Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Archana Dambal

"Journal of clinical and diagnostic research is a welcome change in publishing practices. It aims to reach out to the grass-root level researchers who do not lack in experience, clinical material and ideas, but lack in their knowledge in English language and statistics. The journal achieves it's aim by supporting in these exact domains.
It also gives due credit to all research designs like descriptive and qualitative studies while many journals ignore these important study designs. The rigorous review process does not allow any compromise in quality
It is indexed in many indexing agencies and the articles are available under creative commons licence free of cost
The frequency of publication supports many aspiring authors from India and other countries.
It's wide scope welcomes articles across various specialities in medicine. In an era when there is an unscientific insistence on speciality specific research by regulatory bodies in medical education, JCDR supports collaborative research across specialities. I wish the publisher all the best in his future endeavors."



Dr. Archana Dambal
Department of General Medicine,
Belgaum Institute of Medical Sciences,Belgaum, Karnataka,INDIA,
On 30 Nov 2018




Dr Bhanu K Bhakhri

"The Journal of Clinical and Diagnostic Research (JCDR) has been in operation since almost a decade. It has contributed a huge number of peer reviewed articles, across a spectrum of medical disciplines, to the medical literature.
Its wide based indexing and open access publications attracts many authors as well as readers
For authors, the manuscripts can be uploaded online through an easily navigable portal, on other hand, reviewers appreciate the systematic handling of all manuscripts. The way JCDR has emerged as an effective medium for publishing wide array of observations in Indian context, I wish the editorial team success in their endeavour"



Dr Bhanu K Bhakhri
Faculty, Pediatric Medicine
Super Speciality Paediatric Hospital and Post Graduate Teaching Institute, Noida
On Sep 2018




Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dematolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011

Important Notice

Reviews
Year : 2008 | Month : August | Volume : 2 | Issue : 4 | Page : 1020 - 1023

Macromolecular Drugs: Novel Strategy In Target Specific Drug Delivery

SHARMA R* SHARMA CL **

* Ex. Senior demonstrator,postgraduate department of pharmacology and therapeutics govt. Medical college, Jammu, India.** LT Col (AMC), medical officer , 166 mh, satwari –Jammu cantt, India.

Correspondence Address :
DR. SHARMA R, 216-A, Last Morh, Gandhi Nagar , Jammu-J&K- India.e.mail: drrashmi@india.com

Abstract

Macromolecular drugs are polymer-conjugated drugs, polymeric micelles, liposomal drugs or solid phase depot formulations of various agents. Macromolecular drugs can target selectively, solid tumours by exploiting abnormalities of tumour vasculature, namely, hypervascularisation; aberrant vascular architecture; extensive production of vascular permeability factors stimulating extravasation within tumour tissues; and lack of lymphatic drainage. Dextrans are polysaccharide macromolecular carriers devoid of selective transport properties and may serve as one of the most promising carrier candidates for a wide variety of therapeutic agents like hormones (oxytocin and vasopressin), iron, methotraxate, etc. Bone targeting by conjugation of drugs with bisphosphates has shown promise in enhancing their effects in bones and reducing adverse drug reactions. Tetracyclin–conjugated estradiol and oligopeptide–conjugated estradiol are the other novel bone–specific drug carriers (oligopeptides) with high affinity for hydroxyapatite crystals.

Keywords

polymer-conjugated drugs, Dextrans, Tetracyclin–conjugated estradiol, bisphosphates.

How to cite this article :

SHARMA R, SHARMA CL . MACROMOLECULAR DRUGS: NOVEL STRATEGY IN TARGET SPECIFIC DRUG DELIVERY . Journal of Clinical and Diagnostic Research [serial online] 2008 August [cited: 2019 Sep 17 ]; 2:1020-1023. Available from
http://www.jcdr.net/back_issues.asp?issn=0973-709x&year=2008&month=August&volume=2&issue=4&page=1020-1023&id=283

