Drug Development Essay

Penicillin: Theory of Development Penicillin Introduction: Penicillin, one of the most ubiquitous and widely used antibiotic over-the-counter drugs of our time, played a major role during World War II. Its use had been so important, in a time when its supply so limited, it was consumed faster than produced, so that urine of individuals receiving treatment had to be collected in order to isolate and re-use penicillin in it. In fact, although Scottish scientist Alexander Fleming is considered the discoverer of penicillin, he actually stopped studying penicillin after 1931 when he was convinced penicillin would not last long in the human body to kill pathogenic bacteria. His study was later resumed in 1934 that then preceded several developments that changed the course of wars. Penicillin prior to Alexander Fleming’s discovery has been noted for its antibacterial effects. It was in Fleming’s St Mary’s Hospital Laboratory in London, now Imperial College teaching hospitals, where he noticed a halo of inhibition of bacterial growth around a contaminant blue-green mould on a plate culture of Staphylococcus. He concluded that the mould release a substance that stop the growth of bacteria. He grew a pure culture of the mould and learned it was a Penicillum mould or Penicillum chrysogenum. At that stage, it was already found that penicillin is most effective against Gram-negative organisms. Fleming became positive of its disinfectant properties. In 1939, Australian scientist Howard Walter Florey with his team composed of Ernst Boris Chain, A. D. Gardner, Norman Heatley, M. Jennings, J. Orr-Ewing and G. Sanders at the Sir William Dunn School of Pathology, University of Oxford showed the “in vivo” bacterial action of penicillin proving further its harmlessness and effect in mice. In March 14, 1942, John Bumstead and Orvan Hess successfully treated a patient with penicillin (Saxon, 1999 and Krauss, 1999). Discussion: Penicillin abbreviated as PCN is a group of β-lactam antibiotics that treat bacterial infections caused by Gram-positive organisms. From its discovery, the antibiotic has been developed into several forms with the basic Penam Skeleton with the molecular formula R-C9H11N2O4S with R as a variable side chain. Below is the penicillin nuleus: Source: Wikipedia Penicillins are easily secreted that 80% is cleared within three to four hours of administration. Scientists later found uricosuric agent probenecid could compete for the organic acid transporter responsible for secretion thus increasing penicillin’s concentration and prolonging its activity. Although the advent of synthetic forms of mass production decreased the use of probenecid (Silverthorn, 2004), it is still useful until today for infections that require high concentrations of penicillins (Rossi, 2006). Dorothy Crowfoot Hodgkin determined the chemical structure of penicillin in early 1940s that catapulted its synthetic production. Ampicillin was the first major development of penicillin allowing the treatment for both Gram-positive and Gram-negative infections. Amoxicillin followed with improved duration of action. Beta-lactamase-resistant penicillins were soon developed which include the varieties flucloxacillin, dicloxacillin and methicillin for treatment of beta-lactamase-producing bacteria such as Staphylococcus species. The β-lactam antibiotics inhibit the formation of peptidoglycan cross links in the bacterial cell wall with the β-lactam moiety of penicillin binding to the transpeptidase enzyme which links the peptidoglycan molecules in bacteria. This weakens the cell wall of the bacterium and causes cell cell cytolisis or death. Also, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases that digest the bacteria's existing peptidoglycan.This disables multiplication of bacteria. This hypothesis was postulated by Scott Williams. Benzathine benzyl penicillin or Benzathine penicillin is a variety that is slowly absorbed into the circulation after intramuscular injection, and then hydrolyzed to benzipenicillin in vivo. It is used for prolonged low concentrations allowing antibiotic action until after 2-4 weeks of single IM dose of administration. Wyeth markets this with the trade name Bicillin. Indications include Prophylaxis of rheumatic fever and early or latent syphilis (Rossi, 2004). Benzylpenicillin or popularly known as penicillin G is adnistered in parenteral route or through injection or infusion because it is unstable to the stocmach’s hydrochloric acid. With phenoxymethylpenicillin, higher tissue concentrations can be achieved than is possible causing increased antibacterial activity. Indications include treatment for Bacterial endocarditis, Meningitis, Aspiration pneumonia or lung abscess, Community-acquired pneumonia, Syphilis, and Septicaemia in children (Rossi, 2006). Below is the