Alexis Massol González is a civil engineer and environmentalist from Puerto Rico. He graduated in civil engineering in  University of Puerto Rico at Mayagüez in 1965 and was awarded the Goldman Environmental Prize in 2002 for his efforts on the protection of Puerto Rico's mountain forests due to threats from mining interests. In 1980 he and his wife Tinti Deyá Díaz established Casa Pueblo, a non-profit environmental watchdog community-based organization in Adjuntas. One of the organization's achievements was protecting the forest surrounding their town by establishing Bosque del Pueblo in 1996. It was the first community-managed forest in Puerto Rico. A book he authored, Casa Pueblo: A Puerto Rican Model of Self-Governance, published in 2022, "offers a chronological account of Casa Pueblo's evolution from a small group of concerned citizens to an internationally recognized model for activism."

References

forestry in Puerto Rico
Goldman Environmental Prize awardees
living people
people from Adjuntas, Puerto Rico
Puerto Rican civil engineers
Puerto Rican environmentalists
year of birth missing (living people)

Alexis Massol González


Fentanyl, also spelled fentanil, is a highly potent synthetic piperidine opioid drug primarily used as an analgesic. Because fentanyl is 50 to 100 times more potent than morphine, its primary clinical utility is in pain management for cancer patients and those recovering from painful surgical operations. Fentanyl is also used as a sedative. Depending on the method of delivery, fentanyl can be very fast acting and ingesting a relatively small quantity can cause overdose.
Fentanyl works by activating μ-opioid receptors.
Fentanyl is also commonly known as fentanyl citrate and is sold under the brand name Sublimaze, among others.

Pharmaceutical fentanyl's adverse effects resemble those of other narcotic opioids, including addiction, confusion, respiratory depression (which, if extensive and untreated, may lead to arrest), drowsiness, nausea, visual disturbances, dyskinesia, hallucinations, delirium, a subset of the latter known as "narcotic delirium", analgesia, narcotic ileus, muscle rigidity, constipation, loss of consciousness, hypotension, coma, and death. Alcohol and other drugs (i.e., cocaine and heroin) can synergistically exacerbate fentanyl's side effects. Naloxone (also known as Narcan) can reverse the effects of an opioid overdose; however, because fentanyl is so potent, multiple doses might be necessary.

Fentanyl was first synthesized by Paul Janssen in 1959 and was approved for medical use in the United States in 1968. In 2015,  were used in healthcare globally. , fentanyl was the most widely used synthetic opioid in medicine; in 2019, it was the 278th most commonly prescribed medication in the United States, with more than a million prescriptions. It is on the World Health Organization's List of Essential Medicines.

Fentanyl continues to fuel an epidemic of synthetic opioid drug overdose deaths in the United States. From 2011 to 2021, prescription opioid deaths per year remained stable, while synthetic opioid deaths per year increased from 2,600 overdose  to 70,601. Since 2018, fentanyl and its analogues have been responsible for most drug overdose deaths in the United States, causing over 71,238 deaths in 2021. Fentanyl constitutes the majority of all drug overdose deaths in the United States since it overtook heroin in 2018. The United States National Forensic Laboratory estimates fentanyl reports by federal, state, and local forensic laboratories increased from 4,697 reports in 2014 to 117,045 reports in 2020. Fentanyl is often mixed, cut, or ingested alongside other drugs, including cocaine and heroin. Fentanyl has been reported in pill form, including pills mimicking pharmaceutical drugs such as oxycodone. Mixing with other drugs or disguising as a pharmaceutical makes it difficult to determine the correct treatment in the case of an overdose, resulting in more deaths. Fentanyl's ease of manufacture and high potency makes it easier to produce and smuggle, resulting in fentanyl replacing other abused narcotics and becoming more widely used.

Medical uses

Anesthesia
Intravenous fentanyl is often used for anesthesia and as an analgesic. To induce anesthesia, it is given with a sedative-hypnotic, like propofol or thiopental, and a muscle relaxant. To maintain anesthesia, inhaled anesthetics and additional fentanyl may be used. These are often given in 15–30minute intervals throughout procedures such as endoscopy and surgeries and in emergency rooms.

For pain relief after surgery, use can decrease the amount of inhalational anesthetic needed for emergence from anesthesia. Balancing this medication and titrating the drug based on expected stimuli and the person's responses can result in stable blood pressure and heart rate throughout a procedure and a faster emergence from anesthesia with minimal pain.

Regional anesthesia
Fentanyl is the most commonly used intrathecal opioid because its lipophilic profile allows a quick onset of action (5–10 min) and intermediate duration of action (60–120 min). Spinal administration of hyperbaric bupivacaine with fentanyl may be the optimal combination. The almost immediate onset of fentanyl reduces visceral discomfort and even nausea during the procedure.

Obstetrics
Fentanyl is sometimes given intrathecally as part of spinal anesthesia or epidurally for epidural anaesthesia and analgesia. Because of fentanyl's high lipid solubility, its effects are more localized than morphine, and some clinicians prefer to use morphine to get a wider spread of analgesia. It is widely used in obstetrical anesthesia because of its short time to action peak (about 5 minutes), the rapid termination of its effect after a single dose, and the occurrence of relative cardiovascular stability. In obstetrics, the dose must be closely regulated in order to prevent large amounts of transfer from mother to fetus. At high doses, the drug may act on the fetus to cause postnatal respiratory distress. For this reason, shorter acting agents such as alfentanyl or remifentanil may be more suitable in the context of inducing general anaesthesia.

Pain management

The bioavailability of intranasal fentanyl is about 70–90%, but with some imprecision due to clotted nostrils, pharyngeal swallow, and incorrect administration. For both emergency and palliative use, intranasal fentanyl is available in doses of 50, 100, and 200µg. In emergency medicine, safe administration of intranasal fentanyl with a low rate of side effects and a promising pain-reducing effect was demonstrated in a prospective observational study in about 900out-of-hospital patients.

In children, intranasal fentanyl is useful for the treatment of moderate and severe pain and is well tolerated. Furthermore, a 2017 study suggested the efficacy of fentanyl lozenges in children as young as five, weighing as little as 13kg. Lozenges are more inclined to be used as the child is in control of sufficient dosage, in contrast to buccal tablets.

Chronic pain
It is also used in the management of chronic pain including cancer pain. Often, transdermal patches are used. The patches work by slowly releasing fentanyl through the skin into the bloodstream over 48 to 72hours, allowing for long-lasting pain management. Dosage is based on the size of the patch, since, in general, the transdermal absorption rate is constant at a constant skin temperature. Each patch should be changed every 72hours. Rate of absorption is dependent on a number of factors. Body temperature, skin type, amount of body fat, and placement of the patch can have major effects. The different delivery systems used by different makers will also affect individual rates of absorption, and route of administration. Under normal circumstances, the patch will reach its full effect within 12 to 24hours; thus, fentanyl patches are often prescribed with a fast-acting opioid (such as morphine or oxycodone) to handle breakthrough pain. It is unclear if fentanyl gives long-term pain relief to people with neuropathic pain.

Breakthrough pain
Sublingual fentanyl dissolves quickly and is absorbed through the sublingual mucosa to provide rapid analgesia. Fentanyl is a highly lipophilic compound, which is well absorbed sublingually and generally well tolerated. Such forms are particularly useful for breakthrough cancer pain episodes, which are often rapid in onset, short in duration, and severe in intensity.

Palliative care

In palliative care, transdermal fentanyl patches have a definitive, but limited role for:

 people already stabilized on other opioids who have persistent swallowing problems and cannot tolerate other parenteral routes such as subcutaneous administration.
 people with moderate to severe kidney failure.
 troublesome side effects of oral morphine, hydromorphone, or oxycodone.

When using the transdermal patch, patients must be careful to minimize or avoid external heat sources (direct sunlight, heating pads, etc.), which can trigger the release and absorption of too much medication and cause potentially deadly complications.

Combat medicine
USAF Pararescue combat medics in Afghanistan used fentanyl lozenges in the form of lollipops on combat casualties from IED blasts and other trauma. The stick is taped to a finger and the lozenge put in the cheek of the person. When enough fentanyl has been absorbed, the (sedated) person generally lets the lollipop fall from the mouth, indicating sufficient analgesia and somewhat reducing the likelihood of overdose and associated risks.

Dyspnea
Fentanyl can also be used for patients in whom morphine is not tolerated, or whose breathlessness is refractory to morphine. Fentanyl is especially useful for concomitant treatment in palliative care settings where pain and shortness of breath are severe and need to be treated with high strength opioids.

Other
Some routes of administration such as nasal sprays and inhalers generally result in a faster onset of high blood levels, which can provide more immediate analgesia but also more severe side effects, especially in overdose. The much higher cost of some of these appliances may not be justified by marginal benefit compared with buccal or oral options. Intranasal fentanyl appears to be equally effective as IV morphine and superior to intramuscular morphine for the management of acute hospital pain.

A fentanyl patient-controlled transdermal system (PCTS) is under development, which aims to allow patients to control administration of fentanyl through the skin to treat postoperative pain. The technology consists of a "preprogrammed, self-contained drug-delivery system" that uses electrotransport technology to administer on-demand doses of 40µg of fentanyl hydrochloride over ten minutes. In a 2004 experiment including 189 patients with moderate to severe postoperative pain up to 24hours after major surgery, 25% of patients withdrew due to inadequate analgesia. However, the PCTS method proved superior to the placebo, showing lower mean VAS pain scores and having no significant respiratory depression effects.

Adverse effects

Fentanyl's most common side effects, which affect more than 10% of people, include nausea, vomiting, constipation, dry mouth, somnolence, confusion, and asthenia (weakness). Less frequently, in 3–10% of people, fentanyl can cause abdominal pain, headache, fatigue, anorexia and weight loss, dizziness, nervousness, anxiety, depression, flu-like symptoms, dyspepsia (indigestion), shortness of breath, hypoventilation, apnoea, and urinary retention. Fentanyl use has also been associated with aphasia. Despite being a more potent analgesic, fentanyl tends to induce less nausea, as well as less histamine-mediated itching, than morphine.

The duration of action of fentanyl has sometimes been underestimated, leading to harm in a medical context. In 2006, the United States Food and Drug Administration (FDA) began investigating several respiratory deaths, but doctors in the United Kingdom were not warned of the risks with fentanyl until September 2008. The FDA reported in April 2012 that twelve young children had died and twelve more had become seriously ill from separate accidental exposures to fentanyl skin patches.

