Jump to content

Common cold

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Jocorok (talk | contribs) at 09:32, 29 September 2009 (Conservative management). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Common cold
SpecialtyFamily medicine, infectious diseases, otorhinolaryngology Edit this on Wikidata

Acute viral rhinopharyngitis, or acute coryza, known as an upper respiratory virus, or commonly called a cold, is a contagious, viral infectious disease of the upper respiratory system, primarily caused by rhinoviruses, (picornaviruses) or coronaviruses. It is the most common infectious disease in humans[citation needed]; there is no known cure, but it is very rarely fatal.

Collectively, colds, influenza, and other infections with similar symptoms are included in the diagnosis of influenza-like illness. Often, influenza and the common cold are mistaken for each other, even by professional healthcare workers, although most of the recommended home treatments (drinking plenty of warm fluids, keeping warm, etc.) are similar if not the same. The symptoms of influenza often include a fever, however, and are more severe than the cold.

Symptoms

Common symptoms are cough, sore throat, runny nose, blocked nose, and sneezing; sometimes accompanied by 'pink eye', muscle aches, fatigue, malaise, headaches, muscle weakness, uncontrollable shivering, loss of appetite, and rarely extreme exhaustion. Fever is more commonly a symptom of influenza, another viral upper respiratory tract infection (URTI) whose symptoms broadly overlap with the cold[1] but are more severe.[2] Symptoms may be more severe in infants and young children (due to their immune system not being fully developed) as well as the elderly (due to their immune system often being weakened).

Those suffering from colds often report a sensation of chilliness even though the cold is not generally accompanied by fever, and although chills are generally associated with fever, the sensation may not always be caused by actual fever.[1] In one study, 60% of those suffering from a sore throat and upper respiratory tract infection reported headaches[1], often due to nasal congestion. The symptoms of a cold usually resolve after about one week; however, it is not rare that symptoms last up to three weeks.

Complications

The common cold can lead to opportunistic coinfections or superinfections such as acute bronchitis, bronchiolitis, croup, pneumonia, sinusitis, otitis media, or strep throat. People with chronic lung diseases such as asthma and COPD are especially vulnerable. Colds may cause acute exacerbations of asthma, emphysema or chronic bronchitis.[3]

Cause and susceptibility

The common cold is most often caused by infection with one of the 99 known serotypes of rhinovirus, a type of picornavirus.[4][5] Around 30-50% of colds are caused by rhinoviruses.[1] Other viruses causing colds are coronavirus (causing 10-15%[1]), human parainfluenza viruses, human respiratory syncytial virus, adenoviruses, enteroviruses, or metapneumovirus.[6] 5-15% are caused by influenza viruses.[1] In total over 200 serologically different viral types cause colds.[1] Coronaviruses are particularly implicated in adult colds. Of over 30 coronaviruses, 3 or 4 cause infections in humans, but they are difficult to grow in the laboratory and their significance is thus less well-understood.[6] Due to the many different types of viruses and their tendency for continuous mutation, it is impossible to gain complete immunity to the common cold.

Sleep

Lack of sleep has been associated with the common cold. Those who sleep fewer than 7 hours per night were three times more likely to develop an infection when exposed to a rhinovirus when compared to those who sleep more than 8 hours per night.[7] Some argue[who?] that, although the hour may seem a small amount, it allows the immune system to build up slightly more, allowing our bodies to protect against the cold along with other infections.[citation needed]

Vitamin D

A 2009 study found that low levels of vitamin D were associated with increased rates of the common cold.[8] Whether taking vitamin D supplements decreases rates of cold has not yet been determined.

Exposure to cold weather

Exposure to cold weather has not been proven to increase the likelihood of "catching" a cold

An ancient belief still common today claims that a cold can be "caught" by prolonged exposure to cold weather such as rain or winter conditions, which is where the disease got its name.[9] Although common colds are seasonal, with more occurring during winter, experiments so far have failed to produce evidence that short-term exposure to cold weather or direct chilling increases susceptibility to infection, implying that the seasonal variation is instead due to a change in behaviors such as increased time spent indoors at close proximity to others.[6][10][11][12][13]

With respect to the causation of cold-like symptoms, researchers at the Common Cold Centre at Cardiff University[14] conducted a study to "test the hypothesis that acute cooling of the feet causes the onset of common cold symptoms."[15][16][17] The study measured the subjects' self-reported cold symptoms, and belief they had a cold, but not whether an actual respiratory infection developed. It found that a significantly greater number of those subjects chilled developed cold symptoms 4 or 5 days after the chilling. It concludes that the onset of common cold symptoms can be caused by acute chilling of the feet. Some possible explanations were suggested for the symptoms, such as placebo, or constriction of blood vessels of the nasal passages which might lead to reduced immunity, however "further studies are needed to determine the relationship of symptom generation to any respiratory infection."

