Botulinum toxin

neurotoxin protein produced by the bacterium Clostridium botulinum. It is one of the most poisonous naturally occurring substances in the world, and it is the most toxic protein.^[1] Though it is highly toxic, it is used in minute doses both to treat painful muscle spasms, and as a cosmetic treatment in some parts of the world. It is sold commercially under the brand names Botox, Dysport, and Myobloc for this purpose. The terms Botox, Dysport, and Myobloc are trade names and are not used generically to describe the neurotoxins produced by C. botulinum.

History

Between 1817 and 1822 the German physician and poet Justinus Kerner described botulinium toxin, using the terms "sausage poison" and "fatty poison"^[2], as this bacterium often causes poisoning by growing in badly handled or prepared meat products. He first conceived a possible therapeutic use of botulinium toxin. In 1870, Muller (another German physician) coined the name botulism, from Latin botulus = "sausage". In 1895, Emile van Ermengem first isolated the bacterium Clostridium botulinum. In 1944, Edward Schantz cultured Clostridium botulinum and isolated the toxin, and, in 1949, Burgen’s group discovered that botulinum toxin blocks neuromuscular transmission.

By 1973, Alan B Scott, MD, of Smith-Kettlewell Institute used botulinium toxin type A (BTX-A) in monkey experiments, and, in 1980, he officially used BTX-A for the first time in humans to treat strabismus. In December 1989, BTX-A (BOTOX) was approved by the US Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients over 12 years old. The cosmetic effect of BTX-A was initially described by ophthalmologist Jean Carruthers and dermatologist Alastair Carruthers, a husband-and-wife team working in Vancouver, Canada, although the effect had been observed by a number of independent groups. On April 15, 2002, the FDA announced the approval of botulinum toxin type A (BOTOX Cosmetic) to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines). BTX-A has also been approved for the treatment of excessive underarm sweating. The acceptance of BTX-A use for the treatment of spasticity and muscle pain disorders is growing, with approvals pending in many European countries and studies on headaches (including migraine), prostatic symptoms, asthma, obesity and many other possible indications are ongoing.

Botox is manufactured by Allergan Inc (U.S.) for both therapeutic as well as cosmetic use. The formulation is best stored at cold temperature of 2-8 degrees Celsius. Dysport is a therapeutic formulation of the type A toxin developed and manufactured in Ireland and which is licenced for the treatment of focal dystonias and certain cosmetic uses in many territories world wide. Neuronox is a new type A toxin manufactured by Medy-Tox Inc (South Korea).

Botulinium Toxin Type B (BTX-B) received FDA approval for treatment of cervical dystonia on December 21, 2000. Trade names for BTX-B are Myobloc in the United States, and Neurobloc in the European Union.

Chemical overview & lethality

There are seven serologically distinct toxin types, designated A through G; 3 subtypes of A have been described. The toxin is a two-chain polypeptide with a 100-kDa heavy chain joined by a disulfide bond to a 50-kDa light chain. This light chain is an enzyme (a protease) that attacks one of the fusion proteins (SNAP-25, syntaxin or synaptobrevin) at a neuromuscular junction, preventing vesicles from anchoring to the membrane to release acetylcholine. By inhibiting acetylcholine release, the toxin interferes with nerve impulses and causes flaccid (sagging) paralysis of muscles in botulism as opposite to the spastic paralysis seen in tetanus.

It is possibly the most acutely toxic substance known, with a median lethal dose of about 1 ng/kg^[3], meaning that a few hundred grams could theoretically kill every human on earth (for perspective, the rat poison strychnine, often described as highly toxic, has an LD₅₀ of 1,000,000 ng/kg, and it would take four hundred tons to kill every human).

It is also remarkably easy to come by: Clostridium spores are found in soil practically all over the earth.

Food-borne botulism usually results from ingestion of food that has become contaminated with spores (such as a perforated can) in an anaerobic environment, allowing the spores to germinate and grow. The growing (vegetative) bacteria produce toxin. It is the ingestion of preformed toxin that causes botulism, not ingestion of the spores or vegetative organism.

Infant (intestinal) and wound botulism both result from infection with spores which subsequently germinate, resulting in production of toxin and the symptoms of botulism.