Respiratory depression
The most dangerous adverse effect of fentanyl is respiratory depression, that is, decreased sensitivity to carbon dioxide leading to reduced rate of breathing, which can cause anoxic brain injury or death. This risk is decreased when the airway is secured with an endotracheal tube (as during anesthesia). This risk is higher in specific groups, like those with obstructive sleep apnea.

Other factors that increase the risk of respiratory depression are:
 High fentanyl doses
 Simultaneous use of methadone
 Sleep
 Older age
 Simultaneous use of CNS depressants like benzodiazepines (xanax ,valium or klonopin), barbiturates, alcohol, and inhaled anesthetics
 Hyperventilation
 Decreased CO2 levels in the serum
 Respiratory acidosis
 Decreased fentanyl clearance from the body
 Decreased blood flow to the liver
 Renal insufficiency

Sustained release fentanyl preparations, such as patches, may also produce unexpected delayed respiratory depression. The precise reason for sudden respiratory depression is unclear, but there are several hypotheses:
 Saturation of the body fat compartment in people with rapid and profound body fat loss (people with cancer, cardiac or infection-induced cachexia can lose 80% of their body fat).
 Early carbon dioxide retention causing cutaneous vasodilation (releasing more fentanyl), together with acidosis, which reduces protein binding of fentanyl, releasing yet more fentanyl.
 Reduced sedation, losing a useful early warning sign of opioid toxicity and resulting in levels closer to respiratory-depressant levels.

Another related complication of fentanyl overdoses includes the so-called wooden chest syndrome, which quickly induces complete respiratory failure by paralyzing the thoracic muscles, explained in more detail in the Muscle rigidity section below.

Heart and blood vessels
 Bradycardia: Fentanyl decreases the heart rate by increasing vagal nerve tone in the brainstem, which increases the parasympathetic drive.
 Vasodilation: It also vasodilates arterial and venous blood vessels through a central mechanism, by primarily slowing down vasomotor centers in the brainstem. To a lesser extent, it does this by directly affecting blood vessels. This is much more profound in patients who have an already increased sympathetic drive, like patients who have high blood pressure or congestive heart failure. It does not affect the contractility of the heart when regular doses are administered.

Muscle rigidity
If high boluses of fentanyl are administered quickly, muscle rigidity of the vocal cords can make bag-mask ventilation very difficult. The exact mechanism of this effect is unknown, but it can be prevented and treated using neuromuscular blockers.

Wooden chest syndrome
A prominent idiosyncratic adverse effect of fentanyl also includes a sudden onset of rigidity of the abdominal muscles and the diaphragm, which induces respiratory failure; this is seen with high doses and is known as wooden chest syndrome. The syndrome is believed to be the main cause of death as a result of fentanyl overdoses.

Wooden chest syndrome is reversed by naloxone and is believed to be caused by a release of noradrenaline, which activates α-adrenergic receptors and also possibly via an activation of cholinergic receptors.

Wooden chest syndrome is unique to the most powerful opioidswhich today comprise fentanyl and its analogswhile other less-powerful opioids like heroin produce mild rigidity of the respiratory muscles to a much lesser degree.

Overdose

Fentanyl poses an exceptionally high overdose risk in humans, since the amount required to cause toxicity is unpredictable. In its pharmaceutical form most overdose deaths attributed solely to fentanyl occur at serum concentrations at a mean of 0.025µg/mL, with a range 0.005–0.027µg/mL. In contexts of poly-substance use, blood fentanyl concentrations of approximately 7ng/ml or greater have been associated with fatalities. Over 85% of overdoses involved at least one other drug, and there was no clear correlation showing at which level the mixtures were fatal. The dosages of fatal mixtures varied by over three magnitudes in some cases. This extremely unpredictable volatility with other drugs makes it especially difficult to avoid fatalities.

Naloxone (sold under the brand name Narcan) can completely or partially reverse an opioid overdose. In July2014, the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK issued a warning about the potential for life-threatening harm from accidental exposure to transdermal fentanyl patches, particularly in children, and advised that they should be folded, with the adhesive side in, before being discarded. The patches should be kept away from children, who are most at risk from fentanyl overdose. In the US, fentanyl and fentanyl analogs caused over 29,000deaths in 2017, a large increase over the previous four years.

Some increases in fentanyl deaths do not involve prescription fentanyl but are related to illicitly made fentanyl that is being mixed with or sold as heroin. Death from fentanyl overdose continues to be a public health issue of national concern in Canada since September 2015. In 2016, deaths from fentanyl overdoses in the province of British Columbia averaged two persons per day. In 2017 the death rate increased by more than 100% with 368 overdose-related deaths in British Columbia between January and April 2017.

Fentanyl has started to make its way into heroin as well as illicitly manufactured opioids and benzodiazepines. Fentanyl contamination in cocaine, methamphetamine, ketamine, MDMA, and other drugs is common. A kilogram of heroin laced with fentanyl may sell for more than US$100,000, but the fentanyl itself may be produced far more cheaply, for about US$6,000 per kilogram. While Mexico and China are the primary source countries for fentanyl and fentanyl-related substances trafficked directly into the United States, India is emerging as a source for finished fentanyl powder and fentanyl precursor chemicals. The United Kingdom illicit drug market is no longer reliant on China, as domestic fentanyl production is replacing imports.

The intravenous dose causing 50% of opioid-naive experimental subjects to die () is "3mg/kg in rats, 1mg/kg in cats, 14mg/kg in dogs, and 0.03mg/kg in monkeys." The LD50 in mice has been given as 6.9mg/kg by intravenous administration, 17.5mg/kg intraperitoneally, 27.8mg/kg by oral administration. The LD50 in humans is unknown.

In June 2023, overdose deaths in the U.S. and Canada again reached record numbers. According to a 2023 report from the United Nations Office on Drugs and Crime (UNODC) based in Vienna, the increased numbers of deaths are not related to an increased number of users but to the lethal effects of fentanyl itself. Fentanyl would require a special status as it is considerably more toxic than other widely abused opioids and opiates. With regard to overdose deaths in pediatric cases, numbers are also concerning. Based on a report by JAMA network, 37.5 % of all fatal pediatric cases between 1999 and 2021 were related to fentanyl; most of the deaths were among adolescents (89.6%) and children aged 0 to 4 years (6.6%). According to the UNODC, "the opioid crisis in North America is unabated, fueled by an unprecedented number of overdose deaths."

False reports by police of poisonings through secondary exposure
In the late 2010s, some media outlets began to report stories of police officers being hospitalised after touching powdered fentanyl, or after brushing it from their clothing. Topical (or transdermal; via the skin) and inhalative exposure to fentanyl is extremely unlikely to cause intoxication or overdose (except in cases of prolonged exposure with very large quantities of fentanyl), and first responders such as paramedics and police officers are at minimal risk of fentanyl poisoning through accidental contact with intact skin. A 2020 article from the Journal of Medical Toxicology stated that "the consensus of the scientific community remains that illness from unintentional exposures is extremely unlikely, because opioids are not efficiently absorbed through the skin and are unlikely to be carried in the air." The effects being reported in these cases, including rapid heartbeat, hyperventilation and chills, were not symptoms of a fentanyl overdose, and were more commonly associated with a panic attack.

A 2021 paper expressed concern that these physical fears over fentanyl may inhibit effective emergency response to overdoses by causing responding officers to spend additional time on unnecessary precautions, and that the media coverage could also perpetuate a wider social stigma that people who use drugs are dangerous to be around.

One expert in toxicology is extremely skeptical of police truly overdosing through mere touch. "This has never happened", said Dr. Ryan Marino, a toxicologist and emergency room physician who studies addiction at Case Western Reserve University. "There has never been an overdose through skin contact or accidentally inhaling fentanyl."

Prevention
Public health advisories to prevent fentanyl misuse and fatal overdose have been issued by the U.S. Centers for Disease Control (CDC). An initial HAN Advisory, also known as a Health Alert Network Advisory ("provides vital, time-sensitive information for a specific incident or situation; warrants immediate action or attention by health officials, laboratorians, clinicians, and members of the public; and conveys the highest level of importance") was issued during October 2015. A subsequent HAN Alert was issued in July 2018, warning of rising numbers of deaths due to fentanyl abuse and mixing with non-opioids. A December 2020 HAN Advisory warned of:

substantial increases in drug overdose deaths across the United States, primarily driven by rapid increases in overdose deaths involving ... illicitly manufactured fentanyl; a concerning acceleration of the increase in drug overdose deaths, with the largest increase recorded from March 2020 to May 2020, coinciding with the implementation of widespread mitigation measures for the COVID-19 pandemic; significant increases in overdose deaths involving methamphetamine.

81,230 drug overdose deaths occurred during the 12 months from May 2019 to May 2020, the largest number of drug overdoses for a 12-month interval ever recorded for the U.S. The CDC recommended the following four actions to counter this rise:
 local need to expand the distribution and use of naloxone and overdose prevention education,
 expand awareness, access, and availability of treatment for substance use disorders,
 intervene early with individuals at highest risk for overdose, and
 improve detection of overdose outbreaks to facilitate more effective response.

Another initiative is a social media campaign from the United States Drug Enforcement Administration (DEA) called "One Pill Can Kill". This social media campaign's goal is to spread awareness of the prevalence of counterfeit pills that are being sold in America that are leading to the large overdose epidemic in America. This campaign also shows the difference between counterfeit pills and real pills. It also offers resources for help with drug addiction and rehabilitation.

Pharmacology

Classification
Fentanyl is a synthetic opioid in the phenylpiperidine family, which includes sufentanil, alfentanil, remifentanil, and carfentanil. Some fentanyl analogues, such as carfentanil, are up to 10,000 times stronger than morphine.

Structure-activity

The structures of opioids share many similarities. Whereas opioids like codeine, hydrocodone, oxycodone, and hydromorphone are synthesized by simple modifications of morphine, fentanyl and its relatives are synthesized by modifications of meperidine. Meperidine is a fully synthetic opioid, and other members of the phenylpiperidine family like alfentanil and sufentanil are complex versions of this structure.

Like other opioids, fentanyl is a weak base that is highly lipid-soluble, protein-bound, and protonated at physiological pH. All of these factors allow it to rapidly cross cellular membranes, contributing to its quick effect in the body and the central nervous system.