Introduction
Macromolecular drugs are polymer-conjugated drugs, polymeric micelles, liposomal drugs or solid phase depot formulations of various agents(1). Candidate polymers for therapeutic use must be devoid of antigenicity, immounogenicity, haemolytic, procoagulant or cytotoxic activity. Macromolecular drugs must be neutral or slightly negatively charged, as the luminal surfaces of the blood vessels are negatively charged(1). Polymeric drugs can be made through covalent linking of drugs to a polymeric carrier; whereas micellar entrapment of a drug can be achieved by covalent or noncovalent bonds. Amide, ester, hydrazide, azide, imine, thioether, urethane etc. are various chemical bonds used to prepare macromolecular drugs. Polymeric drugs have the advantage of having long t ½ activity against MDR (multidrug resistant) cells, and high retention in the tumour cells.(1)Drugs weighing less than 40 kDa, unless bound to plasma protein, are cleared rapidly into urine, whereas drugs weighing more than 40 kDa usually have long t ½. However, accumulations of drugs should be kept in mind if used for long durations. Moreover, drugs > 40 KDa are taken inside the cell by endocytosis, transported to lysosomes and the active component is released by proteolytic enzymes at low pH.(1) Thereby, these macromolecules counteract the P-glycoprotein-dependent efflux system in MDR. Newly formed tumour vessels are abnormal in form and architecture of fluid transport dynamics (especially tumour tissues lack effective lymphatic drainage), which results in enhanced permeability and retentions of macromolecules and lipids in the tumour cells.

Macromolecules As Anticancer Drugs
(2),(3)Lack of tumour selectivity is the major limitation inherent to most conventional anticancer chemotherapeutic agents. Macromolecular drugs can target solid tumours selectively by exploiting abnormalities of tumour vasculature, namely, hypervascularisation; aberrant vascular architecture; extensive production of vascular permeability factors stimulating extravasation within tumour tissues; and lack of lymphatic drainage. Large molecular size, nanosized macromolecular anticancer drugs administered intravenously, escape renal clearance, cannot penetrate the tight endothelial junctions of normal blood vessels, and can extravasate in tumour vasculature and become trapped in the tumour vicinity. Due to lack of efficient lymphatic drainage in solid tumours, there will be a severalfold increased concencentration of the drug in the tumour, than in the plasma. EPR (enhanced permeability and retention effect) -based selective anticancer drug delivery has hastened the development of various polymer conjugates and polymeric micelles, as well as multifunctional nanoparticles for targeted cancer chemotherapy. Increased efficiency of drug delivery to the tumour, especially of macromolecular drugs, is possible by enhancing the EPR effect with the use of various vascular permeability mediators or potentiators. Suppression of the EPR effect by the use of appropriate inhibitors like bradykinin antagonist HOE 140, protease inhibitors, or NOS inhibitors, may also be possible. Pleural fluid in lung cancer and ascitic fluid in abdominal carcinomatosis may be controlled, and the clinical course of cancer patients may be improved by suppressing vascular permeability with antidotes such as the bradykinin antagonist HOE 140.

Some of the macromolecules showing promises in clinical therapeutics are as follows:
Styrene Maleic Acid Neocarzinostatin
(1) It is a proteinaceous antitumour antibiotic produced by streptomyces carzinostaticus. It acts by inhibiting DNA synthesis through direct DNA strand scission and superoxide generation via a cytochrome p450 reductase .It has prolonged t ½ (10-20 times more than that of neocarzinostatin), with high targeting efficiency. It gets split into neocarzino statin and styrene maleic acid (SMA) polymer by proteolysis, and free MA polymer is eliminated (more through bile and less through kidney). Its efficacy against primary hepatocellular carcinoma and solid tumour has been reported after intra-arterial administration. It shows a 10-28 times higher binding affinity to tumour cells than neocarzinostatin, and can be given orally. Moreover, it has reduced immunogenicity and high plasma albumin binding capacity.

