Acyclovir and Wellcome/Glaxo

Acyclovir (Zovirax) 

Acyclovir in Brief

• Generic name: Acyclovir (acycloguanosine)
• Brand names: Zovirax®
• Therapeutic class: Antiviral
• Pharmacologic class: Acyclic purine nucleoside analogue
• FDA Approved:
  Ointment: March 29, 1982
  Injection: October 22, 1982
  Capsules: January 25, 1985
  Tablets: April 30, 1991
• Pregnancy Category: B
• Originally discovered: 1974, USA 

History

Acyclovir was the first successful antiviral agent in the world. It was originally synthesized in 1974 by Howard Schaeffer at Wellcome Research Laboratories (now GlaxoSmithKline). After Schaeffer's discovery, Gertrude B. Elion and her team went to work, studying how the drug worked, why it worked, and why it was so nontoxic. They detected that acyclovir remains inert until it meets the herpes virus.

For four years, from 1974 to 1977, more than seventy-five researchers kept acyclovir secret. The first report detailing the selective antiviral activity of acyclovir against herpes viruses was published in 1977 2.

Acyclovir got FDA approval and was released commercially in 1982. It was marked under the trade name Zovirax by the Burroughs Wellcome Company. The original formulation was a topical ointment. Acyclovir became available in oral formulation (200 mg capsules) in 1985 6.

FDA approved uses

• Oral
• Initial genital herpes
• Recurrent genital herpes
• Herpes zoster infections (shingles)
• Chickenpox (varicella)
• Topical
• Recurrent herpes labialis (cold sores)
• Parenteral
• Herpes simplex, mucosal and cutaneous
• Severe initial episodes of genital herpes
• Herpes simplex encephalitis
• Neonatal herpes simplex infection
• Varicella-zoster (shingles) infections

Off-label & Investigational uses

• Prevention of HSV-2 transmission 13
• Cytomegalovirus infection and disease after organ transplantation 9
• Herpes simplex virus infection after organ transplantation 10,11
• Ocular herpes simplex 15
• Herpes zoster ophthalmicus 17
• Varicella pneumonia16
• Infectious mononucleosis 4
• Reduces the need for cesarean delivery for recurrent herpes in women whose first clinical episode of genital herpes occurred during pregnancy 18.
• Herpetic gingivostomatitis 5

Spectrum of activity

Acyclovir exhibits activity against four of the five major herpes-group viruses:

• Herpes simplex virus type 1 (HSV-1) 7
• Herpes simplex virus type 2 (HSV-2) 7
• Varicella zoster virus (VZV) 7
• Epstein-Barr virus (EBV)5, 7
• Cytomegalovirus (CMV) (poor activity) 7, 8

Acyclovir is most active against HSV-1 followed by HSV-2 19. Its activity against VZV also is considerable but ten-fold less.

Acyclovir "pros" and "cons"

Advantages:

• High efficacy against HSV and VZV infections
• Very effective for the suppression of recurrent genital herpes, a sexually transmitted infection. Acyclovir reduces recurrence by about 90%.
• Excellent clinical safety profile 6 -- aside from drug hypersensitivity, there are no absolute contraindications to acyclovir
• Safe during pregnancy -- although there are no large, controlled studies of acyclovir safety in pregnant women, a prospective epidemiological registry of acyclovir use during pregnancy showed no increase in the incidence of birth defects.
• Continuous suppressive therapy with acyclovir has been shown to be safe for as long as 5-10 years.
• Minimal toxicity - acyclovir cannot interfere with DNA synthesis in cells that are not infected with the virus
• Well-tolerated by most patients
• Highly effective for suppression of HSV shedding 13, 14
• Minor risk of drug interactions
• Inexpensive

Disadvantages:

• The main weakness of acyclovir is its low oral bioavailability due to low water solubility -- only 15-30% of an oral dose is absorbed. Also, bioavailability decreases with increasing dose. Liquid formulation has lower oral bioavailability.
• Inconvenient frequent dosing regimen (4-5 times) because of the short half-life of less than 4 hours.
• Risk of renal failure and nephrotoxicity12 due to crystallization of acyclovir sodium following parenteral administration.
• Does not eradicate latent virus.