Fentanyl analogs
Fentanyl analogs are types of fentanyl with various modifications on any number of positions, but still maintain, or even exceed, its pharmacological effects. Many fentanyl analogs are termed "designer drugs" because they are synthesized solely to be used in an illicit manner. Carfentanyl, a fentanyl analog, has an additional carboxylic acid group attached to the 4 position. Carfentanyl is 20-30 more times as potent as fentanyl, and is common in the illicit drug chain. The drug is commonly used to tranquilize elephants and other large animals.

Mechanism of action

Fentanyl, like other opioids, acts on opioid receptors. These receptors are G-protein-coupled receptors, which contain seven transmembrane portions, intracellular loops, extracellular loops, intracellular C-terminus, and extracellular N-terminus. The extracellular N-terminus is important in differentiating different types of binding substrates. When fentanyl binds, downstream signaling leads to the inhibitory effects, such as decreased cAMP production, decreased calcium ion influx, and increased potassium efflux. This inhibits the ascending pathways in the central nervous system to increase pain threshold by changing the perception of pain; this is mediated by decreasing propagation of nociceptive signals, resulting in analgesic effects.

As a μ-receptor agonist, fentanyl binds 50 to 100 times more potently than morphine. It can also bind to the delta and kappa opioid receptors but with a lower affinity. It has high lipid solubility, allowing it to more easily penetrate the central nervous system. It attenuates "second pain" with primary effects on slow-conducting, unmyelintated C-fibers and is less effective on neuropathic pain and "first pain" signals through small, myelinated A-fibers.

Fentanyl can produce the following clinical effects strongly, through μ-receptor agonism:

 Supraspinal analgesia (μ1)
 Respiratory depression (μ2)
 Physical dependence
 Muscle rigidity

It also produces sedation and spinal analgesia through Κ-receptor agonism.

Therapeutic effects
 Pain relief: Primarily, fentanyl provides the relief of pain by acting on the brain and spinal μ-receptors.
 Sedation: Fentanyl produces sleep and drowsiness, as the dosage is increased, and can produce the δ-waves often seen in natural sleep on electroencephalogram.
 Suppression of the cough reflex: Fentanyl can decrease the struggle against an endotracheal tube and excessive coughing by decreasing the cough reflex, becoming useful when intubating people who are awake and have compromised airways. After receiving a bolus dose of fentanyl, people can also experience paradoxical coughing, which is a phenomenon that is not well understood.

Detection in biological fluids
Fentanyl may be measured in blood or urine to monitor for abuse, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Commercially available immunoassays are often used as initial screening tests, but chromatographic techniques are generally used for confirmation and quantitation. The Marquis Color test may also be used to detect the presence of fentanyl. Using formaldehyde and sulfuric acid, the solution will turn purple when introduced to opium drugs. Blood or plasma fentanyl concentrations are expected to be in a range of 0.3–3.0 μg/L in persons using the medication therapeutically, 1–10 μg/L in intoxicated people, and 3–300 μg/L in victims of acute overdosage. Paper spray-mass spectrometry (PS-MS) may be useful for initial testing of samples.

Detection for harm reduction purposes

Fentanyl can be qualitatively detected in drug samples using commercially available fentanyl testing strips or spot reagents. Following the principles of harm reduction, this test is to be used directly on drug samples opposed to urine. To prepare a sample for testing, approximately 10mg of the drug, about the size of hair on Abraham Lincoln's head on a penny, should be diluted into 1 teaspoon, or 5mL, of water. Research in Dr. Lieberman's lab at the University of Notre Dame has reported false positive results on BTNX fentanyl testing strips with methamphetamine, MDMA, and diphenhydramine. Preparing drugs following the 10mg per 1 teaspoon rule will generally eliminate false positive results.

Characterization (NMR)
For synthetic preparation, fentanyl has been characterized and confirmed by proton and carbon NMR. Nuclear magnetic resonance (NMR) spectroscopy relies on the relative chemical environment for a molecule's atoms depending on the functionalities present, relaying useful information for chemists preparing a compound.

Proton

1H NMR (600 MHz, CDCl3) δ 7.48−7.37 (m, 3H), 7.33−7.27 (m, 2H), 7.25−7.17 (m, 3H), 7.13−7.05 (m, 2H), 4.88−4.71 (br, 1H), 3.83−3.47 (br, 2H), 3.20−3.09 (br, 2H), 3.09−2.99 (br, 2H), 2.82−2.70 (br, 2H), 2.13−1.99 (br, 4H), 1.94 (q, J = 7.4, 2H), 1.01 (t, J = 7.4, 3H)

Carbon

13C NMR (150 MHz, CDCl3) δ 174.0, 138.1, 137.0, 129.9, 129.8, 129.0, 128.9, 128.7, 127.0, 59.1, 52.6, 50.7, 31.3, 28.4, 28.0, 9.5

Synthesis
Fentanyl is a 4-anilopiperidine class synthetic opioid. The synthesis of Fentanyl is accomplished by one of four main methods as reported in scientific literature: the Janssen, Seigfried, Gupta, or Suh method.

Janssen

The original synthesis as patented in 1964 by Paul Janssen involves synthesis of benzylfentanyl from N-Benzyl-4-Piperidone. The resulting benzylfentanyl is used as feedstock to norfentanyl. It is norfentanyl that forms fentanyl upon reaction with phenethyl chloride.

Siegfried

The Siegfried method involves the initial synthesis of N-phenethyl-4-piperidone (NPP). This NPP byproduct is reductively aminated to 4-anilino-N-phenethylpiperidine (4-ANPP). Fentanyl is produced following the reaction of 4-ANPP with an acyl chloride. The Siegfried method has been used in the early 2000s to manufacture fentanyl in both domestic and foreign clandestine laboratories.

Gupta

The Gupta (or 'one-pot') method starts from 4-Piperidone and skips the direct use of 4-ANPP/NPP; rather the compounds are formed only as impurities or temporary intermediates. For the first half of 2021, the United States DEA found the Gupta method was the predominant synthesis route in their samples of seized fentanyl. In 2022, Braga and coworkers described a synthesis of fentanyl involving continous flow that uses reagents similar to the ones described for the Gupta procedure.

Suh
The Suh (or 'total synthesis') method skips the direct use of piperidine precursors in favor of creating the ring system in-situ.

History
Fentanyl was first synthesized in Belgium by Paul Janssen under the label of his relatively newly formed Janssen Pharmaceutica in 1959. It was developed by screening chemicals similar to pethidine (meperidine) for opioid activity. The widespread use of fentanyl triggered the production of fentanyl citrate (the salt formed by combining fentanyl and citric acid in a 1:1 stoichiometric ratio). Fentanyl citrate entered medical use as a general anaesthetic in 1968, manufactured by McNeil Laboratories under the trade name Sublimaze.

In the mid-1990s, Janssen Pharmaceutica developed and introduced into clinical trials the Duragesic patch, which is a formulation of an inert alcohol gel infused with select fentanyl doses, which are worn to provide constant administration of the opioid over a period of 48 to 72hours. After a set of successful clinical trials, Duragesic fentanyl patches were introduced into medical practice.

Following the patch, a flavored lollipop of fentanyl citrate mixed with inert fillers was introduced in 1998 under the brand name of Actiq, becoming the first quick-acting formation of fentanyl for use with chronic breakthrough pain.

In 2009, the US Food and Drug Administration (FDA) approved Onsolis (fentanyl buccal soluble film), a fentanyl drug in a new dosage form for cancer pain management in opioid-tolerant subjects. It uses a medication delivery technology called BEMA (BioErodible MucoAdhesive), a small dissolvable polymer film containing various fentanyl doses applied to the inner lining of the cheek.

Fentanyl has a US Drug Enforcement Administration (DEA) Administrative Controlled Substances Code Number (ACSCN) of 9801. Its annual aggregate manufacturing quota has significantly reduced in recent years from 2,300.000kg in 2015 and 2016 to only 731.452kg in 2021, a nearly 68.2% decrease.

Society and culture

Legal status
In the UK, fentanyl is classified as a controlled Class A drug under the Misuse of Drugs Act 1971.

In the Netherlands, fentanyl is a List I substance of the Opium Law.

In the U.S., fentanyl is a Schedule II controlled substance per the Controlled Substance Act. Distributors of Abstral are required to implement an FDA-approved risk evaluation and mitigation strategy (REMS) program. In order to curb misuse, many health insurers have begun to require precertification and/or quantity limits for Actiq prescriptions.

In Canada, fentanyl is considered a scheduleI drug as listed in Canada's Controlled Drugs and Substances Act.

Estonia is known to have been home to the world's longest documented fentanyl epidemic, especially following the Taliban ban on opium poppy cultivation in Afghanistan.

A 2018 report by The Guardian indicated that many major drug suppliers on the dark web have voluntarily banned the trafficking of fentanyl.

The fentanyl epidemic has erupted in a highly acrimonious dispute between the U.S. and Mexican governments. While U.S. officials blame the flood of fentanyl crossing the border primarily on Mexican crime groups, President Andrés Manuel López Obrador insists that the main source of this synthetic drug is Asia. He believes that the crisis of a lack of family values in the United States drives people to use the drug.

Recreational use
Illicit use of pharmaceutical fentanyl and its analogues first appeared in the mid-1970s in the medical community and continues in the present. More than 12 different analogues of fentanyl, all unapproved and clandestinely produced, have been identified in the U.S. drug traffic. In February 2018, the U.S. Drug Enforcement Administration indicated that illicit fentanyl analogs have no medically valid use, and thus applied a "Schedule I" classification to them.

Fentanyl analogues may be hundreds of times more potent than heroin. Fentanyl is used orally, smoked, snorted, or injected. Fentanyl is sometimes sold as heroin or oxycodone, which can lead to overdose. Many fentanyl overdoses are initially classified as heroin overdoses. Recreational use is not particularly widespread in the EU except for Tallinn, Estonia, where it has largely replaced heroin. Estonia has the highest rate of 3-methylfentanyl overdose deaths in the EU, due to its high rate of recreational use.

Fentanyl is sometimes sold on the black market in the form of transdermal fentanyl patches such as Duragesic, diverted from legitimate medical supplies. The gel from inside the patches is sometimes ingested or injected.

Another form of fentanyl that has appeared on the streets is the Actiq lollipop formulation. The pharmacy retail price ranges from US$15 to US$50 per unit based on the strength of the lozenge, with the black market cost ranging from US$5 to US$25, depending on the dose. The attorneys general of Connecticut and Pennsylvania have launched investigations into its diversion from the legitimate pharmaceutical market, including Cephalon's "sales and promotional practices for Provigil, Actiq and Gabitril."

