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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5714_Библиотеки_им_академика_М_И_Перельмана.pdf
Recent Advances in Biopharmaceuticals
295
Table 19.5 List of recent antibiotics available in market
Generic name Brand names Common uses Mechanism of action
1. Aminoglycosides
Amikacin Amikin
In infections caused by Gram-negative
bacteria, E. coli, Pseudomonas
aeruginosa. Effective against aerobic
bacteria and tularemia.
Binding to the bacterial 30S ribosomal
subunit (some work by binding to
the 50S subunit), inhibiting the
translocation of the peptidyl-tRNA
from the A-site to the P-site and also
causing misreading of mRNA, leaving
the bacterium unable to synthesize
proteins vital to its growth
Gentamicin Garamycin
Kanamycin Kantrex
Neomycin Mycifradin
Netilmicin Netromycin
Tobramycin Nebcin
Paromomycin Humatin
2. Carbacephem
Loracarbef Lorabid
A wide variety of bacterial
infections
Prevents bacterial cell division by
inhibiting cell wall synthesis
3. Carbapenems
Ertapenem Invanz
Bactericidal. Empiric broad-spectrum
antibacterial coverage.
Inhibition of cell wall synthesis
Doripenem Doribax
Imipenem/
cilastatin
Primaxin
Meropenem Merrem
4. Cephalosporins (fi rst generation)
Cefadroxil Duricef
Gram-positive infections
Same mode of action as other `-lactam
antibiotics: disrupt the synthesis of the
peptidoglycan layer of bacterial cell
walls
Cefazolin Ancef
Cefalotin/
cefalothin
Keflin
Cefalexin Keflex
6. Macrolides and ansamycins: They are a large group of antibiotics. They are characterized
by a core ring structure containing 12 or more carbon atoms to which one or more sugar is
attached.
7. Ansamycins: They are synthesized by condensation of a large number of acetate and
propionate units. Amongst the best known are the rifampicins that are particularly active
against Gram-positive bacteria and mycobacteria.
8. Peptide and other antibiotics: They consist of a chain of amino acids that often have cyclized
ring-like structure. The first such antibiotics isolated were bacitracin and gramicin.
9. Vancomycin: A glycopeptide acts by interfering with bacterial cell wall synthesis and is
particularly active against Gram-positive bacteria. Chloramphenicol was first isolated from
a culture of Streptomyces venezuelae in 1947. But, it is now obtained by direct chemical
synthesis and is effective against Gram-negative and Gram-positive bacteria, rickettsias and
chlamydias.
(Continued)
Textbook of Pharmaceutical Biotechnology
296
Generic name Brand names Common uses Mechanism of action
5. Cephalosporins (second generation)
Cefaclor Ceclor
Less Gram-positive cover, improved
Gram-negative cover
Disrupt the synthesis of the
peptidoglycan layer of bacterial
cell walls
Cefamandole Mandol
Cefoxitin Mefoxin
Cefprozil Cefzil
Cefuroxime Ceftin, Zinnat
6. Cephalosporins (third generation)
Cefixime Suprax
Gram-negative organisms, except
pseudomonas. Reduced Gram-positive
cover
Disrupt the synthesis of the
peptidoglycan layer of bacterial
cell walls
Cefdinir
Omnicef,
Cefdiel
Cefditoren Spectracef
Cefoperazone Cefobid
Cefotaxime Claforan
Cefpodoxime Vantin
Ceftazidime Fortaz
Ceftibuten Cedax
Ceftizoxime Cefizox
Ceftriaxone Rocephin
7. Cephalosporins (fourth generation)
Cefepime Maxipime Covers pseudomonal infections
Disrupt the synthesis of the
peptidoglycan layer of bacterial
cell walls
8. Cephalosporins (fi fth generation)
Ceftobiprole
In methicillin-resistant Staphylococcus
aureus infection
Disrupt the synthesis of the
peptidoglycan layer of bacterial
cell walls
9. Glycopeptides
Teicoplanin Targocid
Certain kinds of bacterial infection in
the bowel
Inhibiting peptidoglycan synthesisVancomycin Vancocin
Telavancin Vibativ
10. Lincosamides
Clindamycin Cleocin Serious streptococcal infections in
penicillin-allergic patients. Topically
for acne
Binds to 50S subunit of bacterial
RNA, thereby inhibiting protein
synthesis
Lincomycin Lincocin
11. Lipopeptide
Daptomycin Cubicin Gram-positive organisms
Binds to the membrane and cause
rapid depolarization, resulting in a
loss of membrane potential, leading to
inhibition of protein, DNA and RNA
synthesis
(Continued)
Recent Advances in Biopharmaceuticals
297
Generic name Brand names Common uses Mechanism of action
12. Macrolides
Azithromycin Zithromax
Clarithromycin Biaxin
Streptococcal infections, syphilis.