The toxin itself is rapidly destroyed by heat, such as in thorough cooking.^[4] However, the spores which produce the toxin are heat-tolerant and will survive boiling at 100 degrees Celsius for an extended period of time. ^[5]

Medical uses

Researchers discovered in the 1950s that injecting overactive muscles with minute quantities of botulinum toxin type A decreased muscle activity by blocking the release of acetylcholine at the neuromuscular junction, thereby rendering the muscle unable to contract for a period of 4 to 6 months.^{[citation needed]}

Alan Scott, a San Francisco ophthalmologist, first applied tiny doses of the toxin in a medicinal sense to treat ‘crossed eyes’ (strabismus) and ‘uncontrollable blinking’ (blepharospasm), but needed a partner to gain regulatory approval to market his discovery as a drug. Allergan, Inc., a pharmaceutical company that focused on prescription eye therapies and contact lens products, bought the rights to the drug in 1988 and received FDA approval in 1989.^{[citation needed]} Allergan renamed the drug Botox.

Cosmetically desirable effects of Botox were first discovered by Vancouver-based cosmetic surgeons Drs. Alastair and Jean Carruthers.^[6] The serendipitous discovery occurred when the husband-and-wife team observed the softening of patients’ frown lines following treatment for eye muscle disorders, leading to clinical trials and subsequent FDA approval for cosmetic use in April 2002.^{[citation needed]} As of 2006, Botox injection is the most common cosmetic operation in the United States.^{[citation needed]}

Besides its cosmetic application, Botox is used in the treatment of

• migraine headaches

• cervical dystonia (spasmodic torticollis) (a neuromuscular disorder involving the head and neck)^[7]

• blepharospasm (involuntary blinking)^[8]

• severe primary axillary hyperhidrosis (excessive sweating)^[9]

• Achalasia (failure of the lower esophageal sphincter to relax)

Other uses of botulinum toxin type A that are widely known but not specifically approved by FDA include treatment of:

• pediatric incontinence^[10], incontinence due to overactive bladder,^[11] and incontinence due to neurogenic bladder.^[12]

• anal fissure^[13]

• spastic disorders associated with injury or disease of the central nervous system including trauma, stroke, multiple sclerosis, Parkinson’s disease, or cerebral palsy

• focal dystonias affecting the limbs, face, jaw, or vocal cords

• TMJ pain disorders

• diabetic neuropathy

• wound healing

• excessive salivation

• VCD Vocal Cord Dysfunction a spasming of the vocal cords

• Reduction of the Masseter muscle for decreasing the size of the lower jaw

In the Journal of Dermatologic Surgery, Eric Finzi claims to have treated clinically depressed patients with botox. On Good Morning America, he claimed that by taking away the ability to frown, he was somehow taking away the ability to feel depressed.^[14]

Treatment and prevention of chronic headache^[15] and chronic musculoskeletal pain^[16] are emerging uses for botulinum toxin type A. In addition, there is evidence that Botox may aid in weight loss by increasing the gastric emptying time.^[17]

Links to deaths

On September 2005, a paper published in the Journal of American Academy of Dermatology reported from the FDA saying that use of Botox has resulted in 28 deaths between 1989 and 2003, though none were attributed to cosmetic use.^[18]

On February 8, 2008, the FDA announced that Botox has "been linked in some cases to adverse reactions, including respiratory failure and death, following treatment of a variety of conditions using a wide range of doses," due to its ability to spread to areas distant to the site of the injection.^[19]

Several cases of death have been linked to the use of fake Botox.^[20]

Side effects

Side effects can be predicted from the mode of action (muscle paralysis) and chemical structure (protein) of the molecule, resulting broadly speaking in two major areas of side effects: paralysis of the wrong muscle group and allergic reaction. Bruising at the site of injection is a side effect not of the toxin, but rather the mode of administration. In cosmetic use, this means that the client will complain of inappropriate facial expression such as drooping eyelid, uneven smile, loss of ability to close the eye. This will wear off in around 6 weeks. Bruising is prevented by the clinician applying pressure to the injection site, but may still occur, and will last around 7 - 10 days. When injecting the masseter muscle of the jaw, loss of muscle function will result in a loss or reduction of power to chew solid foods. All cosmetic treatments are of limited duration, and can be as short a period as six weeks, but usually one reckons with an effective period of between 3 and 8 months. At the extremely low doses used medicinally, botulinum toxin has a very low degree of toxicity.

Reported adverse events from cosmetic use includes headaches, focal facial paralysis, muscle weakness, dysphagia, flu-like syndromes, and allergic reactions^[21].