Non-medical use of fentanyl by individuals without opioid tolerance can be very dangerous and has resulted in numerous deaths. Even those with opiate tolerances are at high risk for overdoses. Like all opioids, the effects of fentanyl can be reversed with naloxone, or other opiate antagonists. Naloxone is increasingly available to the public. Long acting or sustained release opioids may require repeat dosage. Illicitly synthesized fentanyl powder has also appeared on the United States market. Because of the extremely high strength of pure fentanyl powder, it is very difficult to dilute appropriately, and often the resulting mixture may be far too strong and, therefore, very dangerous.

Some heroin dealers mix fentanyl powder with heroin to increase potency or compensate for low-quality heroin. In 2006, illegally manufactured, non-pharmaceutical fentanyl often mixed with cocaine or heroin caused an outbreak of overdose deaths in the United States and Canada, heavily concentrated in the cities of Dayton, Ohio; Chicago, Illinois; Detroit, Michigan; and Philadelphia, Pennsylvania.

Enforcement

Several large quantities of illicitly produced fentanyl have been seized by U.S. law enforcement agencies. In November2016, the DEA uncovered an operation making counterfeit oxycodone and Xanax from a home in Cottonwood Heights, Utah. They found about 70,000pills in the appearance of oxycodone and more than 25,000 in the appearance of Xanax. The DEA reported that millions of pills could have been distributed from this location over the course of time. The accused owned a tablet press and ordered fentanyl in powder form from China. A seizure of a record amount of fentanyl occurred on 2 February 2019, by U.S. Customs and Border Protection in Nogales, Arizona. The  of fentanyl, which was estimated to be worth US$3.5M, was concealed in a compartment under a false floor of a truck transporting cucumbers. The "China White" form of fentanyl refers to any of a number of clandestinely produced analogues, especially α-methylfentanyl (AMF). One US Department of Justice publication lists "China White" as a synonym for a number of fentanyl analogues, including 3-methylfentanyl and α-methylfentanyl, which today are classified as Schedule I drugs in the United States. Part of the motivation for AMF is that, despite the extra difficulty from a synthetic standpoint, the resultant drug is more resistant to metabolic degradation. This results in a drug with an increased duration.

In June 2013, the United States Centers for Disease Control and Prevention (CDC) issued a health advisory to emergency departments alerting to 14 overdose deaths among intravenous drug users in Rhode Island associated with acetylfentanyl, a synthetic opioid analog of fentanyl that has never been licensed for medical use. In a separate study conducted by the CDC, 82% of fentanyl overdose deaths involved illegally manufactured fentanyl, while only 4% were suspected to originate from a prescription.

Beginning in 2015, Canada has seen a number of fentanyl overdoses. Authorities suspected that the drug was being imported from Asia to the western coast by organized crime groups in powder form and being pressed into pseudo-OxyContin tablets. Traces of the drug have also been found in other recreational drugs, including cocaine, MDMA, and heroin. The drug has been implicated in deaths of people from all walks of life—from homeless individuals to professionals—including teens and young parents. Because of the rising deaths across the country, especially in British Columbia where 1,716deaths were reported in 2020 and 1,782 from January to October2021, Health Canada is putting a rush on a review of the prescription-only status of naloxone in an effort to combat overdoses of the drug. In 2018, Global News reported allegations that diplomatic tensions between Canada and China hindered cooperation to seize imports, with Beijing being accused of inaction.

Fentanyl has been discovered for sale in illicit markets in Australia in 2017 and in New Zealand in 2018. In response, New Zealand experts called for wider availability of naloxone.

In May 2019, China regulated the entire class of fentanyl-type drugs and two fentanyl precursors. Nevertheless, it remains the principal origin of fentanyl in the United States: Mexican cartels source fentanyl precursors from Chinese suppliers such as Yuancheng Group, which are finished in Mexico and smuggled to the United States. Following the 2022 visit by Nancy Pelosi to Taiwan, China halted cooperation with the United States on combatting drug trafficking.

India has also emerged as a source of fentanyl and fentanyl precursors, where Mexican cartels have already developed networks for the import of synthetic drugs. It is possible that fentanyl and precursor production may disperse to other countries, such as Nigeria, South Africa, Indonesia, Myanmar, and the Netherlands.

In 2020, the Myanmar military and police confiscated 990 gallons of "methyl fentanyl", as well as precursors for the illicit synthesis of the drug. According to the United Nations Office on Drugs and Crime, the Shan State of Myanmar has been identified as a major source for fentanyl derivatives. In 2021, the agency reported a further drop in opium poppy cultivation in Burma, as the region's synthetic drug market continues to expand and diversify.

In 2023, a California police union director was charged with importing synthetic opioids, including fentanyl and tapentadol disguised as chocolate. U.S. law enforcement had been slow in their response to the fentanyl crisis, according to the Washington Post. The response by the federal government to the fentanyl crisis had also faltered, according to the press release.  Overdose deaths by fentanyl and other illegally imported opioids were surging since 2019 and are presently a major cause of death in all U.S. states.

According to the national archives and the DEA, direct fentanyl shipments from China have stopped since 2022. The majority of illicit fentanyl and analogues now entering the U.S. from Mexico are final products in form of "tablets" and adulterated heroin from previously synthesized fentanyl. From the sophistication of full fentanyl synthesis and acute toxicity in laboratory environments, 'clandestine' labs in Mexico relate to making an illicit dosage form from available fentanyl rather than the synthesis itself. Based on further research by investigators, fentanyl and analogues are likely synthesized in labs that have the appearance of a legal entity, or are diverted from pharmaceutical laboratories.

Recalls
In February2004, a leading fentanyl supplier, Janssen Pharmaceutica Products recalled one lot, and later, additional lots of fentanyl (brand name: Duragesic) patches because of seal breaches that might have allowed the medication to leak from the patch. A series of classII recalls was initiated in March2004, and in February2008, the ALZA Corporation recalled their 25µg/h Duragesic patches due to a concern that small cuts in the gel reservoir could result in accidental exposure of patients or health care providers to the fentanyl gel. In April 2023, Teva Pharmaceuticals USA recalled 13 lots of their Fentanyl Buccal Tablets CII due to missing safety information sheets on how to properly administer their product. The corporation issued a consumer recall report and stressed the importance of safety in the use and administration of opioid therapeutics.

Brand names
Brand names include Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Haldid, Onsolis, Instanyl, Abstral, Lazanda and others.

Cost
In the United States, the 800 mcg tablet was 6.75 times more expensive as of 2020 than the lozenge. As of 2023, the average cost for an injectable fentanyl solution (50 mcg/mL) is around US$17 for a supply of 20 milliliters, depending on the pharmacy. In a 2020 report by the Australian Institute of Criminology, a 100-microgram transdermal patch was valued from between AU$75 and AU$450 on illicit markets. Furthermore, in another 2020 study, the average price per gram of non-pharmaceutical fentanyl on various cryptomarkets was US$1,470.40 for offerings of less than five grams; the average for offers over five grams was US$139.50. In addition, on DreamMarket furanfentanyl (Fu-F), the most common analog on said market, the average price per gram was US$243.10 for retail listings and US$26.50 per gram for wholesale listings.

Storage and disposal
The fentanyl patch is one of a few medications that may be especially harmful, and in some cases fatal, with just one dose, if misused by a child. Experts have advised that any unused fentanyl patches be kept in a secure location out of children's sight and reach, such as a locked cabinet.

In British Columbia, Canada, where there are environmental concerns about toilet flushing or garbage disposal, pharmacists recommend that unused patches be sealed in a child-proof container that is then returned to a pharmacy. In the United States where patches cannot always be returned through a medication take-back program, flushing is recommended for fentanyl patches, because it is the fastest and surest way to remove them from the home to prevent ingestion by children, pets or others not intended to use them.

Notable deaths
 On 25 September 2003, American professional wrestler Anthony Durante, also known as "Pitbull #2", died from a fentanyl-induced overdose.
 On 24 May 2009, Wilco guitarist Jay Bennett died from an accidental overdose of fentanyl.
 On 24 May 2010, Slipknot bassist Paul Gray died from an overdose of morphine and fentanyl.
 Medical examiners concluded that musician Prince died on 21 April 2016 from an accidental fentanyl overdose. Fentanyl was among many substances identified in counterfeit pills recovered from his home, especially some that were mislabeled as Watson 385, a combination of hydrocodone and paracetamol.
 On 21 April 2016, American author and journalist Michelle McNamara died from an accidental overdose; medical examiners determined fentanyl was a contributing factor.
 On 11 November 2016, Canadian video game composer Saki Kaskas died of a fentanyl overdose; he had been battling heroin addiction for over a decade.
 On 15 November 2017, American rapper Lil Peep died of an accidental fentanyl overdose.
 On 19 January 2018, the Los Angeles County Department of Medical Examiner said musician Tom Petty died from an accidental drug overdose as a result of mixing medications that included fentanyl, acetyl fentanyl, and despropionyl fentanyl (among others). He was reportedly treating "many serious ailments" that included a broken hip.
 On 7 September 2018, American rapper Mac Miller died from an accidental overdose of fentanyl, cocaine and alcohol.
 On 16 December 2018, American tech entrepreneur Colin Kroll, founder of social media video-sharing app Vine and quiz app HQ Trivia, died from an overdose of fentanyl, heroin, and cocaine.
 On 1 July 2019, American baseball player Tyler Skaggs died from pulmonary aspiration while under the influence of fentanyl, oxycodone, and alcohol.
 On 1 January 2020, American rapper, singer, and songwriter Lexii Alijai died from accidental toxicity resulting from the combination of alcohol and fentanyl.
 On 20 August 2020, American singer, songwriter and musician Justin Townes Earle died from an accidental overdose caused by cocaine laced with fentanyl.
 On 24 August 2020, Riley Gale, frontman for the Texas metal band Power Trip, died as a result of the toxic effects of fentanyl in a manner that was ruled accidental.
 On 2 March 2021, American musician Mark Goffeney, also known as "Big Toe" (because being born without arms, he played guitar with his feet), died from an overdose of fentanyl.
 On 22 April 2021, Digital Underground frontman, rapper, and musician Shock G died from an accidental overdose of fentanyl, meth, and alcohol.
 On 6 September 2021, actor Michael K. Williams, who rose to fame through his critically acclaimed role as Omar Little on the HBO drama series The Wire, died from an overdose of fentanyl, parafluorofentanyl, heroin, and cocaine.
 On 28 September 2022, rapper Coolio (Artis Leon Ivey, Jr) died from an accidental overdose of fentanyl, heroin, and methamphetamine.
 On 31 July 2023, Angus Cloud, best known for his portrayal of Fezco on the HBO drama series Euphoria, died from an accidental overdose of methamphetamine, cocaine, fentanyl, and benzodiazepines.
 On 15 September 2023, an infant died at a daycare due to fentanyl contamination, which is also believed to have caused sickness in other children.