Another possibility which remains to be explored involves the role that proteins of the complement system play in the prevention of a sustained infection. Decreased temperature may result in a drop in tissue permeability and, as a result, may lead to reduced plasma leakage. Among the many proteins suspended in plasma are complement proteins (e.g. C3) which serve to disable, destroy, or tag for destruction foreign particulate (in this case viral capsids). Thus, sustained exposure to cold may inhibit the effectiveness of the complement system and allow the virus a better chance of establishing a state of infection.[citation needed]

ICAM-1, the receptor that Rhinovirus binds to in order to infect cells, is known to increase in number and receptiveness in response to many irritants, including dust and pollen. That a cold climate in combination with varying degrees of humidity can act as a similar "irritant" needs to be investigated.[citation needed]

Pathophysiology

The common cold is a disease of the upper respiratory tract

The common cold virus is transmitted mainly from contact with the saliva or nasal secretions of an infected person, either directly, in aerosol form generated by coughing and sneezing, or from contaminated surfaces.[18]

Symptoms are not necessary for viral shedding or transmission, as a percentage of asymptomatic subjects exhibit viruses in nasal swabs.[19] It is generally not possible to identify the virus type through symptoms, although influenza can be distinguished by its sudden onset, fever, and cough.[1]

The major entry point for the virus is normally the nose, but can also be the eyes (in this case drainage into the nasopharynx would occur through the nasolacrimal duct). From there, it is transported to the back of the nose and the adenoid area. The virus then attaches to a receptor, ICAM-1, which is located on the surface of cells of the lining of the nasopharynx. The receptor fits into a docking port on the surface of the virus. Large amounts of virus receptor are present on cells of the adenoid. After attachment to the receptor, virus is taken into the cell, where it starts an infection.[3] Rhinovirus colds do not generally cause damage to the nasal epithelium. Macrophages trigger the production of cytokines, which in combination with mediators cause the symptoms. Cytokines cause the systemic effects. The mediator bradykinin plays a major role in causing the local symptoms such as sore throat and nasal irritation.[1]

The common cold is self-limiting, and the host's immune system effectively deals with the infection. Within a few days, the body's humoral immune response begins producing specific antibodies that can prevent the virus from infecting cells. Additionally, as part of the cell-mediated immune response, leukocytes destroy the virus through phagocytosis and destroy infected cells to prevent further viral replication. In healthy, immunocompetent individuals, the common cold resolves in seven days on average.[3]

Incubation period and progression of disease

The upper respiratory viral replication cycle begins 8 to 12 hours after initial infection.[3] Symptoms usually begin 2 to 5 days after initial infection but occasionally occur in as little as 10 hours after.[20] Symptoms peak 2–3 days after symptom onset, whereas influenza symptom onset is constant and immediate.[1] The symptoms usually resolve spontaneously in 7 to 10 days but some can last for up to three weeks.[21]

The first indication of an upper respiratory virus is often a sore or scratchy throat. Other common symptoms are runny nose, congestion, and sneezing.[6] These are sometimes accompanied by muscle aches, fatigue, malaise, headache, weakness, or loss of appetite.[14] Cough and fever generally indicate influenza rather than an upper respiratory virus with a positive predictive value of around 80%.[1] Symptoms may be more severe in infants and young children, and in these cases it may include fever and hives.[22] Upper respiratory viruses may also be more severe in smokers.[23]

Prevention

The best way to avoid a cold is to wash hands thoroughly and regularly; and to avoid touching the eyes, nose, mouth, and face. Anti-bacterial soaps have no extraordinary effect on the cold virus; it is the mechanical action of hand washing with the soap that removes the virus particles.[24] Rhinoviruses can live up to 3 hours outside the body on the skin or objects.[6]

In 2002, the Centers for Disease Control and Prevention recommended alcohol-based hand gels as an effective method for reducing infectious viruses on the hands of health care workers.[25] As with hand washing with soap and water, alcohol gels provide no residual protection from re-infection.