There has been a petition by Public Citizen to the FDA requesting regulatory action concerning the possible spread of botulinum toxin (Botox, Myobloc) from the site of injection to other parts of the body (HRG Publication #1834): Public Citizen

[edit] Biochemical mechanism of toxicity

The heavy chain of the toxin is particularly important for targeting the toxin to specific types of axon terminals. The toxin must get inside the axon terminals in order to cause paralysis. Following the attachment of the toxin heavy chain to proteins on the surface of axon terminals, the toxin can be taken into neurons by endocytosis. The light chain is able to leave endocytotic vesicles and reach the cytoplasm. The light chain of the toxin has protease activity. The type A toxin proteolytically degrades the SNAP-25 protein, a type of SNARE protein. The SNAP-25 protein is required for the release of neurotransmitters from the axon endings.^[22] Botulinum toxin specifically cleaves these SNAREs, and so prevents neuro-secretory vesicles from docking/fusing with the nerve synapse plasma membrane and releasing their neurotransmitters.

Though it affects the nervous system, common nerve agent treatments (namely the injection of atropine and 2-pam-chloride) will increase mortality by enhancing botulin toxin’s mechanism of toxicity. Attacks involving botulinum toxin are distinguishable from those involving nerve agent in that NBC detection equipment (such as M-8 paper or the ICAM) will not indicate a "positive" when a sample of the agent is tested. Furthermore, botulism symptoms develop relatively slowly, over several days compared to nerve agent effects, which can be instantaneous.

Documented outbreaks

Please help improve this article or section by expanding it. Further information might be found on the talk page or at requests for expansion. (March 2008)

Bon Vivant incident

On July 2, 1971 the FDA released a public warning after learning that a New York man had died and his wife had become seriously ill due to botulism after eating a can of Bon Vivant vichyssoise soup. The company began a recall of the 6,444 cans of vichyssoise soup made in the same batch as the can known to be contaminated. The FDA discovered that the company’s processing practices raised questions not only about these lots of the vichyssoise, but also about all other products packed by the company. The effectiveness check of the recall had revealed a number of swollen or otherwise suspect cans among Bon Vivant’s other products, so FDA extended the recall to include all Bon Vivant products. The FDA shut down the company’s Newark, New Jersey plant on July 7, 1971. Only five cans of Bon Vivant soup were found to be contaminated with the botulin toxin, all in the initial batch of vichyssoise recalled and part of the first 324 cans tested. The ordeal destroyed public confidence in the company’s products and the Bon Vivant name. Bon Vivant filed for bankruptcy within a month of the announcement of the recall. ^[23]

Treatment of botulinum poisoning

The case fatality rate for botulinum poisoning between 1950 and 1996 was 15.5%, down from approximately 60% over the previous 50 years.^[24] Death is generally secondary to respiratory failure due to paralysis of the respiratory muscles, so treatment consists of antitoxin administration and artificial ventilation. If initiated on time, these are quite effective. Occasionally, functional recovery may take several weeks to months.

There are two primary Botulinum Antitoxins available for treatment of botulism.

• Trivalent (A,B,E) Botulinum Antitoxin is derived from equine sources utilizing whole antibodies (Fab & Fc portions). This antitoxin is available from the local health department via the CDC.

• The second antitoxin is Heptavalent (A,B,C,D,E,F,G) Botulinum Antitoxin which is derived from "despeciated" equine IgG antibodies which have had the Fc portion cleaved off leaving the F(ab’)2 portions. This is a less immunogenic antitoxin that is effective against all known strains of botulism where not contraindicated. This is available from the US Army. On June 1, 2006 the US Department of Health and Human Services awarded a $363 million contract with Cangene Corporation for 200,000 doses of Heptavalent Botulinum Antitoxin over five years for delivery into the Strategic National Stockpile beginning in 2007.^[25]

 

  represents a range of human emotions and experiences related to the senses of affection and sexual attraction.^[1] The word love can refer to a variety of different feelings, states, and attitudes, ranging from generic pleasure to intense interpersonal attraction. This diversity of meanings, combined with the complexity of the feelings involved, makes love unusually difficult to consistently define, even compared to other emotional states.

As an abstract concept love usually refers to a strong, ineffable feeling towards another person. Even this limited conception of love, however, encompasses a wealth of different feelings, from the passionate desire and intimacy of romantic love to the nonsexual. Love in its various forms acts as a major facilitator of interpersonal relationships and, owing to its central psychological importance, is one of the most common themes in the creative arts.