Governmental usage
In August 2018, Nebraska became the first American state to use fentanyl to execute a prisoner. Carey Dean Moore, at the time one of the longest-serving death row inmates in the United States, was executed at the Nebraska State Penitentiary. Moore received a lethal injection, administered as an intravenous series of four drugs that included fentanyl citrate, to inhibit breathing and render the subject unconscious. The other drugs included diazepam as a tranquilizer, cisatracurium besylate as a muscle relaxant, and potassium chloride to stop the heart. The use of fentanyl in execution caused concern among death penalty experts because it was part of a previously untested drug cocktail. The execution was also protested by anti-death penalty advocates at the prison during the execution and later at the Nebraska capitol building.

Russian Spetsnaz security forces are suspected to have used a fentanyl analogue, or derivative (suspected to be carfentanil and remifentanil), to rapidly incapacitate people in the Moscow theater hostage crisis in 2002. The siege was ended, but many hostages died from the gas after their health was severely taxed during the days long siege. The Russian Health Minister later stated that the gas was based on fentanyl, but the exact chemical agent has not been clearly identified.

Veterinary use
Fentanyl is commonly used for analgesia and as a component of balanced sedation and general anesthesia in small animal patients. In addition, its efficacy is higher than many other pure-opiate and synthetic pure-opioid agonists regarding vomiting, depth of sedation, and cardiovascular effects when given as a continuous infusion as well as a transdermal patch. As with other pure-opioid agonists, fentanyl has been associated with dysphoria in dogs.

Furthermore, transdermal fentanyl's potency and short duration of action make it popular as an intra-operative and post-operative analgesic in cats and dogs. This is usually done with off-label fentanyl patches manufactured for humans with chronic pain. In 2012, a highly concentrated (50mg/mL) transdermal solution, trade name Recuvyra, has become commercially available for dogs only. It is FDA approved to provide four days of analgesia after a single application before surgery. It is not approved for multiple doses or other species. The drug is also approved in Europe.

References

Further reading

External links

Analgesics
Anilides
Belgian inventions
Euphoriants
General anesthetics
HERG blocker
Mu-opioid receptor agonists
Piperidines
Products introduced in 1960
Propionamides
Synthetic opioids
Transdermal patches
Wikipedia medicine articles ready to translate
World Health Organization essential medicines

Fentanyl


The New England Governors and Eastern Canadian Premiers (NEG-ECP) Climate Change Action Plan 2001 is a resolution adopted on August 28, 2001, by the New England Governors and the Eastern Canadian Premiers. The resolution calls for a reduction in  greenhouse gas (GHG) emissions to 1990 levels by 2010, at least 10% below 1990 levels by 2020, 35-45% below 1990 levels by 2030, and a 75-85% reduction of 2001 levels by 2050.

Participating are the six states belonging to New England: Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, and Vermont; as well as the Eastern Canadian provinces: New Brunswick, Newfoundland and Labrador, Nova Scotia, Prince Edward Island, and Quebec.

In addition, the Northeast States for Coordinated Air Use Management (NESCAUM) is building a Regional Greenhouse Gas Registry (RGGR) to help track emissions in the region.  This effort is similar to that of the California Climate Action Registry.

History

The drafting of the action plan began when the NEG-ECP adopted the Resolution Concerning Global Warming and its Impacts on the Environment (Resolution 25-9) on July 16–18, 2000. It addresses that "global warming, given its harmful consequences to the environment and the economy, is a joint concern for which a regional approach to strategic action is required."

Action items

The Action Plan outlines nine major action items, designed to aid the participating states in meeting committed goals:

Action Item 1: The Establishment of a Regional Standardized GHG Emissions Inventory
Action Item 2: The Establishment of a Plan for Reducing GHG Emissions and Conserving Energy
Action Item 3: The Promotion of Public Awareness
Action Item 4: State and Provincial Governments to Lead by Example
Action Item 5: The Reduction of Greenhouse Gases from the Electricity Sector
Action Item 6: The Reduction of the Total Energy Demand Through Conservation
Action Item 7: The Reduction and/or Adaptation of Negative Social, Economic and Environmental Impacts of Climate Change
Action Item 8: A Decrease in the Transportation Sector's Growth in GHG Emissions
Action Item 9: The Creation of a Regional Emissions Registry and the Exploration of a Trading Mechanism

Later developments

The New England states later began participating in the Regional Greenhouse Gas Initiative to regulate greenhouse gas emissions from electricity generation.

Canada's carbon tax has since been applied to all Canadian provinces and territories.

See also

 Climate change in Canada
 Climate change in the United States
 Climate Stewardship Bill
 The Climate Registry
 Western Regional Climate Action Initiative
 Midwestern Greenhouse Gas Reduction Accord
 List of climate change initiatives

References

External links
 New England Governors and Eastern Canadian Premiers (NEG-ECP) Climate Change Action Plan 2001
 New England Governors' Conference, Inc.
 New England Climate Coalition
 State Climate Action Plan Fact Sheet

Canada–United States relations
Climate change in the United States
Climate change in Canada
Action plans

New England Governors and Eastern Canadian Premiers Climate Change Action Plan 2001


Jean-Yves Beziau (; born January 15, 1965, in Orléans, France is a Swiss Professor in logic at the University of Brazil, Rio de Janeiro, and Researcher of the Brazilian Research Council. He is permanent member and former president of the Brazilian Academy of Philosophy. Before going to Brazil, he was Professor of the Swiss National Science Foundation at the University of Neuchâtel in Switzerland and researcher at Stanford University working with Patrick Suppes.

Career
Béziau works in the field of logic—in particular, paraconsistent logic, the square of opposition and universal logic.  He holds a Maîtrise in Philosophy from Pantheon-Sorbonne University, a DEA in Philosophy from Pantheon-Sorbonne University, a PhD in Philosophy from the University of São Paulo, a MSc and a PhD in Logic and Foundations of Computer Science from Paris Diderot University.

Béziau is the editor-in-chief of the journal Logica Universalis and of the South American Journal of Logic—an online, open-access journal—as well as of the Springer book series Studies in Universal Logic. He is also the editor of College Publication's book series Logic PhDs

He has launched four major international series of events: UNILOG (World Congress and School on Universal Logic), SQUARE (World Congress on the Square of Opposition), WOCOLOR (World Congress on Logic and Religion), LIQ (Logic in Question).

Béziau created the World Logic Day (January 14).

Selected publications
 "What is paraconsistent logic?"  In D. Batens et al. (eds.), Frontiers of Paraconsistent Logic, Research Studies Press, Baldock, 2000, pp. 95–111.
 Handbook of Paraconsistency (ed. with Walter Carnielli and  Dov Gabbay).  London: College Publication, 2007.
 "Semantic computation of truth based on associations already learned" (with Patrick Suppes), Journal of Applied Logic, 2 (2004), pp. 457–467.
 "From paraconsistent logic to universal logic", Sorites,  12 (2001), pp. 5–32.
 Logica Universalis: Towards a General Theory of Logic (ed.)  Basel: Birkhäuser Verlag, 2005, Second Edition 2007.
 "Logic is not logic", 'Abstracta' 6 (2010), pp. 73–102.
  "The power of the hexagon", Logica Universalis, 6 (2012), pp. 1–43.
  "History of truth-values",  in D.M.Gabbay and J.Woods (eds) Handbook of the History of Logic, Vol. 11 - Logic: a history of its central concepts, Elsevier, Amsterdam, 2012, pp. 233–305
 The Square of Opposition: a General Framework for Cognition (ed. with Gillman Payette).  Bern: Peter Lang, 2012.
 "The new rising of the square of opposition", in J.-Y.Béziau and D.Jacquette (eds), Around and Beyond the Square of Opposition, Birkhäuser, Basel, 2012, pp. 6–24.
 La pointure du symbole (ed.)  Paris: Petra, 2014.
  "The relativity and universality of logic", Synthese, 192 (2015), pp 1939–1954.
"Logical Autobiography 50", in A.Koslow and A.Buchsbaum (eds), The Road to Universal Logic, Vol.2, Birkhäuser, Basel, 2015, pp. 19–104.
"MANY 1 - A Transversal Imaginative Journey across the Realm of Mathematics", in M.Chakraborty and M.Friend (eds), Special Issue on Mathematical Pluralism of the Journal of Indian Council of Philosophical Research, May 2017, Volume 34, Issue 2, pp 259–287.
"Being aware of rational animals", in G.Dodig-Crnkovic and R.Giovagnoli (eds), Representation and Reality: Humans, Animals and Machines, Springer International Publishing, Cham, 2017, pp. 319–331.
"A Chromatic Hexagon of Psychic Dispositions", in M.Silva (ed), How Colours Matter to Philosophy, Springer International Publishing, Cham, 2017, pp. 273–388.
"An Analogical Hexagon", International Journal of Approximate Reasoning, 94 (2018), pp. 1–17.
"The Pyramid of Meaning", in J.Ceuppens, H.Smessaert, J. van Craenenbroeck and G.Vanden Wyngaerd (eds), A Coat of Many Colours - D60, Brussels, 2018.
"An unexpected feature of classical propositional logic in the Tractatus", in G.Mras, P.Weingartner and B.Ritter (eds), Philosophy of Logic and Mathematics: Proceedings of the 41st International Ludwig Wittgenstein Symposium, De Gruyter, Berlin, Munich, Boston, 2019.
"Is God Paraconsistent?" (with Newton da Costa) in Beyond Faith and Rationality Essays on Logic, Religion and Philosophy, Springer International Publishing, Cham, 2020, pp. 321–333
"Metalogic, Schopenhauer and Universal Logic",  in J.Lemanski (ed), Language, Logic, and Mathematics in Schopenhauer, Birkhäuser, Basel, 2020, pp. 207–257.
"The Mystery of the Fifth Logical Notion (Alice in the Wonderful Land of Logical Notions)", Studia Humana, Volume 9:3/4 (2020), pp. 19–36.