Peginterferon Alfa (1) Interferon apha,beta and gamma are used as antitumour agents in renal cell cancer, kaposi’s sarcoma or leukaemia, and for management of HCV(hepatitis c virus).Being smaller in size, they have short plasma t ½ (8hrs.). Pegylated (PEGylation is the process of covalent attachment of poly(ethylene glycol) polymer chains to another molecule versions) of IFN -2a and IFN  -2b are developed with prototypes having single straight chain polyethylene glycol (PEG) molecules of 5 KDa and 12 KDa per molecule of interferon, respectively. Further improvement is made by conjugating IFN - -2a with the 40 KDa PEG moiety. The PEG-IFN--2a (subcutaneous) produces slower penetration and delivery to the circulating blood and has decreased systemic clearance to 1/10th of the native protein. 2’,5’ oligoadenylate synthetase, an antiviral response enzyme reaches its maximum level at 48 hr. and remains at a plateau for over 1 week after PEG-IFN -2a administrations, as compared to the maximum level at 24 hrs after IFN -2a administration. Moreover, PEG IFN  -2a (40 KDa) has better tolerability profile than IFN -2a, and is associated with better safety profile than IFN  -2a + ribavirin therapy (anaemia associate with rebavirin therapy), with better out come in HCV infection .

Pegylated Liposomal Doxorubicin
(1) Liposomes are coated with PEG to confer a stealth character, resulting in a diminished uptake by the reticuloendothelial system, and hence a longer plasma t ½ . FDA has already approved pegylated liposomal doxorubicin for treatment of AIDS related kaposi’s sarcoma. In a phase II study, it has been shown that mesothelioma pegylated liposomal doxorubicin is effective, with modest toxicity. PEG- immunoliposome encapsulated doxorubicin (MCC-465), where PEG is tagged with the F(ab)2 fragment of human antibody IgG against gastric caranoma, is currently under clinical investigation for treatment of stomach cancer.

Pegylated Adenosine Deaminase
(1)PEGF-conjugatedADA(adenosine deaminase), has a human t ½ of 48-72 hours, and its once weekly administration in a dose of 15 U/kg significantly reduces adenosine levels in erythrocytes and results in full restoration of lymphocyte function .PEG-conjugated ADA was approved by US FDA in 1990 for use in conjugated adenosine deaminase deficiency.

Pegaspargase
(1) Severe allergic reactions and pancreatitis are reported with use of L-aspargine from E. Coli and plant pathogen Erwinia. Conjugation of PEG to E coli L-asparaginase results in reduction in toxicity and prolonged plasma t ½.

Dextran conjugates as macromolecular drugs
(4)Dextrans are polysaccharide macromolecular carriers devoid of selective transport properties, and may serve as one of the most promising carrier candidates for a wide variety of therapeutic agents due to their excellent physico-chemical properties and physiological acceptance. Dextrans of different chemical composition are synthesized by a large number of bacteria confined to the family Lactobacillaceae, Streptobacterium dextranicum and Leuconostoc mesenteroids. The product of microbiological synthesis is called as 'native-dextran'. Clinical dextrans are obtained from high molecular weight native dextrans after their partial depolymerisation by acid hydrolysis and fractionation. Dextran conjugates can either be irreversibly linked or reversibly linked. Irreversible dextran conjugates have been employed extensively in experimental medicine, and find wide applications in the field of biotechnology and related areas. Important enzymes that have been linked to dextran are a-amylase, arginase, asparaginase, carboxypeptidase, catalase, β -galactosidase, hyaluronidase, NAD+, streptokinase, papain and a-chymotrypsin. Various hormones like oxytocin and vasopressin have been linked to dextran so as to increase their water solubility along with retention of their activity. Enhanced lymphatic uptake of bleomycin, improved therapeutic efficiency of isometamidium, and reduced nephrotoxicity of gentamicin has been reported, when these drugs were administered in the form of dextran sulphate complexes. Parenteral iron-dextran has been used for the rapid regeneration of the red cell mass in anaemia and in patients intolerant of oral forms of iron. Pentavalent antimonials are rapidly excreted in urine, and have short duration of action. So, it has been complexed with dextran, which after intramuscular injection, is slowly absorbed from the injection site, and hence sufficient blood levels are maintained so as to suppress the Leishmania donavani infection effectively. Dextran can be attached to the drug to form a prodrug by various techniques like direct linkage, attachment through intercalated spacer arm, use of modulator ligand and tissue specific receptor ligand e.g., methotrexate (MTX)-dextran conjugates, Dextran-nalidixic acid ester (colon specific prodrug).

