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

Users Online : 65436

AbstractConclusionKey MessageReferences
Article in PDF How to Cite Citation Manager Readers' Comments (0) Audio Visual Article Statistics Link to PUBMED Print this Article Send to a Friend
Advertisers Access Statistics Resources

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 ones 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 journalsNo manuscriptsNo 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 : 2009 | Month : August | Volume : 3 | Issue : 4 | Page : 1690 - 1696

Romiplostim:A Novel c-Mpl/CD110 Receptor Ligand for the Management of Idiopathic Thrombocytopenic Purpura

PATEL H*, PATEL N**, VYAS A***, PATEL M ****, PANDEY S*****

*,**,***,***(M.Pharm),*****(Phd) Dept of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Kasturba Hospital, Manipal, Karnataka, 576 104(India)

Correspondence Address :
Patel Hiren
223, Raman Block,
Manipal, Udupi,
Karnataka-576 104(India)
E.mail:hiren379@gmail.com
+919742502730

Abstract

Idiopathic Thrombocytopenic Purpura (ITP) is an autoimmune disease characterised predominantly by an antibody mediated destruction of platelets. Few treatment options are available for ITP like corticosteroids, IV immunoglobulins, splenectomy, rituximab, danazole and cyclophosphamide. All these treatment options work by reducing the destruction of platelets by antibody. However recent evidence suggests that production of platelet is reduced in 75% of thrombocytopenic patient with ITP. Romiplostim is a novel thrombopoetin receptor agonist approved by USFDA in August 2008 that increases the platelet count in ITP patients unresponsive to corticosteroids, immunoglobulins or splenectomy. Romiplostim is not currently available in India. The addition of Romiplostim in the treatment options for ITP will surely improve the outcomes in ITP patients.

Keywords

Romiplostim, Thrombopoetin receptor agonist, Idiopathic Thrombocytopenic Purpura

Idiopathic thrombocytopenic purpura, also known as primary immune thrombocytopenic purpura, is an autoimmune disorder that is characterized predominantly by antibody-mediated platelet destruction (1),(2).The clinical manifestations of ITP are highly variable and range from complete lack of symptoms to frank haemorrhage from any site, the most serious of which is intracranial(3).

Corticosteroids, intravenous immunoglobulins, splenectomy, rituximab, danazol and cyclophosphamide are the available current therapy which primarily focuses on reduction of this platelet destruction (4). If the patient’s situation is not life threatening, corticosteroids are the standard initial treatment(5). Intravenous immunoglobulins are generally recommended for patients with critical bleeding and for those who are unresponsive to corticosteroids(5). The platelet count can also be supported by the administration of anti-D immunoglobulin, which is active in 70–75% of Rh-positive patients in the pre splenectomy setting(6). Splenectomy is traditionally considered to be the second line of treatment in adults with ITP, in whom achieving a normal safe platelet count with initial corticosteroid therapy has failed. For those who are refractory to or who relapse after splenectomy, there is a long list of available approaches like rituximab, danazol and immunosuppressive agents, but immunosuppressive agents are associated with an increased risk of infection(7).

However, recent evidence suggests that decreased platelet production might also have a role in ITP (8). For example, kinetic studies have shown that platelet production is not increased in over 75% of thrombocytopenic patients with chronic ITP, which is contrary to expectations, (9),(10) and thrombopoietin concentrations are normal or near normal in patients with this disease(11),(12),(13) Moreover, anti platelet antibodies inhibit the in-vitro growth of megakaryocyte precursor cells and bone marrow megakaryocytes in ITP, which can be apoptotic(14). Often, current therapies aimed at the reduction of platelet destruction are either ineffective or poorly tolerated. Therefore, treatments targeting the increasing platelet production alone, or in combination with existing therapies, provide an opportunity to improve outcomes in patients with this chronic disease (15).

After the identification and isolation of thrombopoietin and the thrombopoietin receptor c-Mpl in the process of platelet production in 1994, two agents, recombinant human thrombopoietin rHuTPO and rHu- MGDF, underwent study in a multitude of settings. Although initially promising action, the development of these agents was halted in 1998 after the emergence of neutralizing antibodies that cross-reacted with endogenous TPO, producing consistent thrombocytopaenia in healthy subjects(16).