References

External links
 Jean-Yves Beziau's personal homepage

1965 births
Mathematical logicians
Living people
Logicians
Scientists from Orléans
Paraconsistent logic

Jean-Yves Béziau


Takeshi Kaneshiro Tree is a bishop wood located on Mr. Brown Avenue, Chishang Township, Taitung County, Taiwan. Because of advertisements made in June 2013 by EVA Air with Takeshi Kaneshiro in this tree, it was named Takeshi Kaneshiro Tree. Since then, this tree has become a famous landmark attracting countless tourists to visit this place like a pilgrimage. It is estimated that the annual output value of tourism will reach NT$500 million. However, after the increase of tourists, a small number of people littering and destroying of crops by trampling has caused concern by local citizens to the extent that local farmers wanted to cut down the tree.

Takeshi Kaneshiro tree fell during Typhoon Matmo on July 23, 2014. After treatment by Japanese and Taiwanese arborists, the tree has been raised back and gradually restored.

See also
 List of individual trees

References

Individual trees in Taiwan
Taitung County

External links

Takeshi Kaneshiro Tree


Sanctum is a first-person shooter tower defense video game, developed by independent developer Coffee Stain Studios. It was released on Steam for Microsoft Windows on 15 April 2011. The successor, Sanctum 2, was announced in 2012 and released in May 2013.

Plot
In Sanctum, players take on the role of Skye, an elite soldier sent out to protect her home town, Elysion One, from hordes of mysterious alien creatures. To be successful in the task, the player will have to defend a "core" on each level. To accomplish this, the player builds defensive structures, and assists their structures by fending off the enemies themselves.

Gameplay

The gameplay in Sanctum is divided into the building phase and the extermination phase. In the building phase, the player builds structures on a pre-defined grid, using the eight 'towers' chosen at the start of the level. These towers include stationary weapons, teleporters for the player's use, and pads that affect enemies moving over them. The player can also upgrade any of the three weapons equipped at the start. Building and upgrading both cost points, which are gained when enemies are killed.

In the extermination phase, a wave of one or more enemy types moves across the level towards the core. With each enemy that reaches the core, the condition of the core degrades from 100%; when the condition reaches 0%, the game ends. Unlike most tower defense games, the player is allowed to move about the level during this phase and attack enemies with different weapon types, much like in a typical first-person shooter. Touching enemies will result in the player being knocked back, but no damage is done.

There are ten types of enemies in the game, three of which are air-borne. Because certain towers are more effective against certain enemies, and only a select few towers affect flying enemies, the player must plan for all possibilities when building defenses. To aid the player in this, information about upcoming waves is shown in the pause menu, as well as descriptions of the various enemies, towers, and weapons.

The different enemy types have varying travel speeds, hit points, and resistances. For example, Runners are weak and fast while Soakers have large health pools and travel slowly. Some enemies have complete immunity against certain towers (such as flying enemies not taking any damage from gatling gun towers). Other enemies include the Walker, Bobble-Head, Hoverer, and Tank. This variation of enemy traits forces the player to construct different tower types in order to mount a successful defense.

Development
The beta was made available to all people who pre-purchased the game on Steam. The beta only allowed players to play one map in both singleplayer and multiplayer.

Reception

Sanctum received mixed reviews from critics. The review aggregation website Metacritic currently estimates a score of 70 out of 100, based on 22 reviews.

Sales
Sanctum sold more than 180.000 copies via digital distribution by August 2011.

References

External links

2011 video games
Coffee Stain Studios games
Embracer Group franchises
First-person shooters
Indie games
MacOS games
Tower defense video games
Unreal Engine games
Video games developed in Sweden
Video games featuring female protagonists
Windows games
Multiplayer and single-player video games

Sanctum (2011 video game)


The Oregonian Railway was a  narrow gauge railroad in the Willamette Valley in the U.S. state of Oregon.

History
A group of Scot capitalists formed the Oregonian Railway Company, Limited after purchasing the bankrupt Dayton, Sheridan and Grande Ronde Railroad in 1879.

The first changes made were to move the Dayton terminal, on the Yamhill River, to Fulquartz Landing on the Willamette River.  On the opposite bank of the Willamette, the railroad built Ray's Landing.  This became the north terminus of the narrow gauge line on the east side of the Willamette valley.  The line connected towns such as St. Paul, Woodburn, Silverton, Brownsville, and Coburg.

The railroad also expanded the westside line south to reach Perrydale, Dallas, Monmouth, Independence and Airlie.  The stop at the end of the line was named after the Earl of Airlie, the leader of the Scot capitalists.

Revenues were dropping, and by 1886 or 1887 the railroad granted a long-term lease to Henry Villard of the Oregon & California Railroad.  In later years, Villard would leave the Oregon railroad scene and the line came to be under the control of Southern Pacific Railroad.

See also
List of defunct Oregon railroads
Portland and Willamette Valley Railway
William Reid (Scottish businessman)

References

Culp, Edwin D. (1972). Stations West, The Story of the Oregon Railways, Bonanza Books, Page 65.

1879 establishments in Oregon
3 ft gauge railways in the United States
Defunct Oregon railroads
History of transportation in Oregon
Marion County, Oregon
Narrow gauge railroads in Oregon
Transportation in Polk County, Oregon
Transportation in Yamhill County, Oregon

Oregonian Railway


Uses for the term extreme, which is sometimes spelled xtreme, include:

Geography and astronomy
 Extremes on Earth
 List of extrasolar planet extremes

Mathematics
Extreme value, the largest or smallest element of a set

Science and technology

Science
Extreme weather, severe or unseasonal weather
Extremism, ideas or actions beyond what is deemed acceptable
Extremophile, an organism which thrives in or requires "extreme"

Technology
Extreme Networks, a California-based networking hardware company
Extreme Programming, a software engineering methodology
Xtreme Mod, a peer-to-peer file sharing software for Windows based on eMule

Sports and entertainment

Sports
Extreme sport, a sport featuring speed, height, danger or spectacular stunts
Extreme skiing
Extreme Sports Channel, a Netherlands television channel
Extreme Championship Wrestling, a former wrestling promotion
Xtreme Pro Wrestling
Los Angeles Xtreme, a defunct XFL franchise
Xtreme Turf, an artificial turf or synthetic grass system

Music
Extreme (band), an American band
Extreme (album), an album by Extreme
Xtreme (group), a bachata duo
Xtreme (album), an album by Xtreme
Extremes (album), an album by Collin Raye
Extreme Records, a record label
Agostino Carollo or X-Treme, an Italian singer, DJ, and producer

Entertainment
Extreme (CSI: Miami)
Extreme (TV series)
Going to Extremes, a UK television series
Extreme (Travel Channel series), a US television series
Extreme Associates, an adult film production company
Dance Dance Revolution Extreme, a music video game by Konami
Extreme Paintbrawl, a first-person shooter video game
Dance Dance Revolution Extreme (North America), a music video game by Konami

Games
Extremes (Combat Arms)

Literature
Extreme Studios, a defunct studio of Image Comics
Adam X the X-Treme, a Marvel Comics character
Extreme, an autobiography by Sharon Osbourne

Other uses
Extreme Pita, a Canadian-based restaurant chain
Chevrolet S-10 xtreme

Extreme


Darylle Francis Bernardo Salvador (born April 14, 1992) is a Filipino television actor, model and singer. He started as a commercial model until his debut as an actor in a primetime series under ABS-CBN, Ina, Kapatid, Anak in 2013.

Life and career

1992–2012: Early life and discovery
Bernardo started joining male beauty pageants and won a number of titles. He also started as model for various clothing lines in the Philippines such as Natasha and RUSS. In 2009, he enrolled at Bulacan State University in Malolos, Bulacan under the General Engineering course. In 2010, he became a model and print ad endorser of 3D Fitness Studio and later became one of the "Cosmopolitan 69 Bachelors" of Cosmo Magazine. In 2012, he joined the Mr. Reflector pageant sponsored by the province's newspaper, The Reflector wherein he ended up 2nd place. In the same year, he was the representative of Central Luzon for the Mr. and Ms. State Colleges and Universities Athletic Association (SCUAA) National Olympics held at the Cultural Center of the West Visayas State University in La Paz, Iloilo City wherein he was declared as "Mr. National SCUAA Olympics 2012". Aside from winning the title role, he also garnered 3 miscellaneous awards: "Best in Festival Costume", "Best in Swimwear" and "Best in Barong Tagalog".

2013–present: Career beginnings
Bernardo also joined various reality search programs under his name, Darylle Salvador. He attended singing and dancing workshops when he changed his manager, and was eventually launched as a member of an all-male singing group, The 5ive along with Bryan Olano, Leon Eustaquio, Mykel Ong and Tres Gonzales in March 2013. He began as a television actor through Ina, Kapatid, Anak, a drama series produced by ABS-CBN. In 2013, he appeared in various commercials, one of them for Solaire, the newest entertainment casino in Manila, Philippines. He also appeared in several advertisements of PLDT, Smart Communications and Canon. Bernardo also appeared in political advertisements by former San Juan City mayor, JV Ejercito who ran for Senator in the Philippines in the 2013 midterm elections.

Filmography

Television

References

External links
 Official Facebook account

1992 births
Living people
Star Magic
People from Malolos
Filipino male television actors
Filipino television personalities
21st-century Filipino male singers
Filipino male models
Male actors from Bulacan

Dar Bernardo


Joe Louis Dudley, Sr. (born May 9, 1937) is an American businessman and hair-care entrepreneur. He is the president and chief executive officer for Dudley Products Inc., a manufacturer and distributor of hair and skin care products for the African American community.

Life and career
Dudley was born in Aurora, North Carolina, the fifth of 11 children. When he was in the first grade, he was mistakenly labeled as being mentally retarded because of a speech impediment. He was twice held back by the time he reached the eleventh grade. However, Dudley persevered in his education, eventually gaining a Bachelor of Science Degree in Business Administration from North Carolina Agricultural and Technical State University in Greensboro, North Carolina.

In 1957, Dudley was living in Brooklyn, New York. He invested $10 in a Fuller Products sales kit in 1957, and began selling hair care products door to door in African American neighborhoods. In 1960 he met Eunice Mosley, who was also selling Fuller products on a door-to-door basis. They married the following year.

The Dudleys settled in Greensboro, where they opened a Fuller distributorship. When there was a shortage of Fuller products in 1969, they began manufacturing and selling their own line under the Dudley Products label. Unlike many hair and skin care providers, Dudley chose to market his product line directly to salons rather than to retailers.