Upper respiratory tract infections.
Lower respiratory tract infections,
mycoplasmal infections and Lyme
disease, pneumonia
Inhibition of bacterial protein
biosynthesis by binding reversibly to
the subunit 50S of the bacterial
ribosome, thereby inhibiting
translocation of peptidyl tRNA
Dirithromycin Dynabac
Erythromycin
Erythocin,
Erythroped
Roxithromycin Roxid
Troleandomycin TAO
Telithromycin Ketek
13. Monobactams
Aztreonam Azactam In hospital-acquired infections
Same mode of action as other `-lactam
antibiotics: disrupt the synthesis of the
peptidoglycan layer of bacterial cell
walls
14. Nitrofurans
Furazolidone Furoxone
Bacterial or protozoal diarrhoea or
enteritis
Interferes with several bacterial
enzyme systems. It neither
significantly alters normal bowel flora
nor results in fungal overgrowth
Nitrofurantoin Macrodantin Urinary tract infections Works by killing sensitive bacteria
15. Penicillins
Amoxicillin
Novamox,
Amoxil
In wide range of infections, such as
streptococcal infections, syphilis
Common action for all penicillins
Disrupt the synthesis of the
peptidoglycan layer of bacterial
cell walls
Ampicillin Principen
Carbenicillin Geocillin
Cloxacillin Tegopen
Dicloxacillin Dynapen
Flucloxacillin Floxapen
Mezlocillin Mezlin
Methicillin Staphcillin
Nafcillin Unipen
Oxacillin Prostaphlin
Penicillin G Pentids
Penicillin V Pen-Vee-K
Piperacillin Pipracil
Temocillin Negaban
Ticarcillin Ticar
(Continued)
Textbook of Pharmaceutical Biotechnology
298
Generic name Brand names Common uses Mechanism of action
16. Penicillin combinations
Amoxicillin/
clavulanate
Augmentin
Infections that are proven or strongly
suspected to be caused by
bacteria
Common action for all penicillin
combinations
The second component prevents
bacterial resistance to the first
component
Ampicillin/
sulbactam
Unasyn
Piperacillin/
tazobactam
Zosyn
17. Polypeptides
Bacitracin Nebasulf
In eye, ear or bladder infections.
Applied directly to the eye or inhaled
into the lungs; rarely given by
injection
Inhibits isoprenyl pyrophosphate, a
molecule that carries the building blocks
of the peptidoglycan bacterial cell wall
outside of the inner membrane
Interact with the Gram-negative
bacterial outer membrane and
cytoplasmic membrane. It displaces
bacterial counter ions, which destabilize
the outer membrane. They act like a
detergent against the cytoplasmic
membrane, which alters its permeability
Colistin Coly-Mycin-S
Polymyxin B Neosporine
18. Quinolones
Ciprofloxacin Cipro, Ciproxin,
Ciprobay
Urinary tract infections. Bacterial
prostatitis, community-acquired
pneumonia, bacterial diarrhea,
mycoplasmal infections, gonorrhoea
Common action for all quinolones
Inhibit the bacterial DNA gyrase or
the topoisomerase IV enzyme, thereby
inhibiting DNA replication and
transcription
Enoxacin Penetrex
Gatifloxacin Tequin
Levofloxacin Levaquin
Lomefloxacin Maxaquin
Moxifloxacin Avelox
Nalidixic acid NegGram
Norfloxacin Noroxin
Ofloxacin Floxin, Ocuflox
19. Sulphonamides
Mafenide Sulfamylon
Urinary tract infections (except
sulphacetamide, eye infections, and
mafenide and silver sulphadiazine,
used topically for burns)
Common action for all sulphonamides
Inhibitors of the enzyme DHPS. DHPS
catalyses the conversion of PABA to
dihydropteroate, a key step in folate
synthesis. Folate is necessary for
the cell to synthesize nucleic acids
(nucleic acids are essential building
blocks of DNA and RNA), and in its
absence cells will be unable to divide
Sulphadiazine Micro-sulfon
Silver
sulphadiazine
Silvadene
Sulphamithizole Thiosulfil forte
Sulphamethoxazol
Gantanol
Sulphasalazine Azulfidine
Sulphisoxazole Gantrisin
Trimethoprime Proloprim
(Continued)
Recent Advances in Biopharmaceuticals
299
Generic name Brand names Common uses Mechanism of action
20. Tetracyclines
Demeclocycline Declomycin
In syphilis, chlamydial infections,
Lyme disease, mycoplasmal infections,
acne rickettsial infections, malaria
Common action for all tetracyclines
Inhibit the binding of aminoacyl-tRNA
to the mRNA-ribosome complex.