Romiplostim is a novel thrombopoiesis stimulating peptibody that binds to and activates the human thrombopoietin receptor despite having no sequence homology with human thrombopoietin(16),(17). Due to the different sequences of amino acids with respect to endogenous TPO in romiplostim, there is no risk of producing neutralizing antibodies that cross-reacted with endogenous TPO(18). FDA approved romiplostim in 2008 for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura, who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy(19). It is available only through a restricted distribution program called the NEXUS (Network of Experts Understanding and Supporting Nplate and Patients) Program. Only prescribers and patients registered with the program are able to prescribe, administer and receive the product (19).

Chemistry
Romiplostim is a peptibody of approximately 60 kDa (20). It is engineered mainly to prevent the problem of cross reacting antibodies(17). It consists of a disulphide-bonded human IgG1 heavy chain and kappa light chain constant regions (an Fc fragment) with two identical peptide sequences linked covalently at residue 228 of the heavy chain with the use of polyglycine (Table/Fig 1) (20). The Mpl receptor binding domain stimulates megakaryopoesis in the same way as thrombopoietin and the carrier Fc component of the molecule binds to the FcRn salvage receptor and undergoes endothelial recirculation, resulting in a substantially longer half time than the peptide alone. The Fc portion increases the half life of the compound to around 20 hours (20). The Mpl receptor binding was selected by screening the libraries of peptides having no similarity with that of thrombopoietin, but with a tertiary structure that helps to bind with the receptor (21). This non similarity between romiplostim and thrombopoetin helps in getting the non production of cross reacting antibodies.



Mechanism of action
Romiplostim stimulates platelet production by a mechanism similar to that of endogenous TPO; despite having different sequences of amino acids than TPO(16),(17). So, to understand the mechanism of action of romiplostim, it is necessary to understand the physiology of TPO. Thrombopoietin (TPO) is a growth factor that regulates thrombopoiesis by promoting the viability and growth of megakaryocyte colony-forming cells. In vitro, TPO stimulates both early megakaryocyte development such as megakaryocytic colony forming units (MK-CFU), as well as late maturation such as the number, size and ploidy of megakaryocytes(22).

TPO acts through a TPO receptor (TPO-R), also referred to as c-Mpl or CD110, which is a member of the type 1 cytokine receptor superfamily(23). TPO-R is located on haematopoietic stem cells, megakaryocytic progenitor cells (MK-CFU) and platelets(16). TPO –R stimulation activates the JAK-STAT pathway and it ultimately stimulates the differentiation of megakaryocytes from the earlier progenitor cells, which leads to increased platelet production (Table/Fig 2) (24).

Pharmacokinetics
Systemic exposure (C0 and AUC0-t) to romiplostin after intravenous administration increases more than proportionally with dose. This correlates with the fact of target mediated disposition. Romiplostim binds to c-Mpl on platelets and other cells in the thrombopoiesis linage such as megakaryocytes, and is subsequently internalized and degraded inside these cells. The mean elimination half life is short and increases with the dose (1.5, 2.4 and 13.8 hours for doses of 0.3,1 and 10 mcg/kg, respectively). In the long term extension study in patients with chronic ITP who received a weekly treatment of Romiplostim subcutaneously over the dose range of 3 to 15 mcg/kg, peak serum concentrations were observed around 7 to 50 hrs post dose (median:3.5 days). Serum concentrations varied among the patients and did not correlate with the dose administered (19), (25). The elimination of Romiplostim is governed by c-Mpl receptors. Thus, patients with higher platelet counts are associated with lower serum concentrations and vice versa. In another ITP clinical study, no accumulation in serum romiplostim concentrations was observed after six weekly doses of 3 mcg/kg of romiplostim(19), (21). PK/PD relationships between the Romiplostim dose and platelet counts in ITP patients showed a linear tendency between the baseline normalized platelet count ratio and the dose administered. ITP patients are more sensitive to Romiplostim than the healthy subjects (15), (26), (27). Also, the subcutaneous route of Romiplostim is a convenient, effective and well tolerated treatment option for ITP(28).