 

Definitions

The English word love can have a variety of related but distinct meanings in different contexts. Often, other languages use multiple words to express some of the different concepts which English relies mainly on love to encapsulate; one example is the plurality of Greek words for "love". Cultural differences in conceptualizing love thus make it doubly difficult to establish any universal definition.^[2]American psychologist Zick Rubin try to define love by the psychometrics. His work states that three factors consititute love: attachment, caring and intimacy.^[3][4]

Although the nature or essence of love is a subject of frequent debate, different aspects of the word can be clarified by determining what isn’t "love". As a general expression of positive sentiment (a stronger form of like), love is commonly contrasted with hate (or neutral apathy); as a less sexual and more emotionally intimate form of romantic attachment, love is commonly contrasted with lust; and as an interpersonal relationship with romantic overtones, love is commonly contrasted with friendship, though other definitions of the word love may be applied to close friendships in certain contexts. When discussed in the abstract, love usually refers to interpersonal love, an experience felt by a person for another person. Love often involves caring for or identifying with a person or thing, including oneself (cf. narcissism).

John Major has his own idiosyncratic definition of love^[5]. According to this version, the best sort of relationship involves both pints (of beer) and sex; a suboptimal relationship has only beer or sex; but love is what is left in the relationship once beer and sex are removed.

In addition to crosscultural differences in understanding love, ideas about love have also changed greatly over time. Some historians date modern conceptions of romantic love to courtly Europe during or after the Middle Ages, though the prior existence of romantic attachments is attested by ancient love poetry.^[6] Because of the complex and abstract nature of love, discourse on love is commonly reduced to a thought-terminating cliché, and there are a number of common proverbs regarding love, from Virgil’s "Love conquers all" to The Beatles‘ "All you need is love". Bertrand Russell describes love as a condition of "absolute value", as opposed to relative value. Theologian Thomas Jay Oord said that to love is to "act intentionally, in sympathetic response to others, to promote overall well-being".^[7]

In the Holy Bible1 Corinthians 13 Love is defined as:

1If I speak in the tongues of men and of angels, but have not love, I am only a resounding gong or a clanging cymbal. 2If I have the gift of prophecy and can fathom all mysteries and all knowledge, and if I have a faith that can move mountains, but have not love, I am nothing. 3If I give all I possess to the poor and surrender my body to the flames, but have not love, I gain nothing. 4Love is patient, love is kind. It does not envy, it does not boast, it is not proud. 5It is not rude, it is not self-seeking, it is not easily angered, it keeps no record of wrongs. 6Love does not delight in evil but rejoices with the truth. 7It always protects, always trusts, always hopes, always perseveres. 8Love never fails. But where there are prophecies, they will cease; where there are tongues, they will be stilled; where there is knowledge, it will pass away. 9For we know in part and we prophesy in part, 10but when perfection comes, the imperfect disappears. 11When I was a child, I talked like a child, I thought like a child, I reasoned like a child. When I became a man, I put childish ways behind me. 12Now we see but a poor reflection as in a mirror; then we shall see face to face. Now I know in part; then I shall know fully, even as I am fully known. 13And now these three remain: faith, hope and love. But the greatest of these is love.

A person can be said to love a country, principle, or goal if they value it greatly and are deeply committed to it. Similarly, compassionate outreach and volunteer workers’ "love" of their cause may sometimes be borne not of interpersonal love, but impersonal love coupled with altruism and strong political convictions. People can also "love" material objects, animals, or activities if they invest themselves in bonding or otherwise identifying with that item. If sexual passion is also involved, this condition is called paraphilia.^[8]

Interpersonal love

Interpersonal love refers to love between human beings. It is a more potent sentiment than a simple liking for another. Unrequited love refers to those feelings of love which are not reciprocated. Interpersonal love is most closely associated with interpersonal relationships. Such love might exist between family members, friends, and couples. There are also a number of psychological disorders related to love, such as erotomania.

Scientific views

Throughout history, philosophy and religion have done the most speculation on the phenomenon of love. In the last century, the science of psychology has written a great deal on the subject. In recent years, the sciences of evolutionary psychology, evolutionary biology, anthropology, neuroscience, and biology have added to the understanding of the nature and function of love.