Mode of action

Acyclovir is a synthetic purine nucleoside analogue with inhibitory activity against herpes simplex virus types 1, 2, and varicella-zoster virus. In simple words, it is so similar to substance that the herpes virus needs for reproduction that the virus is deceived and commits suicide.

The inhibitory activity of Acyclovir is highly selective. It is converted to acyclovir monophosphate by virus-specific enzymes thymidine kinase then further converted to acyclovir triphosphate by other cellular enzymes.

Acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase.

The greater antiviral activity of Acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral thymidine kinase.

Time to clear out of the system

The half-life of acyclovir is 3 to 4 hours in people with normal kidney function and up to 20 hours in those with renal impairment.

Further reading

• Acyclovir (Zovirax) versus...
• Acyclovir vs Valacyclovir

References

• 1. Physicians’ Desk Reference, 54th ed; Medical Economics, Thomson Healthcare: Montvale, NJ; 2000.
• 2. Elion, G. B., P. A. Furman, J. A. Fyfe, P. de Miranda, L. Beauchamp, and H. J. Shaeffer. 1977. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine. Proc. Natl. Acad. Sci. USA 74:5716-5720.
• 3. Darby, G. 1995. In search of the perfect antiviral. Antiviral Chem. Chemother. 6(Suppl. 1):54-63.
• 4. Torre D, Tambini R. Acyclovir for treatment of infectious mononucleosis: a meta-analysis. Scand J Infect Dis. 1999;31(6):543-7.
• 5. Nasser M, Fedorowicz Z, Khoshnevisan MH, Shahiri Tabarestani M. Acyclovir for treating primary herpetic gingivostomatitis. Cochrane Database Syst Rev. 2008 Oct 8;(4)
• 6. Tilson HH, Engle CR, Andrews EB. Safety of acyclovir: a summary of the first 10 years experience. J Med Virol. 1993;Suppl 1:67-73. PubMed
• 7. Collins P. The spectrum of antiviral activities of acyclovir in vitro and in vivo. J Antimicrob Chemother. 1983 Sep;12 Suppl B:19-27.
• 8. Freitas VR, Smee DF, Chernow M, Boehme R, Matthews TR. Activity of 9-(1,3-dihydroxy-2-propoxymethyl)guanine compared with that of acyclovir against human, monkey, and rodent cytomegaloviruses. Antimicrob Agents Chemother.1985 Aug;28(2):240-5.
• 9. Legendre C, Ducloux D, Ferroni A, Chkoff N, Geffrier C, Rouzioux C, Kreis H. Acyclovir in preventing cytomegalovirus infection in kidney transplant recipients: a case-controlled study. J Med Virol. 1993;Suppl 1:118-22. PubMed
• 10. Lundgren G, Wilczek H, Lönnqvist B, Lindholm A, Wahren B, Ringdén O. Acyclovir prophylaxis in bone marrow transplant recipients. Scand J Infect Dis Suppl. 1985;47:137-44. PubMed
• 11. Pettersson E, Eklund B, Hockerstedt K, Salmela K, Ahonen J. Acyclovir and renal transplantation. Scand J Infect Dis Suppl. 1985;47:145-8. PubMed
• 12. Lam NN, Weir MA, Yao Z, Blake PG, Beyea MM, Gomes T, Gandhi S, Mamdani M, Wald R, Parikh CR, Hackam DG, Garg AX. Risk of acute kidney injury from oral acyclovir: a population-based study. Am J Kidney Dis. 2013 May;61(5):723-9.
• 13. Wald A, Zeh J, Barnum G, Davis LG, Corey L. Suppression of subclinical shedding of herpes simplex virus type 2 with acyclovir. Ann Intern Med. 1996 Jan 1;124(1 Pt 1):8-15. PubMed
• 14. Sheffield JS, Hollier LM, Hill JB, Stuart GS, Wendel GD. Obstet Gynecol. 2003 Dec;102(6):1396-403. PubMed
• 15. Oral acyclovir for herpes simplex virus eye disease: prevention of epithelial keratitis and stromal keratitis. Herpetic Eye Disease Study Group. Arch Ophthalmol. 2000 Aug;118(8):1030-6. PubMed
• 16. El-Daher N, Magnussen R, Betts RF. Varicella pneumonitis: clinical presentation and experience with acyclovir treatment in immunocompetent adults. Int J Infect Dis. 1998 Jan-Mar;2(3):147-51. PubMed
• 17. Hoang-Xuan T, Büchi ER, Herbort CP, Denis J, Frot P, Thénault S, Pouliquen Y. Oral acyclovir for herpes zoster ophthalmicus. Ophthalmology. 1992 Jul;99(7):1062-70 PubMed
• 18. Scott LL, Sanchez PJ, Jackson GL, Zeray F, Wendel GD Jr. Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes. Obstet Gynecol. 1996 Jan;87(1):69-73.
• 19. K. D. Tripathi. Essentials of Medical Pharmacology. 7th Ed, Jaypee Brothers Medical Publishers 2013.