They do so mainly by binding to the
30S ribosomal subunit in the mRNA
translation complex
Doxycycline Vibramycin
Minocycline Minocin
Oxytetracycline Terramycin
Tetracycline
Sumycin, Ach-
romycin V
21. Drugs against mycobacteria
Clofazimine Lamprene Antileprotic
Probably interfere with templet
function of DNA
Dapsone Avlosulfon Antileprotic
Inhibits PABA incorporation into colic
acid
Capreomycin Capastat Antituberculosis Inhibits protein synthesis
Cycloserine Seromycin Antituberculosis, urinary tract infections Inhibits bacterial cell wall synthesis
Ethambutol Myambutol Antituberculosis
Inhibits arabinogalactan synthesis and to
interfere with mycolic acid incorporation
in mycobacterial cell wall
Ethionamide Trecator Antituberculosis Inhibits peptide synthesis
Isoniazid INH Antituberculosis
Inhibits synthesis of mycolic acid
that is unique fatty acid component of
mycobacterial cell wall
Pyrazinamide Aldinamide Antituberculosis Inhibits mycolic acid synthesis
Rifampicin
(Rifampin in US)
Rifadin,
Rimactane
In mostly Gram-positive and
mycobacteria
Binds to the ` subunit of RNA
polymerase to inhibit transcription
Rifabutin Mycobutin Mycobacterium avium complex Inhibits DNA-dependent RNA synthesis
Streptomycin Antituberculosis As other aminoglycosides
22. Others
Chloramphenicol Chloromycetin
In meningitis, MRSA, typhus, cholera.
Gram-negative, Gram-positive,
anaerobes
Inhibits bacterial protein synthesis
by binding to the 50S subunit of the
ribosome
Fosfomycin Monurol In acute cystitis in women
Inactivates enolpyruvyl transferase,
thereby blocking cell wall synthesis
Fusidic acid Fucidin
In boils, folliculitis sycosis barbae and
cutaneous infections
Blocks bacterial protein synthesis
Linezolid Zyvox
Vancomycin-resistant Staphylococcus
aureus infection
Inhibits bacterial protein synthesis
Metronidazole Flagyl
In infections caused by anaerobic
bacteria; also amoebiasis,
trichomoniasis, giardiasis
Damages DNA in anaerobic
microorganisms
Thiamphenicol Thiocymetin
Used in Gram-negative,
Gram-positiver, anaerobes. Widely
used in veterinary medicine
Chloramphenicol analogue. May
inhibit bacterial protein synthesis
by binding to the 50S subunit of the
ribosome
Tinidazole
Tindamax,
Fasigyn
Protozoan infections
Damages DNA in anaerobic
microorganisms
Abbreviations: DHPS, dihydropteroate synthetase; MRSA, methicillin-resistant Staphylococcus aureus; PABA, para-aminobenzoic acid.
Textbook of Pharmaceutical Biotechnology
300
RECENT ADVANCS IN BIOPHARMACEUTICALS
Applications of Carrier Erythrocytes in the Delivery of Biopharmaceuticals
The carrier erythrocytes are resealed erythrocytes loaded by a drug or other therapeutic agents.