At the request of company founder S.B. Fuller, Dudley moved to Chicago, Illinois, and took over Fuller Products in 1976. They consolidated the company with their operations in 1980, keeping the Dudley Products brand name. Dudley moved the company back to Greensboro in 1984. As of December 2003, with annual revenues of $30 million, the company offers 400 hair and skin care products. It also operates the Dudley Cosmetology University, with locations in North Carolina and two schools in Zimbabwe.

Dudley and his company were featured in Chris Rock's 2009 documentary Good Hair; the company is one of only a handful of African-American-owned companies manufacturing hair products for the African-American community.

References

External links
 Joe L. Dudley biography on dudleyq.com
 Flexible Solar Panel

1939 births
Living people
People from Beaufort County, North Carolina
Businesspeople from Greensboro, North Carolina
North Carolina A&T State University alumni

Joe Dudley


Roel Paulissen (born 27 April 1976 in Hasselt) is a Belgian former professional mountain biker. Throughout his sporting career since 1993, he has won more than ten Belgian national championship titles, mounted top-five finishes at both the European and World Cup series, and claimed a total of four medals, including two golds, in men's cross-country race at the UCI Mountain Bike World Championships. Paulissen also represented his nation Belgium in four editions of the Olympic Games (1996, 2000, 2004, and 2008), where he competed in men's mountain biking since it officially became an Olympic sport in 1996. By the start of the 2010 season, Paulissen had been overshadowed by a doping issue after he tested positive for clomiphene that sidelined and effectively ended his mountain biking career. Having lifted a two-year suspension from doping in early 2013, Paulissen came out from his short retirement to join and race professionally for the Italian team Torpado.

Racing career

Early years
Born and raised in Hasselt, Paulissen discovered and started cycling at the age of sixteen, when he purchased his first ever mountain bike. He took part in numerous regional and local races across Belgium, and soon joined the Ghislain Cycles Club by the following year. In the summer of 1994, Paulissen surprisingly earned his first trophy under the junior category at the Belgian Championships. Because of his exquisite talent and prowess in the sport, Paulissen offered a spot to train and race professionally for the Dutch team called the American Eagle two years later.

International career
Paulissen officially made his international debut for Belgium at the 1996 Summer Olympics in Atlanta, where he finished seventeenth in the inaugural men's cross-country race with a time of 2:33:53.

At the 2000 Summer Olympics in Sydney, Paulissen could not match his best possible ride from Atlanta with a nineteenth-place effort in the same program, posting an official time of 2:16:54.

In 2001, Paulissen became an elite professional rider by officially signing an exclusive, two-year sponsorship contract with Italy's Rainer Wurz MTB Team, and then capped off his season by mounting four top-ten finishes at the UCI World Cup series. With a sudden departure of his teammate and Olympic silver medalist Filip Meirhaeghe because of a doping issue, Paulissen continued to refurnish and penetrate Belgium's cycling success by earning his first World Cup triumph in Houffalize, and a prestigious bronze medal in men's cross-country race at the 2003 UCI World Championships in Lugano, Switzerland. Strong results landed him a place on the Siemens Mobile-Cannondale pro cycling team, followed by his short stint with Belgium's Jong Vlaanderen 2016 at the start of the 2004 season.

While competing for his third Belgian squad at the 2004 Summer Olympics in Athens, Paulissen scored a career-high, fourth place in the men's cross-country race with a time of  2:18:10, finishing just off the podium by more than a minute. In that same year, Paulissen managed to earn another triumph on the second stage of the UCI World Cup series in Houffalize, and eventually edged out his teammate Meirhaeghe to take home the overall silver medal in the final round of the circuit. In 2005, Paulissen took a year off from mountain biking after he was suddenly stricken with rib injuries, fever, and acute bronchitis that prompted his decision to skip from the World Cup series and the Belgian Championships.

In 2006, Paulissen left his team Jong Vlaanderen 2016 for health reasons and long absence to join the Netherlands' Cannondale-Vredestein. He also capped his successful season by collecting the bronze medal in men's marathon race at the UCI World Championships in Oisans, France. A year later, Paulissen continued to flourish his ample success in mountain biking by reclaiming the Belgian national championship title, and later adding a silver to his career hardware at the UCI World Championships in Verviers, trailing behind Switzerland's Christoph Sauser by more than five minutes.

Paulissen won his first Absa Cape Epic in 2005 with team member Bart Brentjens. He then came back again in 2007 with new partner Jakob Fuglsang, placing 2nd place overall. The team then competed in the marathon stage race again in 2008, this time claiming 1st place after 2 stage wins.

2008 season
Paulissen started his 2008 season by defending the men's cross-country race title at the Belgian Championships and by taking part in the Roc d'Azur MTB Marathon tournament, where he registered two more triumphs in the process. In July, Paulissen grabbed his first major success in men's marathon race at the UCI World Championships in Villabassa under a more controversial decision. With only 70 meters left to go, Paulissen held off a sprint duel match against Switzerland's Christoph Sauser for a spectacular finish, until they suddenly made contact with their handlebars and arms near the barrier and then both crashed. Being the first man up after hitting the tarmac hard, Paulissen reluctantly carried his broken bike towards the finish, while his rival Sauser remounted his lead to cross the line first, but ended his campaign with a protest. After the race, the UCI officials decided that Sauser was relegated to second place for riding "dangerously" in the sprint and instead Paulissen was declared the World champion with a time of 4:46:56. Following his controversial triumph, Paulissen admitted, "I am very happy with this success. Unfortunately, this great race in the area where I live ended this way, but I think the jury was right."

Twelve years after his official Olympic debut, Paulissen qualified for his fourth Belgian squad, as a 32-year-old and a cycling team captain, in the men's cross-country race at the 2008 Summer Olympics in Beijing by receiving one of the nation's three available berths for his team from the Union Cycliste Internationale (UCI), based on his top-ten performance at the World Cup series, World Championships, and Mountain Biking World Series. He successfully completed a 4.8-km sturdy, treacherous cross-country course with a nineteenth-place effort in 2:03:30, radically shortening his chances to climb the Olympic podium on his fourth bid.

Post-Olympics
Paulissen started the 2009 season by claiming his tenth Belgian national championship title, and by signing an exclusive, two-year sponsorship contract with Germany's Cannondale Factory Racing pro team. He also defended his men's marathon race title and rainbow jersey at the UCI World Championships in Graz, Austria with a time of 4:34:46, edging out the home nation's Alban Lakata on another tight, sprinted duel match by fifty-one seconds.

On 16 July 2010 Paulissen had been overshadowed by a doping issue after he tested positive for a banned hormone substance clomiphene, mainly used to avert infertility problems. Breaching the team's clear anti-doping policies, Cannondale Factory Racing team had decided to end its sponsorship with Paulissen and consequently drop him off the roster. Moreover, he ordered a two-year suspension from the Union Cycliste Internationale (UCI) for failing the doping test, missing a chance to defend his Belgian national championship title and pursue for his fifth Olympic bid. With an immediate effect from an issue, Paulissen shortly and suddenly ended his sporting career.

Having lifted a two-year doping suspension in November 2012, Paulissen announced his official comeback from a short retirement to join and ride for Italy's Torpado Surfing Shop Team at the start of the 2013 season.

Career achievements

1996
 1st  Belgian MTB Championships (Cross-country, U23), Belgium
 17th Olympic Games (Cross-country), Atlanta, Georgia, (USA)
1998
  European Championships (Cross-country, U23), Belgium
  UCI World Championships (Cross-country, U23), Switzerland
1999
 1st  Belgian MTB Championships (Cross-country, U23), Belgium
 4th UCI World Championships (Cross-country, U23), Sweden
2000
 1st  Belgian MTB Championships (Cross-country), Belgium
  European Championships (Cross-country), Netherlands
 19th Olympic Games (Cross-country), Sydney, (AUS)
2001
 2nd Belgian MTB Championships (Cross-country), Belgium
  UCI World Cup (Cross-country), Kaprun (AUT)
2002
 1st  Belgian MTB Championships (Cross-country), Belgium
  UCI World Cup (Cross-country), Houffalize (BEL)
  European Championships (Cross-country), Lausanne (SUI)
  UCI World Cup (Cross-country), Madrid (ESP)
2003
 1st  Belgian MTB Championships (Cross-country), Belgium
 1st  Overall, Grouse Mountain Bike, Canada
  UCI World Championships (Cross-country), Lugano (SUI)
2004
 2nd Belgian MTB Championships (Cross-country), Belgium
  Overall, UCI World Cup (Cross-country)
  Stage 2, Houffalize (BEL) & Stage 3, Livigno (ITA)
  Stage 1, Madrid (ESP)
 3rd Alpago Trophy, Chies d'Alpago (ITA)
 4th Olympic Games (Cross-country), Athens, (GRE)
2005
 1st Cape Epic, Cape Town (RSA)
 1st  Overall, Roc d'Azur (Marathon), France
  Stage 1, UCI World Cup (Cross-country), Spa Francorchamps (BEL)
  Stage 6, UCI World Cup (Cross-country), Santa Catarina (BRA)
2006
 1st Stage 2, Sunshine Cup, Cyprus
 3rd Belgian MTB Championships (Cross-country), Bastogne (BEL)
  UCI World Championships (Marathon), Oisans (FRA)
 4th Stage 1, UCI World Cup (Cross-country), Curaçao (AHO)
 5th Stage 2, UCI World Cup (Cross-country), Madrid (ESP)
 5th Stage 3, UCI World Cup (Cross-country), Spa Francorchamps (BEL)
2007
 1st  Belgian MTB Championships (Cross-country), Belgium
 1st  Belgian MTB Championships (Marathon), Eijsden (NED)
 1st  Overall, Afxentia Stage Race, Cyprus
 2nd Stage 1 & 3
 3rd Stage 2
 2nd Overall Absa Cape Epic (Marathon)
  UCI World Championships (Marathon), Verviers (BEL)
 4th Overall, UCI World Cup (Cross-country)
  Stage 3, Champéry (SUI)
 4th Stage 4, Houffalize (BEL)
 5th Stage 2, Maribor (SLO)
2008
 1st  Belgian MTB Championships (Cross-country), Malmedy (BEL)
 1st Roc d'Azur (Cross-country & marathon), France
 1st  Mountain, Sunshine Cup, Voroklini (CYP)
   UCI World Championships (Marathon), Villabassa (ITA)
 1st Stage 1, Afxentia Stage Race, Cyprus
 1st  Overall Absa Cape Epic (Marathon)
 2nd Stage 3, Afxentia Stage Race, Cyprus
 7th UCI World Championships (Cross-country), Val di Sole (ITA)
 7th Stage 8, UCI World Cup (Cross-country), Canberra (AUS)
 8th Stage 1, UCI World Cup (Cross-country), Houffalize (BEL)
 12th Stage 4, UCI World Cup (Cross-country), Vallnord (AND)
 19th Olympic Games (Cross-country), Beijing (CHN)
 22nd Stage 5, UCI World Cup (Cross-country), Fort William (GBR)
2009
 1st  Belgian MTB Championships (Cross-country), Belgium
   UCI World Championships (Marathon), Graz (AUT)
2010
 1st Stage 3, Belgacom Grand Prix, Verviers (BEL)
 6th Stage 4, Belgacom Grand Prix, Averbode (BEL)
 12th Stage 3, UCI World Cup (Cross-country), Offenburg (GER)
 14th Stage 2, UCI World Cup (Cross-country), Houffalize (BEL)
2013
 2nd Belgian MTB Championships (Marathon), Belgium
 12th Roc d'Azur (Marathon), France
 19th UCI World Championships (Marathon), Kirchberg (AUT)
2017
 1st  Belgian MTB Championships (Marathon), Belgium