Published: March 31, 2008
Last reviewed: July 14, 2017

http://www.emedexpert.com/facts/acyclovir-facts.shtml

UK company wins global medicine award for its ground-breaking potential MS treatment

A leading scientist battling to halt the development of Multiple Sclerosis has revealed that clinical human trials will start by 2020, after her company was honoured with a major nano medicine award. Dr Su Metcalfe's regenerative nanomedicine company, LIFNano™, was named Most Promising Nanomedicine Project at the International Nano Medicine Awards in Berlin on Tuesday, November 7.

Founded by Dr. Metcalfe, LIFNano™ slowly releases nanoparticles which are forecast to trigger natural healing in the brain. They contain Leukaemia Inhibitory Factor (LIF), to counter the disease process as it attacks the brain and spinal cord.

Dr. Metcalfe, who earned a PhD in pathology at the University of Cambridge, launched the technology company LIFNano™in 2013 and has been recognised many times already in the last few years. She said, upon receiving this global award “It has always been about getting this to patients. We have found evidence in our animal trials showing significant healing of damaged brain tissue in addition to the potent protection of brain cells.” Dr Metcalfe, who is based in Cambridge, England went on to say, “We are honoured to have been selected for this international award, but our absolute focus is ensuring patients see the benefits through clinical trials in 2020.”

Dr. Su. Metcalfe (middle), picking up the Most Promising Nanomedicine Project at the International Nano Medicine Awards in Berlin on Tuesday, November 7.

Battling with Multiple Sclerosis

Multiple sclerosis (MS), is a neurological disease that attacks the brain and spinal cord. It affects more than 2.3 million people around the world and occurs when the immune system attacks the myelin sheath, the protective coating that encases nerve cells. This triggers symptoms such as vision problems, poor balance and muscle spasms. It could lead to total disability and dementia. The disease is forecast to cost in excess of $100 billion annually around the globe.

The issue with current treatments has been that they typically greatly diminish the activity of immune cells and they need to be used on a regular basis. Although these treatments prevent those immune cells from ravaging myelin within the brain, they also leave the body vulnerable to infection. None protects the brain. Metcalfe’s nanoparticles reset and correct the fault that causes MS as they deliver the natural stem cell growth factor LIF, directly and specifically to the sites of nerve damage, and keep the immune system from attacking myelin. They do not impair immunity and allow immune cellsto mobilize against harmful invaders when needed. What’s more, LIF can actually help repair damaged myelin within the brain.