The common cold is caused by a large variety of viruses, which mutate quite frequently during reproduction, resulting in constantly changing virus strains. Thus, successful immunization is highly improbable.

Treatment

Poster encouraging citizens to "Consult your Physician" for treatment of the common cold

The common cold usually resolves spontaneously in 7 to 10 days, but some symptoms can last for up to three weeks.[21] There are no medications or herbal remedies proven to shorten the duration of illness. Treatment is symptomatic support usually via providing analgesics for fever, headache and myalgia, nasal decongestants and antihistamines for nasal congestion and runniness, and lozenges for sore throat.

Conservative management

The National Institute of Allergy and Infectious Diseases suggests getting plenty of rest, drinking fluids to maintain hydration, gargling with warm salt water, using cough drops, throat sprays, or over-the-counter pain or cold medicines.[6] Saline nasal drops may help alleviate congestion.[26]

Treatments that may help alleviate symptoms include analgesics, decongestants, and cough suppressants,[citation needed] first-generation antihistamines such as brompheniramine, chlorpheniramine, diphenhydramine and clemastine (which reduce mucus gland secretion and thus combat blocked/runny noses but also may make the user drowsy). Second-generation antihistamines do not have a useful effect on colds.[citation needed]

Contrary to common belief, vitamin C has not been shown to be beneficial in the prevention and treatment of the common cold, which indicates that routine mega-dose prophylaxis is not rationally justified for community use. But evidence suggests, that it could be justified in people exposed to brief periods of severe physical exercise or cold environments.[27]

Antibiotics

Antibiotics only target bacteria and thus do not have any beneficial effect against the common cold.

Antivirals

There are no approved antiviral drugs for the common cold.

Cold medicines

Various cold medicines exist which claim to help relieve symptoms. They include antitussives, antihistamines and decongestants. They are not recommended for use in children.[28]

Alternative treatments

Many alternative treatments are used to treat the common cold. None, however, are supported by solid scientific evidence.[23] Some alternative treatments, like echinacea have not been shown to have any effects on the frequency of infection, the duration of infection, or the severity of symptoms of the common cold.[29][30] Other alternative treatments which similarly lack solid scientific evidence include calendula[31], ginger[32], garlic[33] and vitamin C supplements.[34]

Prognosis

Although the disease is generally mild and self-limiting, patients with common colds often seek professional medical help, use over-the-counter drugs, and may miss school or work days. The annual cumulative societal cost of the common cold in developed countries is considerable in terms of money spent on remedies, and hours of lost productivity.

There are no antiviral drugs approved to treat or cure the infection; all medications used are palliative and treat symptoms only. Alternative treatments such as vitamin C, echinacea, and zinc have been proposed but none of them has been shown to decrease the duration of the illness,[23] and thus none of them is approved by the Food and Drug Administration or European Medicines Agency. To prevent infection, washing or disinfecting[35] hands has been found effective, as this minimizes person-to-person transmission of the virus.

Epidemiology

Upper respiratory tract infections are the most common infectious diseases among adults and teens, who have two to four respiratory infections annually.[36] Children may have six to ten colds a year (and up to 12 colds a year for school children).[6][37] In the United States, the incidence of colds is higher in the fall (autumn) and winter, with most infections occurring between September and April. The seasonality may be due to the start of the school year, or due to people spending more time indoors (thus in closer proximity with each other) increasing the chance of transmission of the virus.[6]

History

"Definition of a Cold." Benjamin Franklin's notes for a paper he intended to write on the common cold.