References

External links

NBC 2008 Olympics profile

1976 births
Living people
Belgian male cyclists
Cross-country mountain bikers
Cyclists at the 1996 Summer Olympics
Cyclists at the 2000 Summer Olympics
Cyclists at the 2004 Summer Olympics
Cyclists at the 2008 Summer Olympics
Olympic cyclists for Belgium
UCI Mountain Bike World Champions (men)
Sportspeople from Hasselt
Cyclists from Limburg (Belgium)
Cape Epic winners

Roel Paulissen


Fairview Wine and Cheese farm is a South African producer of wines and cheeses based in the Paarl region of the Western Cape province. It is owned and run by Charles Back, who also owns The Goats do Roam Wine Company and The Spice Route Winery.

Location
The Fairview farm is on the south western slopes of the Paarl mountain range, approximately 60 km from Cape Town. The farm comprises 320 hectares, of which 120 hectares are planted to vineyard. The farm ranges in altitude from 400m above sea level on the slopes of the mountain to 180m on the valley floor. The farm is located at 33°46'21″ south 18°55'25″ east.

Early history
The current Fairview property was first designated as a farm by the then Governor of the Cape Simon van der Stel in 1693, with Steven Vervey the first official owner. Vervey is thought to be one of the French Huguenots who arrived in the Cape in 1688. The earliest recorded name for the property is Bloemkoolfontein (directly translated from Afrikaans as cauliflower fountain) and hints at the mixed agriculture that took place on the property over the centuries. Towards the end of the 19th century the name of the property was officially changed to Fairview. Charles Back purchased the Fairview farm from a Mr Hugo in 1937 for the sum of 6500 pounds. Fairview has been in the Back family to the present day.

The Backs
Charles Louis Back was a Lithuanian immigrant to the Cape, who arrived in South Africa in 1902. He settled in Paarl where he set up a butcher shop as well as selling farm produce from the local farmers. Through these dealings he was offered a piece of land on the farm Klein Babylonstoren in the Paarl winelands. In 1916 Charles Back purchased what would later become the Backsberg farm from David Louw and left the butchery behind to become a wine farmer. In 1926 he was awarded the General Smuts Trophy for South Africa's champion wine. After establishing himself and learning the trade, Charles Back purchased Fairview from Hugo in 1937, for the sum of 6500 pounds. Charles Back had two sons, Sydney and Cyril, in whom Back instilled a love for the land, as well as a strong work ethic. When Charles died in 1955, he left Backsberg to Sydney and Fairview to Cyril.

Cyril spent much of his first years at Fairview replanting and planning vineyards. In 1974, Cyril broke away from the KWV; as a result, the first wines under the Fairview Estate label were bottled in this year. In 1975, Cyril held South Africa's first public wine auction and, together with his wife, Beryl, began to recognise the farm's possibilities of public visitation. Fairview become one of the first farms to open cellar door sales to the public.

Cyril's son, Charles, joined Fairview in 1978, after completing his winemaking studies at Elsenburg agricultural college. In 1981, Charles built Fairview's goat tower.

History
The first recorded wine production on the property was in 1699 and wine grape cultivation has continued to this day. When Charles Back purchased Fairview in 1937 the farm was primarily planted to the then common varietal Cinsau(l)t, and this formed the majority of the wine produced at Fairview in the 1940s and 1950s.

When Cyril Back took over in 1955, following his father's death, he replanted most of the Fairview vineyards. He introduced Cabernet Sauvignon, Shiraz and Pinotage to the property. In 1974 Cyril Back was amongst the first producers to break away from the strictly regulated body controlling South African wine at the time, where grape growers supplied their grapes to the co-operative KWV. He established Fairview as an independent estate and the first wines were bottled under the Fairview label in 1974, from grapes grown exclusively on the Fairview property. The first wines bottled were a Cabernet Sauvignon, Shiraz and Pinotage. In 1975 Cyril Back held South Africa's first public wine auction, with his entire 1975 production selling in under three hours. This auction pre-dated the now famous Nederburg Auction, which started the following year.

With Charles Back joining his father in 1978, Fairview's range of wines began to diversify, with white wines being added to the portfolio and new varietals being planted. Charles also introduced innovative winemaking practices. Using the Gamay varietal, Fairview produced South Africa's first Beaujolais nouveau style wine in 1987 using the traditional carbonic maceration method. During the late 1980s Charles began watch the international wine trends more closely, making subtle adjustments to bring the quality of his wines in line with international standards. These markets had always been closed to South African wines due to Apartheid sanctions. Charle's proactive approach meant that when democracy came to South Africa and the markets opened, Fairview's wine style and quality was quickly recognised internationally. Cyril Back died in 1995 and Charles took full control of Fairview. In 1997 Charles Back appointed Anthony de Jager as head winemaker at Fairview.

Current production
Approximately 50 000 twelve bottle cases are produced under the Fairview label annually. Seventy percent of Fairview's production is exported, with the company's leading export markets being the United States, Canada, the United Kingdom, Sweden and Germany.
In 2008 Fairview launched the La Capra range of wines, an endorsed label targeting the retail and value end of the wine market.

Grape varietals
Fairview produces a wide range of varietals under its label and 70% of production is red wine. Grapes for these wines are sourced from Charles Back's own vineyards as well as from contracted growers.
Amongst others, the Fairview range of wines includes:
White wines: Sauvignon Blanc, Riesling, Chardonnay, Viognier, Oom Pagel Semillon and Viognier Special Late Harvest.
Red wines: Shiraz, Pinotage, Mourvèdre, Cabernet Sauvignon, Merlot, Tannat, Petite Sirah, Pinotage Viognier, Sweet Red, Solitude Shiraz, The Beacon Shiraz, Jakkalsfontein Shiraz, Pegleg Carignan, Primo Pinotage and the farm's flagship Cyril Back.

Cheesemaking at Fairview

History
Cheese production at Fairview started in 1980, when Cyril Back purchased a herd of Saanen milking goats and brought them to the farm. At the time, goats milk cheese was an unknown product in South Africa. Cyril employed the assistance of Michele Agostinelli to begin the Fairview Vineyard Cheesery, producing a small range of goats' milk cheeses for sale from the farm. In 1992, Louis Lourens was employed as head cheese maker. In 1995 Jersey milk was introduced and subsequently the range of cheeses produced expanded to include cow's milk cheeses as well as a range of products combining cow and goats' milk.

Current production
Fairview is South Africa's leading producer of artisanal and speciality cheeses. In 2008, the Fairview goat herd is the largest commercial goat herd in Africa, numbering 750 does in the permanent milking herd. The milk from these goats, along with the milk from an exclusive single Jersey cow herd are brought to the Vineyard Cheesery daily. There are over twenty permanent lines in the Fairview cheese range, including blue mould, white mould and cream cheese products.  These products are available at major retailers throughout South Africa.

Tourism
Fairview Wine and Cheese estate is one of the most visited attractions in the Cape winelands. The farm offers tasting of its full range of wines and cheeses in their tasting room, seven days a week. There is also an eatery on the farm, which is housed in a converted wine cellar. Wine tourism has seen strong growth in South Africa and Fairview's combination of wine and cheese is very popular amongst locals as well as international tourists.

See also
 Goat tower
 Spice Route Paarl
 South African wine

External links
Fairview official website

Wineries of South Africa
South African brands
Paarl
Buildings and structures in the Western Cape
Tourist attractions in the Western Cape

Fairview Wine and Cheese


The Colt Mk 12 is a 20 mm autocannon that was widely used by the United States Navy after World War II.

Development
The Mk 12 was an advanced derivative of the wartime Hispano HS 404 that was used on French, British and some American fighter aircraft during World War II. It used a lighter projectile with a bigger charge for better muzzle velocity and higher rate of fire at the cost of hitting power. It entered U.S. Navy and U.S. Marine Corps service in the mid-1950s, replacing the earlier M3 cannon.

In service, the Mk 12 proved less than satisfactory. Although its muzzle velocity and rate of fire were acceptable, it was inaccurate and frequently unreliable. Pilots of the F-8 Crusader over North Vietnam, in particular, appreciated the presence of the cannon, but jams and stoppages were common, especially following hard dogfighting maneuvers.

Nevertheless, the Mk 12 was standard cannon armament on gun-armed American naval fighters and attack aircraft from the early 1950s to the early 1970s, including the F4D Skyray, F3H Demon, A-4 Skyhawk, F-8 Crusader, F-11 Tiger and early navy versions of the LTV A-7 Corsair II.

International customers of the A-4 Skyhawk, F-8 Crusader, and the A-7 Corsair II also used the Mk 12 cannon: Argentina, Australia, Brazil, France, Kuwait, Malaysia, New Zealand, the Philippines and Portugal. The only exceptions were Israel and Singapore. The Israeli Air Force replaced the Mk 12 cannon with the French 30 mm DEFA cannon (a revolver design) in its Skyhawks, while the Republic of Singapore Air Force fitted the British 30 mm ADEN cannon (another revolver). Indonesia later bought some used A-4s from Israel.

As of 2013, the Mk 12 cannon is still in use in Skyhawks of the Argentine Air Force and the Brazilian Navy.

See also
 M39 cannon

Autocannon
Aircraft guns
20 mm artillery

Colt Mk 12 cannon