Benzylpeninicillin nucleaus: Source: Wikipedia Phenoxymethylpenicillin or penicillin V is an orally-active form of penicillin appropriate where low tissue concentration is needed. Indications include treatment for infections caused by Streptococcus pyogenes such as tonsillitis, pharyngitis, and skin infections, prophylaxis of rheumatic fever, and moderate-to-severe gingivitis (with metronidazole) (Rossi, 2006). Procaine benzylpenicillin or procaine penicillin is a combination of benzylpenicillin with the local anaesthetic agent procaine. I is slowly absorbed into the circulation after instramuscular injection aimed at reducing pain and discomfort widely used in veterinarian practices. Indications include treatment for syphilis, respiratory tract infections where compliance with oral treatment is unlikely, and cellulitis, erysipelas, and an adjunct in the treatmnent of anthrax (Rossi, 2006). Narrow spectrum penicillinase-resistant penicillins are one of the structurally modified or semi-synthetic penicillins effective against beta-lactamases produced by Staphylococcus aureus. They are also known as anti-staphylococcal penicillins that include Methicillin, Dicloxacillin, Flucloxacillin, and Oxacillin. Moderate spectrum penicillins are one of the structurally modified or semi-synthetic penicillins that increase the spectrum of action and, in the case of amoxicillin, improve oral bioavailability which includes, Amoxicillin and Ampicillin widely used for children. Extended Spectrum Penicillins or Antipseudomonal penicillins ticarcillin, azlocillin, carbenicillin and piperacillin were the last to be developed and are used for Gram-negative bacteria and also indicated for Pseudomonas aeruginosa. Allergy, Hypersensitivity and Contraindications: Adverse drug reactions of ≥1% of patients associated with the use of penicillins include diarrhea, nausea, rash, urticaria, and superinfection such as candidiasis. Others which may be rare (0.1–1% of patients) include fever, vomiting, erythema, dermatitis, angioedema, and pseudomembranous colitis. Pain and inflammation also occur in parenteral administration. Allergic reactions to β-lactam antibiotic occur in about 10% of patients receiving that agent. Anaphylaxis, or allergic suffocation occur in about 0.01% of patients (Rossie, 2006). Risk of cross-reactivity warrants contraindication of to β-lactam antibiotic to all patients with history of severe reactions such as urticaria, anaphylaxis, interstitial nephritis. Conclusion: Penicillin with its wide variety of choices made it possible for previously lethal diseases and infections curable. And with the development to synthtic formulae, it became accessible even to the most marginalized of the society. It is one of the most celebrated breakthrough in conventional medicine with its discovery propelling a wider array of medicinal drugs that inhibits growth of bacteria and fight infection that causes harm in the body. It is very interesting to note that the various additions or modification of the penicillin led to its wider indication to other forms of human, and even animal infection. Likewise, with the discovery of penicillin inhibiting growth as well as its property causing cell cytolitis, other branches of research, study and medicinal developments occurred leading to a continuous spectrum of research. It is therefore rational to credit the discovery of penicillin as one of the highlights of conventional medicine and therapy. As medical science march towards addressing worse conditions such as most incurable cancer diseases and destruction of cells (such as that of acquired immune deficiency virus or AIDS), researchers and scientitts can always look back to the properties of penicillin, its development and how it works in order to progress. Nevertheless, as it is, penicillins show other possible developments that might, in the future address which are now terminal diseases as cells become the center of discussion and themes within medical science. Already, it has proven its worth as previous developments addressed certain conditions, evolved to treat other else, and continue so until now. With penicillin, we can all look forward to advancement that could possiby alter most dreaded diseases of today. Reference: Fleming, A. “On the On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzæ.” Br J Exp Pathol 10 (31): 226–36. 1929. Krauss, K. (editor). Yale-New Haven Hospital Annual Report (PDF). Yale, New Haven Hospital 1999. Rossi, S. (editor). Australian Medicines handbook. Adelaide: Australian Medicines Handbook. 2004-2006. Saxon, W. “Anne Miller, 90, first patient who was saved by penicillin. The New York Times, June 9, 1999. Silverthorn, DU. Human Physiology: An Integrated Appproach. Upper Saddle River, pearson Education. 2004 Wikipedia. “Penicillin.” Wikimedia. Accessed October 2006 from http://wikipedia.org