The name "common cold" came into use in the 16th century, due to the similarity between its symptoms and those of exposure to cold weather.[38] Norman Moore relates in his history of the Study of Medicine that James I continually suffered from nasal colds, which were then thought to be caused by polypi, sinus trouble, or autotoxaemia.[39]

In the 18th century, Benjamin Franklin considered the causes and prevention of the common cold. After several years of research he concluded: "People often catch cold from one another when shut up together in small close rooms, coaches, etc. and when sitting near and conversing so as to breathe in each other's transpiration." Although viruses had not yet been discovered, Franklin hypothesized that the common cold was passed between people through the air. He recommended exercise, bathing, and moderation in food and drink consumption to avoid the common cold.[40] Franklin's theory on the transmission of the cold was confirmed some 150 years later.[41]

Common Cold Unit

In the United Kingdom, the Common Cold Unit was set up by the Medical Research Council in 1946. The unit worked with volunteers who were infected with various viruses.[42] The rhinovirus was discovered there.[43] In the late 1950s, researchers were able to grow one of these cold viruses in a tissue culture, as it would not grow in fertilized chicken eggs, the method used for many other viruses. In the 1970s, the CCU demonstrated that treatment with interferon during the incubation phase of rhinovirus infection protects somewhat against the disease[44], but no practical treatment could be developed. The unit was closed in 1989, two years after it completed research of zinc gluconate lozenges in the prophylaxis and treatment of rhinovirus colds, the only successful treatment in the history of the unit.[45]

Social and cultural

Economic cost

A British poster from World War II describing the cost of the common cold[46]

Template:Globalize/USA In the United States, the common cold leads to 75 to 100 million physician visits annually at a conservative cost estimate of $7.7 billion per year. Americans spend $2.9 billion on over-the-counter drugs and another $400 million on prescription medicines for symptomatic relief.[36][47]

More than one-third of patients who saw a doctor received an antibiotic prescription, which has implications for antibiotic resistance from overuse of such drugs.[47]

An estimated 22 to 189 million school days are missed annually due to a cold. As a result, parents missed 126 million workdays to stay home to care for their children. When added to the 150 million workdays missed by employees suffering from a cold, the total economic impact of cold-related work loss exceeds $20 billion per year.[6][36][47]

Research

Biota Holdings are developing a drug, currently know as BTA798, which targets rhinovirus. The drug has recently successfully completed Phase IIa clinical trials.[48][49]

ViroPharma and Schering-Plough are developing an antiviral drug, pleconaril, that targets picornaviruses, the viruses that cause the majority of common colds. Pleconaril has been shown to be effective in an oral form.[50][51] Schering-Plough is developing an intra-nasal formulation that may have fewer adverse effects.[52]

Researchers from University of Maryland, College Park and University of Wisconsin–Madison have mapped the genome for all known virus strains that cause the common cold.[52]