If LIFNano™ holds up in clinical trials, “that would be a really significant addition to the treatments we have,” explained Bruce Bebo, executive vice president of research at the National Multiple Sclerosis Society, in an interview in October with OZY. Another benefit is its targeted approach which means fewer side effects expected, using the naturally occurring LIF.

For patients with MS, the potential of LIFNano™ could be profound once clinical trials have been successfully completed. Indeed, in addition to regulating immunity, a further key role of LIF is to sustain a healthy central nervous system, protecting nerves and maintaining myelin. LIFNano is therefore a powerful candidate for treatment of patients suffering from MS, providing a triple action for healing the brain and protecting nerves, repairing myelin and resettingself-tolerance. The beauty of the technology is its simplicity as it lets the body do what nature intended, slowly releasing LIF via the nanoparticles. Time really matters for MS sufferers, as early treatment is known to slow the course of the disease.

Dr Metcalfe's preclinical research has already found no toxicity of the LIF nanoparticles. Remarkably, LIF itself, the PLGA nanoparticles, as well as the anti-body fragment used to direct them have all been already used, separately, in various clinical trials. 

Quantum Leap Nanomedicine

The nanoparticle manufacture has originally been developed jointly by Dr. Metcalfe and Yale University. Ultimately, Yale granted an exclusive license to LIFNano™ to develop the platform for MS, and for other degenerative diseases such as dementia and for auto-immune conditions, for years to come. The company, which has been self-funded to date, uses safe and natural ingredients rather than synthetic drugs.

LIFNano™ has a stellar team and advisers who are now working with Dr Metcalfe, including its Chairman, Florian Kemmerich, who also heads up the Europe-based NanoMed. The company's CEO, Olivier Jarry, joined the company with executive experience at Novartis, Bayer and Bristol-Myers Squibb, in addition to having consulted for giants such as Pfizer, GSK and Sanofi. Commenting on the award Olivier said, “Our treatment has the curative potential to deal with the root cause of MS, rather than just addressing symptoms and we hope to prove this in our human trials.” He went on to say, “the delivery of LIF across the blood brain barrier could profoundly improve therapeutic outcomes, reducing costs and potentially increasing convenience and safety.”

The Chairman of the company, Florian Kemmerich, said, “We have great partners, solid patents and exclusive licenses. This platform technology could go on to have profound impacts on other diseases such as Alzheimer's. We have received a lot of support and more is coming due to the scalability of the platform. We believe that, by successfully delivering these LIF nanoparticles to the brain, we will enable cells damaged by 'rogue' white blood cells to be repaired. This should then re-balance the body, using the natural reparative immune system we all have.”

The EU's European Technology Platform Awards honour firms that have developed a nanomedicine solution “that could bring significant benefits to patients, changing the way diseases are treated or diagnosed or providing new tools for physicians.” It further supports our drive to reach people with MS quickly. The award has previously been won by the Merck group, for a project aiming to develop a nanomedicine oncology product for mucosal therapeutic vaccination.

LIFNano™ and Dr. Metcalfe can add this to several other awards they have won or have been shortlisted for, including the UK government-backed Innovate UK Smart Award, the Merck Serono GMSI award, the Rolex Award for Enterprise and Business Weekly's Woman Entrepreneur of the Year Award.

The company is currently securing investment to complete GMP manufacturing, and secure authorizations to start clinical trials, aiming at generating a ‘proof of concept’ (Phase IIa) in 2020.

To contact the company or to find out more about the technology go to www.lifnano.com or contact investor-relations@lifnano.com

https://nano-magazine.com/news/2017/11/7/uk-company-wins-global-medicine-award-for-its-ground-breaking-potential-ms-treatment/?email=donpatent@gmail.com

Targeting a single protein might treat a broad range of viruses

November 8, 2017

The measles virus is suppressed (right) when a key protein, SPCA1, is decreased in the host. Credit: Hans-Heinrich Hoffmann

Most drugs that fight viruses are designed to target individual pathogens. But scientists at The Rockefeller University have identified a protein that a broad range of viruses require to spread within a host—a discovery that could lead to fighting viruses as varied as parainfluenza, West Nile, and Zika with a single drug.