Chemistry

Biological models of sex tend to view love as a mammalian drive, much like hunger or thirst.^[9] Helen Fisher, a leading expert in the topic of love, divides the experience of love into three partly-overlapping stages: lust, attraction, and attachment. Lust exposes people to others, romantic attraction encourages people to focus their energy on mating, and attachment involves tolerating the spouse long enough to rear a child into infancy.

Lust is the initial passionate sexual desire that promotes mating, and involves the increased release of chemicals such as testosterone and estrogen. These effects rarely last more than a few weeks or months. Attraction is the more individualized and romantic desire for a specific candidate for mating, which develops out of lust as commitment to an individual mate forms. Recent studies in neuroscience have indicated that as people fall in love, the brain consistently releases a certain set of chemicals, including pheromones, dopamine, norepinephrine, and serotonin, which act similar to amphetamines, stimulating the brain’s pleasure center and leading to side-effects such as an increased heart rate, loss of appetite and sleep, and an intense feeling of excitement. Research has indicated that this stage generally lasts from one and a half to three years.^[10]

Since the lust and attraction stages are both considered temporary, a third stage is needed to account for long-term relationships. Attachment is the bonding which promotes relationships that last for many years, and even decades. Attachment is generally based on commitments such as marriage and children, or on mutual friendship based on things like shared interests. It has been linked to higher levels of the chemicals oxytocin and vasopressin than short-term relationships have.^[10] In 2005, Italian scientists at Pavia University found that a protein molecule known as the nerve growth factor (NGF) has high levels when people first fall in love, but these levels return to as they were after one year. Specifically, four neurotrophin levels, i.e. NGF, BDNF, NT-3, and NT-4, of 58 subjects who had recently fallen in love were compared with levels in a control group who were either single or already engaged in a long-term relationship. The results showed that NGF levels were significantly higher in the subjects in love than as compared to either of the control groups.^[11]

Psychology

Further information: Human bonding

Psychology depicts love as a cognitive and social phenomenon. Psychologist Robert Sternberg formulated a triangular theory of love and argued that love has three different components: intimacy, commitment, and passion. Intimacy is a form in which two people share confidences and various details of their personal lives. Intimacy is usually shown in friendships and romantic love affairs. Commitment, on the other hand, is the expectation that the relationship is permanent. The last and most common form of love is sexual attraction and passion. Passionate love is shown in infatuation as well as romantic love. All forms of love are viewed as varying combinations of these three components.

Following developments in electrical theories, such as Coulomb’s law, which showed that positive and negative charges attract, analogs in human life were developed, such as "opposites attract". Over the last century, research on the nature of human mating has generally found this not to be true when it comes to character and personality; people tend to like people similar to themselves. However, in a few unusual and specific domains, such as immune systems, it seems that humans prefer others who are unlike themselves (e.g. with an orthogonal immune system), since this will lead to a baby which has the best of both worlds.^[12] In recent years, various human bonding theories have been developed described in terms of attachments, ties, bonds, and affinities.

Some Western authorities disaggregate into two main components, the altruistic and the narcissistic. This view is represented in the works of Scott Peck, whose works in the field of applied psychology explored the definitions of love and evil. Peck maintains that love is a combination of the "concern for the spiritual growth of another", and simple narcissism.^[13] In combination, love is an activity, not simply a feeling.

Scientific models

Biological models of love tend to see it as a mammalian drive, similar to hunger or thirst.^{[citation needed]} Psychology sees love as more of a social and cultural phenomenon. There are probably elements of truth in both views — certainly love is influenced by hormones (such as oxytocin), neurotrophins (such as NGF), and pheromones, and how people think and behave in love is influenced by their conceptions of love. The conventional view in biology is that there are two major drives in love — sexual attraction and attachment. Attachment between adults is presumed to work on the same principles that lead an infant to become attached to its mother. The traditional psychological view sees love as being a combination of companionate love and passionate love. Passionate love is intense longing, and is often accompanied by physiological arousal (shortness of breath, rapid heart rate). Companionate love is affection and a feeling of intimacy not accompanied by physiological arousal.

Studies have shown that brain scans of those infatuated by love display a resemblance to those with a mental illness. Love creates activity in the same area of the brain that hunger, thirst, and drug cravings create activity in. New love, therefore, could possibly be more physical than emotional. Over time, this reaction to love mellows, and different areas of the brain are activated, primarily ones involving long-term commitments. Dr. Andrew Newberg, a neuroscientist, suggests that this reaction to love is so similar to that of drugs because without love, humanity would die out.