See also

References

  1. ^ a b c d e f g h i j k Eccles R (2005). "Understanding the symptoms of the common cold and influenza". Lancet Infect Dis. 5 (11): 718–25. doi:10.1016/S1473-3099(05)70270-X. PMID 16253889. {{cite journal}}: Unknown parameter |month= ignored (help)
  2. ^ Nordenberg, Tamar (1999). "Colds and Flu: Time Only Sure Cure". Food and Drug Administration. Retrieved 2007-06-13. {{cite web}}: Unknown parameter |month= ignored (help)
  3. ^ a b c d Gwaltney, JM, Hayden, FG (2007). "Understanding the Common Cold: How Cold Virus Infection Occurs".{{cite web}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "coldorg" was defined multiple times with different content (see the help page).
  4. ^ Mary Engel (February 13, 2009). "Rhinovirus strains' genomes decoded; cold cure-all is unlikely: The strains are probably too different for a single treatment or vaccine to apply to all varieties, scientists say". Los Angeles Times.
  5. ^ Palmenberg, A. C. (2009). "Sequencing and Analyses of All Known Human Rhinovirus Genomes Reveals Structure and Evolution". Science. 324: 55. doi:10.1126/science.1165557. PMID 19213880.
  6. ^ a b c d e f g h i "Common Cold". National Institute of Allergy and Infectious Diseases. 2006-11-27. Retrieved 2007-06-11. {{cite web}}: Check date values in: |date= (help)
  7. ^ Cohen S, Doyle WJ, Alper CM, Janicki-Deverts D, Turner RB (2009). "Sleep habits and susceptibility to the common cold". Arch. Intern. Med. 169 (1): 62–7. doi:10.1001/archinternmed.2008.505. PMID 19139325. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Ginde AA, Mansbach JM, Camargo CA (2009). "Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey". Arch. Intern. Med. 169 (4): 384–90. doi:10.1001/archinternmed.2008.560. PMID 19237723. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Zuger, Abigail 'You'll Catch Your Death!' An Old Wives' Tale? Well . . . The New York Times (March 4, 2003). Retrieved on 12-17-08.
  10. ^ Dowling HF, Jackson GG, Spiesman IG, Inouye T (1958). "Transmission of the common cold to volunteers under controlled conditions. III. The effect of chilling of the subjects upon susceptibility". American journal of hygiene. 68 (1): 59–65. PMID 13559211.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Eccles R (2002). "Acute cooling of the body surface and the common cold". Rhinology. 40 (3): 109–14. PMID 12357708.
  12. ^ Douglas, R.G.Jr, K.M. Lindgren, and R.B. Couch (1968). "Exposure to cold environment and rhinovirus common cold. Failure to demonstrate effect". New Engl. J. Med. 279.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Douglas RC, Couch RB, Lindgren KM (1967). "Cold doesn't affect the "common cold" in study of rhinovirus infections". JAMA. 199 (7): 29–30. doi:10.1001/jama.199.7.29. PMID 4289651.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ a b "Common Cold Centre". Cardiff University. 2006. Retrieved 2007-09-06.
  15. ^ Johnson C, Eccles R (2005). "Acute cooling of the feet and the onset of common cold symptoms". Family Practice. 22 (6): 608–13. doi:10.1093/fampra/cmi072. PMID 16286463.
  16. ^ Mothers 'were right' over colds, BBC News, 14 November 2005
  17. ^ Cold Feet? Aah-Choo!, Michael Smith, Medical News: Flu & URI, Medpagetoday, November 14, 2005
  18. ^ Gina Kolata (December 5, 2007). "Study Shows Why the Flu Likes Winter". New York Times.
  19. ^ "Common Cold" (PDF) (pdf). Department of Health, Government of South Australia. 2005. Retrieved 2007-06-20.
  20. ^ Patsy Hamilton. "Facts about the Common Cold Incubation Period". Retrieved 2007-07-03.
  21. ^ a b Heikkinen T, Järvinen A (2003). "The common cold". Lancet. 361 (9351): 51–9. doi:10.1016/S0140-6736(03)12162-9. PMID 12517470. {{cite journal}}: Unknown parameter |month= ignored (help)
  22. ^ "Colds in children". Canadian Pediatric Society. 2005. Retrieved 2007-07-16. {{cite web}}: Unknown parameter |month= ignored (help)
  23. ^ a b c "A Survival Guide for Preventing and Treating Influenza and the Common Cold". American Lung Association. 2005. Retrieved 2007-06-11. {{cite web}}: Unknown parameter |month= ignored (help) Cite error: The named reference "ALA2005" was defined multiple times with different content (see the help page).
  24. ^ "Staying healthy is in your hands - Public Health Agency Canada". 2008-04-17. Retrieved 2008-05-05.
  25. ^ Boyce, John M. (2002-10-25). "Guideline for Hand Hygiene in Health-Care Settings: Guideline for Hand Hygiene in Health-Care Settings Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force" (pdf). Morbidity and Mortality Weekly Report. 51 (RR-16). PMID 12418624. Retrieved 2007-06-21. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  26. ^ "Common Cold". PDRHealth. Thomson Healthcare. Retrieved 2007-07-11.