All viruses use proteins from the host's cellsin order to replicate. A team in Charles M. Rice's lab has identified a calcium-transporting protein that is needed by many viruses during the later stages of their life cycles. The researchers showed that depleting this protein in host cells significantly impairs the viruses' ability to spread, without harming the cells.

By indicating a way that a single medicine could fight many infections, these advances have the potential to multiply the return on time and effort invested in drug development. The researchers' findings were reported this month in Cell Host & Microbe.

"There's been a push to get broader antivirals, and that's difficult because viruses tend to be very different in what they do, exactly," says Hans-Heinrich Hoffmann, the lead author of the study. "The key to creating a broad antiviral medicine is to find a host protein that many viruses need but that is not essential to the cell's survival. And that's exactly what we found here."

From RSV to Zika

The researchers launched their study by trying to find a host protein required by the human respiratory syncytial virus (RSV), a major virus that is particularly dangerous to children and the elderly, causing an estimated 3.4 million hospitalizations a year. There are currently no vaccines against RSV or specific antivirals that fight it.

Even a partial loss of the protein, the calcium pump SPCA1, limited the ability of many viruses to mature and spread, the scientists found. Cells that lack the protein were also less susceptible to initial infection.

After finding that RSV requires SPCA1, the researchers determined that many other viruses, both insect-borne and respiratory, need the protein. Among those is Zika, the mosquito-borne virus linked to brain malformation in infants. As with RSV, there are no approved antivirals for Zika.

Patients lacking proteins

It is one thing to study whether individual cells can survive without a protein. But to be useful as a therapy, researchers would need to understand how a lack of SPCA1 affects an entire organism—such as an actual patient.

There are, in fact, individuals who have reduced levels of SPCA1, as a result of a rare genetic disorder known as Hailey-Hailey disease. The disease causes skin problems, such as blisters and lesions, but is not life-threatening. Furthermore, cell cultures derived from patients with Hailey-Hailey disease indicate that their cells are less susceptible to certain infections, including RSV—a result that correlates with the researchers' other findings.

"We know that these patients get by with only half the normal amount of the protein, and we have evidence that this may even offer a protective effect," says Rice, who is the Maurice R. and Corinne P. Greenberg Professor in Virology and head of the Laboratory is Virology and Infectious Disease. "It's a promising avenue for drug development."

Explore further: 'Exciting' discovery on path to develop new type of vaccine to treat global viruses

More information: H.-Heinrich Hof Diverse Viruses Require the Calcium Transporter SPCA1 for Maturation and Spread, Cell Host & Microbe (2017). DOI: 10.1016/j.chom.2017.09.002

Journal reference: Cell Host & Microbe

Provided by: Rockefeller University

Read more at: https://phys.org/news/2017-11-protein-broad-range-viruses.html#jCp

Study Gives Rare Look at Genetics of HSV1 Transmission from Father to Son

Friday, October 20, 2017

A new study explores how herpes simplex virus might change when passed from one individual to another, information that may prove useful in future development of therapeutics and vaccines.

This rare glimpse into a transmission event reveals nearly perfect genetic transmission of the virus from a father to his son and lays the foundation for future studies exploring the genetic diversity of this virus. A paper describing the study appears online October 20, 2017, in the journal Scientific Reports. It was conducted by scientists at Penn State, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati. 

https://www.nature.com/articles/s41598-017-13936-6

“Millions of people worldwide have herpes simplex virus,” said Moriah Szpara, PhD, assistant professor of biochemistry and molecular biology at Penn State and an author of the paper. “We see locally distinct variants of the virus with distinct genetic fingerprints in different regions around the world, and, with the prevalence of international travel, we’re starting to see a lot of different variants of the virus appearing in one place. This could have implications for how the virus evolves and how we design therapeutics to combat it. Studies of a related virus – human cytomegalovirus – suggest that the virus diversifies after transmission, and we wanted to see if this was also the case for herpes simplex virus.”