They have been exploited extensively in recent years for both temporally and spatially controlled
delivery of a wide range of drugs and other bioactive agents, because of their remarkable
degree of biocompatibility, biodegradability and a number of other potential advantages. The
biopharmaceuticals, such as therapeutically significant peptides and proteins, nucleic acid-based
biologicals, antigens and vaccines, are being delivered using carrier erythrocytes.
Important Features of Carrier Erythrocytes
1. A remarkable degree of biocompatibility, particularly when the autologous cells are used for
drug loading
2. Avoidance of any undesired immune responses against the encapsulated drug
3. Complete biodegradability and the lack of toxic product(s), resulting from the carrier
biodegradation
4. Longer lifespan of the carrier erythrocytes in circulation in comparison to the synthetic
carriers
5. Considerable protection of the organism against the toxic effects of the encapsulated drug,
e.g. antineoplasms
6. Protection of the loaded compound from inactivation by the endogenous factors
7. Desirable size range and the considerably uniform size and shape
8. An easily controllable lifespan within a wide range from minutes to months
9. Relatively inert intracellular environment
10. Possibility of targeted drug delivery to the reticuloendothelial system organs
11. Possibility of an ideal zero-order kinetics of drug release
12. Modification of the pharmacokinetic and pharmacodynamic parameters of the drug
13. Availability of knowledge, techniques and facilities for handling, transfusion and working
with erythrocytes
14. Wide variety of compounds with the capability of being entrapped within the erythrocytes
15. Considerable increase in drug dosing intervals with drug concentration in the safe and effective
level for a relatively long time
16. Possibility of decreasing drug side effects
Practical Approaches to Dose Selection for First-in-Human
Clinical Trials with Novel Biopharmaceuticals
Recent advances in our understanding of disease biology, new therapeutic targets, biomarkers
and innovative modalities have fuelled a dramatic expansion in the development of novel human
therapeutics. Many biotechnology-derived biologicals with high degree of selectivity and affinity
for their intended target are emerging out. As such, they often pose challenges in the development
Recent Advances in Biopharmaceuticals
301
path to approval. One such challenge is the selection of the first-in-human (FIH) dose. This has
come under critical scrutiny as a result of a FIH trial with a superagonist monoclonal antibody
(TGN1412), which resulted in significant injury to healthy volunteers. Regulatory agencies in such
cases have responded with supplemental guidance for the development of novel therapeutics, which
are required to be rigidly followed.
Research Advances on Transgenic Plant Vaccines
The advancement of genetics molecular biology and plant biology in recent years has facilitated
development of vaccination programs (e.g. genetic engineering subunit vaccine, living vector
vaccine, nucleic acid vaccine, etc.). In particular, the technology of the use of transgenic plants
to produce human or animal therapeutic vaccines has received considerable attention. Expressing
vaccine candidates in vegetables and fruits open up a new approach for producing oral/edible
vaccines. The transgenic plant vaccine is a reality today. There are several advantages of transgenic
plant vaccines, such as low cost, easiness of storage and convenient immune inoculation.
The productions converged in edible tissues can be consumed directly without isolation and
purification.
Recent Advances in Analysis of Peptides and Proteins by Mass Spectrometry
The availability of large amounts of purified recombinant proteins together with the possibility
of altering their structures promises to revolutionize both the approach for treatment of diseases
and our understanding of their molecular bases. Many of these proteins are being developed as
potential therapeutic agents, whereas others are being used for diagnostic purposes and for structural
studies aimed at elucidation of their mechanisms of actions. It is the cellular machinery of the host
organism (e.g. bacteria, yeast or transformed mammalian cells) that defines what modifications
of these proteins shall take place. Fast, sensitive and reliable procedures are necessary to bridge
the analytical gap between protein chemistry and molecular genetics. The analytical tools of mass
spectrometry and tandem mass spectrometry, when used in conjunction with conventional chemical
and biochemical techniques, can help to fill this gap, particularly when each approach is used to
take advantage of its unique strength.
The engineering of chloroplast genomes is used against herbicides and pathogens. It is used for
deveopment of edible crop plants and edible vaccines.
Advances in Chloroplast Engineering
The chloroplast is a pivotal organelle in plant cells and eukaryotic algae to carry out photosynthesis
that provides the primary source of glucose. In the last two decades, great progress has been made in
chloroplast engineering. The expression of foreign genes in chloroplasts offers several advantages
over their expression in the nucleus. The high-level expression, transgene stacking in operons and
a lack of epigenetic interference permit stable transgene expression. The transgenic chloroplasts are
generally not transmitted through pollen grains because of the cytoplasmic localization.