Conjugates of Bisphoshonates
(5)Bisphosphonates are synthetic compounds structurally related to pyrophosphate, an endogenous regulator of calcium homeostasis. Because of the P-C-P portion in its chemical structure, it has high affinity for calcium crystals, high bone specific delivery, and high water solubility with kidney as the major route of elimination. Moreover, unlike the POP bond of pyrophosphate, the PCP bond in bisphosphates is resistant to chemical and enzymatic hydrolysis. Hence, after binding to bone, bisphosphates remain there for a long period, with a t ½ of several months. Bone targeting by conjugation of drugs with bisphosphates has shown promise in enhancing their effects in bones and reducing adverse drug reactions.

Tetracyclin–conjugated estradiol and oligopeptide–conjugated estradiol are the other novel bone–specific drug carriers, which are oligopeptides with a high affinity for hydroxyapatite crystals.(5) Estradiol conjugated with hexa-L-aspartic acid peptide and E2-(L-ASP) after a once weekly treatment, showed an efficacy similar to estradiol treatment every 3 days, with less side-effects.(5) It has advantage over bisphosphonates conjugates, as no colloid or precipitate formation is there, with endogenous metals. Radiopharmaceuticals beta-emitter 153Sm is coupled to the phosphonate part of EDTMP (ethylenediamine –tetramethyl-lene phosphonic acid) in a 1:1 ratio with high affinity for bone minerals and skeletal muscles, and has high accumulation in metastatic regions (4 times more than normal tissue) .5 153Sm is also a gamma emitter, hence having advantages of medical imaging for delineating the progression of bone metastases. Fibroblast growth factor-I, bone morphogenetic proteins and transforming growth factor B are also being investigated as potential agents for bone specific delivery, in conjugation with bisphosphonates in osteoporosis.

Macromolecular drugs against human immunodeficiency virus Type1(HIV-1)
(6)Macromolecular drugs against human immunodeficiency virus Type 1 (HIV-1), including antisense oligonucleotides, ribozymes, RNA decoys and transdominant mutant proteins, may be able to interfere with a relatively large number of viral targets, thereby decreasing the likelihood of the emergence of drug-resistant strains. Moreover, it is relatively easy to alter the sequence of some of the macromolecular drugs to counter emerging drug-resistant viruses. The delivery of antisense oligonucleotides and ribozymes to HIV-1 infected or potentially infectable cells by antibody-targeted liposomes, certain cationic lipid formulations and pH-sensitive liposomes, result in significant anti-HIV-1 activity. Delivery of therapeutic genes is another form of macromolecular drug. Moloney murine leukaemia virus- (MoMuLV), adeno-associated virus (AAV)-, or HIV-derived vectors expressing a variety of therapeutic genes, have been used successfully to inhibit HIV-1 replication in cultured cells.

Potential targets for production of conjugated molecules are prostaglandin E2, estradiol and synthetic estrogenic agents for osteoprosis, NSAIDS for osteoarthritis, fluoroquinolones for chronic infections and cisplatin, melphalan, methotrexate and radiopharmaceuticals for cancers(5). Macromolecular drugs may prove to be a novel mode of drug delivery to target site, avoiding side effects with prolonged duration of action and less potential for drug resistance.

References

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Greish K, Fang J, Inutsuka T, Nagamitsu A and Maeda H. Macro molecular therapeutics advantages and prospects with special emphasis on solid tumor targeting . Clin Pharmacokinet 2003; 42(13): 1089-105.
2.
Greish K. Enhanced permeability and retention of macromolecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. J Drug Target. 2007 Aug-Sep; 15(7-8):457-64.
3.
Fang J, Sawa T, Maeda H. Factors and mechanism of "EPR" effect and the enhanced antitumor effects of macromolecular drugs including SMANCS. Adv Exp Med Biol. 2003; 519:29-49.
4.
Dhaneshwar SS, Kandpal M, Gairola N, Kadam SS. Dextran: A promising macromolecular drug carrier. Indian J Pharm Sci 2006; 68:705-14.
5.
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