Clinical studies
Two clinical studies provided the major data assessing the effects of Romiplostim among patients with chronic ITP(29). Study 1 enrolled patients who had not undergone splenectomy and Study 2 enrolled patients who were refractory to splenectomy. Both the studies used randomized (2:1; active: placebo), double-blind, placebo controlled designs with the enrollment of patients who were thrombocytopaenic despite prior therapy with at least one prior ITP medication. Patients were exposed to the study drug for six months with weekly measurement of platelet counts. At the end of the study, patients were observed for another 12 weeks without administration of the study drug.

The primary endpoint was "durable platelet response," defined as at least six weekly platelet counts ≥ 50,000/mcL during the last eight weeks of the drug treatment study, in the absence of "rescue medications" at any time during the 24 week treatment period. The major secondary endpoints involved various comparisons of platelet count "responses" (defined as any weekly platelet count ≥ 50,000/mcL) and comparison of the use of thrombocytopaenia "rescue medications." During the first 12 weeks of the study, investigators could decrease or eliminate the use of any concomitant ITP medications, based upon the observed platelet counts. The baseline characteristics of enrolled subjects were similar between the randomized groups, with most subjects having received multiple prior ITP medications. Within the dataset pool of both studies, 11 patients had received a single prior ITP medication (2 in the placebo group and 9 in the Romiplostim group). In both studies, statistically significant differences were observed for the primary and secondary endpoints, as shown (Table/Fig 3) (15),(18),(30).


Other notable efficacy findings included the number of subjects who were able to discontinue all baseline concomitant ITP medications, as shown in (Table/Fig 4). Overall, an increase in platelet counts from the baseline by ≥ 20,000/mcL at any time point in either study (exclusive of eight weeks following a rescue medication), was achieved by approximately 90% of all subjects receiving Romiplostim and approximately by 30% of subjects receiving placebo. After a median of approximately 39 weeks of Romiplostim therapy in the long term extension study, patients continued to maintain platelet count responses in a pattern similar to those achieved during the 24 weeks of the two phase 3 clinical studies.

Thus, Romiplostim was well tolerated and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP. Many patients were able to reduce or discontinue other ITP medications(15),[ 18].

Indication
• Currently, Romiplostim is indicated for the treatment of thrombocytopaenic patients with chronic ITP.
• In patients of ITP who are nonsplenectomized but have inadequate response or intolerance to corticosteroids and/or immunoglobulins.
• In patients of ITP who are splenectomized but have insufficient response to spelenectomy (30).
• Romiplostim should be used only in patients with ITP where there is an increased risk of bleeding and no attempt should be made to normalize platelet counts of normal individuals(29),(31).

Dosage Regimen
The initial dose for Romiplostim is 1 mcg/kg, based on the actual body weight. Then the dose is adjusted on a weekly basis by increments of 1 mcg/kg until the patient achieves a platelet count ≥ 50 x 109/L or as necessary to reduce the risk for bleeding. The maximum weekly dose is 10mcg/kg. During Romiplostim therapy, CBCs, including platelet count and peripheral blood smears should be assessed weekly until a stable platelet count (≥ 50 x 109/L for at least 4 weeks without dose adjustment) has been achieved. Monitoring of CBCs including platelet counts and peripheral blood smears should continue for one month thereafter.
• If the platelet count is < 50 x 109/L, increase the dose by 1 mcg/kg.
• If the platelet count is > 200 x 109/L for 2 consecutive weeks, reduce the dose by 1 mcg/kg.
• If the platelet count is > 400 x 109/L, do not dose. Continue to assess the platelet count weekly. After the platelet count has fallen to < 200 x 109/L, Romiplostim should be resumed at a dose reduced by 1 mcg/kg.
Romiplostim should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of Romiplostim therapy at the maximum weekly dose of 10mcg/kg. Monitoring of CBCs including platelet counts, should continue weekly for at least 2 weeks following the discontinuation of Romiplostim (19).

Adverse Drug Reactions
Adverse drug reactions of Romiplostim (incidence <5%) as per study reports 1 and 2 were dizziness, insomnia, myalgia and abdominal pain .Headache and arthralgia were reported in both Romiplostin as well as in the placebo arm (19)

In the phase-1 study, the most frequently reported adverse events are confusion, ecchymosis or both, which occurred in 67% of 24 patients (17).

Safety Concerns Over The Following Side Effects Are Yet To Be Determined

>>Reticulin formation and risk for marrow fibrosis
In the phase 3 study, one event (serious) was reported for a patient who received Romiplostim. This subject was a 40 year old man participating in Study 2 who had a history of "reticulin fibrosis" at the time of enrollment for the study (31).