Textbook of Pharmaceutical Biotechnology
302
Chromatography-Free Recovery of Biopharmaceuticals through
Aqueous Two-Phase Process
One of the distinct advantages of large-scale aqueous two-phase extraction is its easy scale up
together with the possibility of continuous operation using traditional liquid–liquid extractors. This
process of extraction would overcome some of the limitations that chromatographic separations
are facing. The future of aqueous two-phase process (ATPPs) includes the further development
of cost-effective smart polymers, which by responding to a change in the environment (e.g. pH
or temperature) are able to change conformation and thereby permitting the recovery of both the
biomolecule of interest and the polymer in opposite phases. Another breakthrough could be from
the integration of magnetic particles into ATPSs that could speed up phase separation and enhance
process throughput.
Recent Advances in Large-Scale Production of Monoclonal
Antibodies and Related Products
The biopharmaceuticals and related products commercially produced are listed along with
indications and antibody types involved in Table 19.6.
Table 19.6 Monoclonal antibodies and related products in market
Name and
year
Target Indication Company
Antibody
type
Orthoclone
OKT3 (1986)
CD3
Acute kidney transplant
rejection
Ortho Biotech Murine
ReoPro
(1994)
Platelet
GP IIb/IIIa
Prevention of blood clot Centocor Murine
Rituxan
(1997)
CD20 Non-Hodgkin’s lymphoma Genentech/Biogen-Idec Chimeric
Panorex
(1995)
17A-1 Colorectal cancer GlaxoSmithKline Murine
Zenapax
(1997)
IL-2Ra
(CD25)
Acute kidney transplant
rejection
Hoffmann-La Roche Humanized
Simulect
(1998)
IL-2R
Prophylaxis of acute organ
rejection
Novartis Chimeric
Synagis
(1998)
RSV Respiratory syncytial virus Medimmune Humanized
Remicade
(1998)
TNF_
Rheumatoid arthritis Centocor Chimeric
Herceptin
(1998)
Her2 Metastatic breast cancer Genentech Humanized
Mylotarg
(2000)
CD33 Acute myelogenous lymphoma Wyeth–Ayerst Humanized
(Continued)
Recent Advances in Biopharmaceuticals
303
Name and
year
Target Indication Company
Antibody
type
Campath
(2001)
CD52
B cell chronic lymphocytic
leukaemia
Takeda Humanized
Zevalin
(2002)
CD20 Non-Hodgkin’s lymphoma Biogen-Idec Murine
Humira
(2002)
TNF_
Rheumatoid arthritis Abbott Humanized
Bexxar
(2003)
CD20 Non-Hodgkin’s lymphoma Corixa/GlaxoSmithKline Murine
Xolair
(2003)
IgE Allergy Genentech/Novartis Humanized
Erbitux
(2004)
EGFR/Her1 Colorectal cancer
Bristol-Myers Squibb/Imclone
(Eli Lilly)
Humanized
Avastin
(2004)
VEGF Colorectal cancer Genentech Humanized
Raptiva
(2004)
CD11a Psoriasis Genentech/Xoma Humanized
Tysabri
(2004)
A4 integrin Multiple sclerosis Biogen-Idec/Elan Humanized
Vectibix
(2006)
EGFR Colorectal cancer Amgen Humanized
Soliris
(2007)
C5
complement
PNH Alexion Humanized
Stelara
(2008)
IL-12 and
IL-23
Psoriasis Centocor Humanized
Simponi
(2008)
TNF_
Rheumatoid arthritis Centocor Humanized
Actemra
(2009)
IL-6 Rheumatoid arthritis Roche Humanized
Abbreviations: IL, interleukin; PNH, paroxysmal nocturnal haemoglobinuria; TNF, tumour necrosis factor.
QUESTIONS
1. Write a note on advantages of DNA technology in the production of biopharmaceuticals.
2. List out biomolecules produced through recombinant DNA technology.
3. Write a note on the recent advances in biopharmaceuticals.
4. Write a note on monoclonal antibodies and related products in market.
5. Give a brief account of plant-derived therapeutics.
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