assist with the implementation of grants. However, the Global Fund's five-year evaluation in 2009 concluded that without a standing body of technical staff, the Global Fund is not able to ascertain the actual results of its projects. It has therefore tended to look at disbursements or the purchase of inputs as performance. It also became apparent shortly after the organization opened that a pure funding mechanism could not work on its own, and it began relying on other agencies – notably the World Health Organization – to support countries in designing and drafting their applications and in supporting implementation. The United Nations Development Programme, in particular, bears responsibility for supporting Global Fund-financed projects in a number of countries. As a result, the organization is most accurately described as a financial supplement to the existing global health architecture rather than as a separate approach. 

The Global Fund Secretariat in Geneva, Switzerland, employs about 700 staff. There are neither offices nor staff based in other countries.

In 2013, the Global Fund adopted a new way of distributing its funds in countries to fight AIDS, tuberculosis and malaria. Under this funding model, eligible countries receive an allocation of money every three years for possible use during same the three-year period. The total amount of all allocations across all countries depends on the amount contributed by governments and other donors through the "replenishment" fundraising during the same three-year period. The countries, through their “country coordinating mechanism” committees, submit applications outlining how they'll use the allocation. The committees name entities, called “principal recipients,” to carry about programs within their respective countries. An independent "technical review panel" reviews the applications. Once the applications are approved, the Global Fund provides funding to the principal recipients based on achievement toward agreed indicators and actual expenses. Performance and expenses are periodically reviewed by a “local fund agent,” which in most countries is an international financial audit company.

Corruption and misuse of funds

In January 2011, the Associated Press reported vast corruption in some programs financed by the Global Fund, citing findings of the Global Fund Office of the Inspector General – an auditing unit independent from the Global Fund Secretariat – that up to two-thirds of funds in some of the reviewed grants were lost to fraud. The Office of the Inspector General report showed that systematic fraud patterns had been used across countries. The Global Fund responded to the story with a news release, stating, "The Global Fund has zero tolerance for corruption and actively seeks to uncover any evidence of misuse of its funds. It deploys some of the most rigorous procedures to detect fraud and fight corruption of any organization financing development."

After the Associated Press story, a number of op-eds, including one by Michael Gerson published in the Washington Post in February 2011, sought to put the controversy surrounding the misuse of Global Fund grants in perspective. Gerson stated, "The two-thirds figure applies to one element of one country's grant - the single most extreme example in the world. Investigations are ongoing, but the $34 million in fraud that has been exposed represents about three-tenths of 1 percent of the money the fund has distributed. The targeting of these particular cases was not random; they were the most obviously problematic, not the most typical."

Global Fund spokesman Jon Liden told the Associated Press, "The messenger is being shot to some extent. We would contend that we do not have any corruption problems that are significantly different in scale or nature to any other international financing institution." Subsequent Global Fund statements omitted any reference to other agencies.

Previous reviews of grants and the Global Fund had shown substantial misconduct in some programs, lack of adequate risk management, and operational inefficiency of the Global Fund. Cases of corruption had also been found in several African countries such as Mali, Mauritania, Djibouti, and Zambia.

Sweden, the Global Fund's 11th-biggest contributor at the time (2011), suspended its US$85 million annual donation until the corruption problems were resolved. Germany, the third-biggest contributor at the time, also blocked any financing until a special investigation was complete. Funding was eventually restored. 

Other cases of abuse of funds, corruption and mismanagement in a series of grants forced the Global Fund to suspend or terminate the grants after such dealings became publicly known in Uganda, Zimbabwe, Philippines, and Ukraine.

In February 2011, the Financial Times reported that the Global Fund board failed to act previously on concerns over accountability including on the conclusion of an external evaluation in 2009 that criticized the organization's weak procurement practices. Warnings of inadequate controls had also been reported periodically. The Financial Times also reported that its own review found that neither Global Fund staff nor “local fund agents” (the entities entrusted with audit-like tasks at the country level) had noticed the deficiencies reported by the inspector general.

In 2012, the Global Fund hired a chief risk officer, Cees Klumper. After pushing countries to reclaim stolen funds from the parties responsible and recovering only about half, the organization began in 2014 as a last resort reducing future grants by twice the amount of misappropriated funds. As of February 2016, this resulted in US$14.8 million of reductions (collectively) for Bangladesh, Guatemala, Nigeria and Sri Lanka.