>>Risk for malignancy or progression of malignancy
In the two phase 3 studies, only seven adverse events for "neoplasia" were reported, five in the placebo group (n = 41) and two in the Romiplostim group (n = 84). The two neoplasms in the Romiplostim group consisted of a basal cell carcinoma in one subject and a B cell lymphoma in another subject (31).

>>Thrombotic risk
Within the pool of the two phase 3 studies, only three thrombotic events were reported.

Overall, within the safety dataset of 204 patients with chronic ITP, a total of 14 patients experienced thrombotic events following Romiplostim initiation, inclusive of the uncontrolled exposure (31).


>>Alteration of intrinsic TPO/worsening of thrombocytopaenia after cessation of Romiplostim therapy
In the phase 1 and 2 studies, (n = 57 patients receiving Romiplostim), four subjects experienced a decrease in platelet counts below the pretreatment baseline levels. All counts approximated baseline levels within 14 days of the thrombocytopaenia onset (31).

>> Immunogenicity
Overall, 17/204 (8%) of patients exposed to Romiplostim developed binding antibodies against the drug and 9/204 (4%) developed binding antibodies against TPO. No patient developed neutralizing antibodies to TPO. One patient with chronic ITP developed neutralizing antibodies to Romiplostim in the open-label, extension study (31).

Conclusion

Romiplostim is a novel drug that can be used effectively in ITP where corticosteroids, immunoglobulins and splenectomy are not successful. It marks an era of a new biological therapy directed towards the production of thrombocytes in ITP patients. It proves to be beneficial in preventing an emergency situation like bleeding in patients with ITP.

Abbreviations
ITP: - Idiopathic thrombocytopenic purpura
TPO: - Thrombopoietin
c-Mpl: - Murine myeloproliferative leukaemia proto-oncogene
rHuTPO: - Recombinant human thrombopoietin
rHu- MGDF: - Recombinant human megakaryocyte growth and differentiation factor
MK-CFU: - Megakaryocytic-colony forming units
SD:-Standard deviation
CBC: -Complete blood count
AUC: - Area under curve

Key Message

Romiplostim is novel thrombopoesis stimulating peptibody found to be potentially useful in treatment of ITP where corticosteroids, immunoglobulins or splenectomy has failed. There are less incidences of development of autoantibodies against Romiplopstim as found in other agents of its class.