Herpes simplex virus type 1 (HSV-1) is a highly contagious infection that commonly causes oral and genital lesions. More severe symptoms can also occur, such as eye disease and, in rare cases, encephalitis -- inflammation of the brain that can cause flu-like symptoms, confusion, seizures, or problems with movement. Although some medications can reduce the severity and frequency of the symptoms, there is no cure for HSV-1 and no guaranteed way to prevent transmission. HSV-1 can be transmitted through contact with sores or saliva around the mouth –  as is often the case in familial transmission – or sexually.

“Capturing transmission of herpes simplex virus is incredibly difficult,” said Szpara, “in part because the social stigma associated with having the virus makes it unlikely for sexual partners to admit when they transmit it. The virus also lasts a lifetime. Unlike the flu, which comes and goes, HSV remains in an individual’s body for the remainder of their life. Periods of latency and reactivation make it hard to know exactly when the virus was first transmitted.” 

“In this study, we had a known case of familial transmission,” said Nancy Sawtell, PhD, professor in Infectious Diseases at Cincinnati Children’s and paper co-author. “Samples from a father and son were cultured in the lab, enabling us to investigate potential differences of the virus after transmission. To gain a comprehensive look at the results of transmission, we used genetic sequencing, and we examined each virus in an animal model to compare the level of virulence, or the ability to cause disease. Animal models have the ability to reflect the interactions of all the body’s systems at once — the outer surface, the immune system, and the nervous system all interact during the response to herpes simplex virus infection.”

Genetically, the viruses taken from the father and son were a near-perfect match. The viruses also had similar pathology when tested in mice – they grew at a similar rate and had a similar ability to set up long-term infection in the brain. Although the viruses from the father and son were not completely identical, these results suggest that HSV-1 may not change much when transmitted between closely related individuals. However, the researchers suspect that transmission between unrelated hosts may provide a more dramatic opportunity for change.

“An individual’s immune system exerts selection pressure on a virus,” said Utsav Pandey, graduate student at Penn State and first author of the study. “The son got at least half of his immune system from his father, so it was probably a similar selective environment. Unrelated individuals likely differ more in their immune system, which could shape the virus.”

The research team also compared the performance of the viruses from the father and son to two separate clinical cultures of HSV-1. The variants from the father and son were less virulent — less severe — when tested in mice. Additionally, the genome sequence of the viruses in the father and son, who were from the United States, did not fit in as expected with other HSV-1 genomes that have been genetically sequenced from the United States or Europe.

“This study broadens our knowledge of what herpes simplex virus variants are circulating in the U.S.,” said Szpara. “It’s not just the United States/European variants that are used in vaccine development and clinical studies. When we think about designing therapeutics and vaccines, we need to know how the virus can differ or we may design something that only controls the virus from a particular region.”

To further understand how genetic diversity of HSV-1 is generated, the researchers plan to turn their attention to studying transmission of the virus between unrelated individuals. “If we could understand how much the virus changes when passed between unrelated individuals and how the virus’ genetics influences the level of virulence or level of harm the virus can do,” said Szpara, “then hopefully we can design better treatments for HSV-1.”

In addition to Szpara and Sawtell, the research team includes Utsav Pandey, graduate student at Penn State; Daniel Renner, computational scientist at Penn State; and Richard Thompson, professor of molecular genetics, biochemistry, and microbiology at the University of Cincinnati. The work was funded by the National Institutes of Health and the Pennsylvania Department of Health Commonwealth Universal Research Enhancement (CURE) program and supported by the Huck Institutes of the Life Sciences at Penn State.

Contact Information

Nick Miller
513-803-6035
nicholas.miller@cchmc.org

https://www.cincinnatichildrens.org/news/release/2017/herpes-simplex-virus