  27. ^ Douglas RM (2007), "Vitamin C for preventing and treating the common cold." Cochrane Database Syst Rev. PMID: 17636648 [PubMed - indexed for MEDLINE]
  28. ^ "UpToDate Inc".
  29. ^ "An Evaluation of Echinacea angustifolia in Experimental Rhinovirus Infections". New England Journal of Medicine. 2005. {{cite web}}: Unknown parameter |month= ignored (help)
  30. ^ "Echinacea for the Prevention and Treatment of Colds in Adults: Research Results and Implications for Future Studies". National Center for Complementary and Alternative Medicine. 2005. {{cite web}}: Unknown parameter |month= ignored (help)
  31. ^ Jimenez-Medina E, Garcia-Lora A, Paco L et al. (2006). A new extract of the plant Calendula officinalis produces a dual in vitro effect: cytotoxic anti-tumor activity and lymphocyte activation. BMC Cancer. 6:6.
  32. ^ Jakes, Susan (2007-01-15). "Beverage of Champions". Retrieved on 2007-08-02.
  33. ^ Hamel, Paul B. and Mary U. Chiltoskey 1975 Cherokee Plants and Their Uses -- A 400 Year History. Sylva, N.C. Herald Publishing Co. (p. 35)
  34. ^ ROBERT F. CATHCART III (1996). "Preparation of Sodium Ascorbate for IV and IM Use". orthomed.com. Retrieved on 2007-02-21
  35. ^ Stoppler, Melissa (2008-10-07). "10 Tips to Prevent the Common Cold". MedicineNet. Retrieved 2009-05-16.
  36. ^ a b c Garibaldi RA (1985). "Epidemiology of community-acquired respiratory tract infections in adults. Incidence, etiology, and impact". Am. J. Med. 78 (6B): 32–7. doi:10.1016/0002-9343(85)90361-4. PMID 4014285.
  37. ^ Simasek M, Blandino DA (2007). "Treatment of the common cold". American family physician. 75 (4): 515–20. PMID 17323712.
  38. ^ "Cold". Online Etymology Dictionary. Retrieved 2008-01-12.
  39. ^ Wylie, A, (1927). "Rhinology and laryngology in literature and Folk-Lore". The Journal of Laryngology & Otology. 42 (2): 81–87. doi:10.1017/S0022215100029959.{{cite journal}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  40. ^ "Scientist and Inventor: Benjamin Franklin: In His Own Words... (AmericanTreasures of the Library of Congress)". Retrieved 2007-12-23.
  41. ^ Andrewes CH, Lovelock JE, Sommerville T (1951). "An experiment on the transmission of colds". Lancet. 1 (1): 25–7. doi:10.1016/S0140-6736(51)93497-6. PMID 14795755.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  42. ^ Reto U. Schneider (2004). Das Buch der verrückten Experimente (Broschiert). München: Goldmann. ISBN 344215393X.
  43. ^ Tyrrell DA (1988). "Hot news on the common cold". Annu. Rev. Microbiol. 42: 35–47. doi:10.1146/annurev.mi.42.100188.000343. PMID 2849371.
  44. ^ Tyrrell DA (1987). "Interferons and their clinical value". Rev. Infect. Dis. 9 (2): 243–9. PMID 2438740.
  45. ^ Al-Nakib, W (1987). "Prophylaxis and treatment of rhinovirus colds with zinc gluconate lozenges". J Antimicrob Chemother. 20 (6): 893–901. doi:10.1093/jac/20.6.893. PMID 3440773. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  46. ^ http://vads.bath.ac.uk/flarge.php?uid=33443&sos=0
  47. ^ a b c Fendrick AM, Monto AS, Nightengale B, Sarnes M (2003). "The economic burden of non-influenza-related viral respiratory tract infection in the United States". Arch. Intern. Med. 163 (4): 487–94. doi:10.1001/archinte.163.4.487. PMID 12588210.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  48. ^ "The new pill that could signal the death of the common cold". 2008. Retrieved 2009-08-19. {{cite web}}: Unknown parameter |month= ignored (help)
  49. ^ "Biota Press Release" (PDF). 2009. Retrieved 2009-08-19. {{cite web}}: Unknown parameter |month= ignored (help)
  50. ^ Pevear, Daniel C. (1999-09-01). "Activity of Pleconaril against Enteroviruses". Antimicrobial Agents and Chemotherapy. 43 (9): 2109–2115. PMID 10471549. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |day= ignored (help); Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  51. ^ McConnell, J. (2 October 1999). "Enteroviruses succumb to new drug". The Lancet. 354 (9185): 1185. doi:10.1016/S0140-6736(05)75393-9. {{cite journal}}: Check date values in: |date= (help); Cite has empty unknown parameter: |quotes= (help)
  52. ^ a b "Effects of Pleconaril Nasal Spray on Common Cold Symptoms and Asthma Exacerbations Following Rhinovirus Exposure (Study P04295AM2)". ClinicalTrials.gov. U.S. National Institutes of Health. 2007. Retrieved 2007-04-10. {{cite web}}: Unknown parameter |month= ignored (help) Cite error: The named reference "CTgov" was defined multiple times with different content (see the help page).