References

1.
. George JN, El-Harake MA, Raskob GE. Chronic idiopathic thrombocytopenic purpura. N Engl J Med 1994; Nov 3; 331(18): 1207–11.
2.
. Karpatkin S. Autoimmune (idiopathic) thrombocytopenic purpura. Lancet 1997; May 24; 349(9064): 1531–6.
3.
. Cohen YC, Djulbegovic B, Shamai-Lubovitz O, Mozes B. The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Intern Med 2000; Jun 12; 160 (11): 1630-8.
4.
. George JN, Kojouri K, Perdue JJ, Vesely SK. Management of patients with chronic, refractory idiopathic thrombocytopenic purpura. Semin Hematol 2000; Jul; 37(3): 290–8.
5.
. George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996; Jul 1 ; 88(1): 3–40.
6.
. Scaradavou A, Woo B, Woloski BM, Cunningham-Rundles S, Ettinger LJ, Aledort LM et al. Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood 1997; Apr 15; 89 (8): 2689-700.
7.
. Stasi R, Provan D. Management of immune thrombocytopenic purpura in adults. Mayo Clin Proc 2004; Apr; 79 (4): 504-22
8.
. McMillan R, Wang L, Tomer A, Nichol J, Pistillo J. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood 2004; Oct 23; 103(4): 1364–9.
9.
. Heyns AD, Lotter MG, Badenhorst PN, Kock FD, Pieters H, Herbst C et al. Kinetics and sites of destruction of 111Indium-oxine-labeled platelets in idiopathic thrombocytopenic purpura: a quantitative study. Am J Hematol 1982; 12(2): 167–77.
10.
. Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW, Slichter SJ. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J Clin Invest 1987; Jul; 80(1): 33–40.
11.
. Nichol JL. Thrombopoietin levels after chemotherapy and in naturally occurring human diseases. Curr Opin Hematol 1998; May; 5(3): 203–8.
12.
. Kosugi S, Kurata Y, Tomiyama Y, et al. Circulating thrombopoietin level in chronic immune thrombocytopenic purpura. Br J Haematol 1996; 93(3): 704–6.
13.
. Emmons RV, Reid DM, Cohen RL, et al. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte defi ciency and low when due to increased platelet destruction. Blood 1996; 87: 4068–71.
14.
. Houwerzijl EJ, Blom NR, van der Want JJ, Esselink MT, Koornstra JJ, Smit JW et al. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood 2004; Jan 15; 103(2): 500–6.
15.
. Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomized controlled trial. Lancet 2002; Feb 2; 371: 395–403.
16.
. Kuter DJ. New thrombopoietic growth factors. Blood 2007; Jun 1; 109(11): 4607–16
17.
. Bussel JB, Kuter DJ, George JN, Mcmillan R, Aledort LM, Conklin GT et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med 2006; Oct 19; 355(16): 1672–81.
18.
. Bussel JB, Kutter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL. Safety and efficacy of long term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood [serial online] 2008 Nov 3 [cited 2009 Jan 28]: Available from: URL: http://bloodjournal.hematologylibrary.org/cgi/content/abstract/blood-2008-04-150078v1
19.
. Food and drug administration. Highlights of prescribing information of romiplostim [Online]. 2008 Aug [cited 2009 Jan 28]; 1,2,6,8. Available from: URL: http://www.fda.gov/cder/foi/label/2008/125268lbl.pdf
20.
. Peetersk K, Stassen JM, Collen D, Geet CV, Freson K. Emerging treatments for thrombocytopenia: Increasing platelet production. Drug discovery today 2008; Sep;13(17/18):798-806
21.
. Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor. Clin Pharmacol Ther 2004; 76 (6): 628-38
22.
. Stasi R, Evangelista ML, Amadori S. Novel thrombopoietic agents: A review of their use in idiopathic thrombocytopenia purpura. Drugs. 2008; 68(7):901-12.
23.
. Methia N, Louache F, Vainchenker W, Wendling F. Oligodeoxynucleotides antisense to the proto-oncogene c-mpl specifically inhibit in vitro megakaryopoiesis. Blood 1993; Sep 1; 82(5):1395-401.
24.
. Lodish H, Berk A, Kaiser CA, Krieger M, Scott MP, Bretscher A et al. Molecular cell biology. 6th ed. New York: W. H. Freeman and Company; 2008. P. 672-6.
25.
. Clinical Pharmacology and biopharmaceutics Reviews of romiplostim. Food and drug Administration [online].[cited 2009 Jan 28];Available from: URL: http://www.fda.gov/cder/foi/nda/2008/125268s000_ClinPharmR.pdf
26.
. Kumagi Y, Fujita T, Ozaki M, Sahashi K, Ohkura M, Ohtsu T, et al. Pharmacodynamics and pharmacokinetics of AMJ531, a Thrombopoesis Stimulating peptibody, in Healthy Japanese Subjects: A Randomized, Placebo Controlled study. J Clin Pharmacol 2007; 47:1489-97
27.
. Newland A, Caulier MT, Kappers, Klunne M, et al.An open label, unit dose finding study of AMG 531, a novel thrombopoesis stimulating peptibody in patient with ITP. Br J Haematol.2006; 135:547-553
28.
. George J, Bussel JB, Lyons RM, Pullarkat V, Redner R, Terreu D.et al.Self injection of Romiplostim by patients with chronic immune thrombocytopenic Purpura(ITP). Blood [serial online] 2008 Dec [cited 2009 Jan 29]; 112: Available from : URL: http://www.cancercaresouthtexas.com/docs/SelfInjection%20of%20Romiplostim%20by%20Patients%20with%20Chronic%20Immune%20Throbocytopeni.pdf
29.
. Cines DB, Yasothan U, Kirkpatrick P. Romiplostim. Nature Review Drug Discovery 2008 Nov 7:887-88.
30.
. Oncologic drug advisory committee. FDA advisory committee briefing document on romiplostim [Online]. 2008 Mar [cited 2009 Jan 25]; 3,6-9. Available from: URL: http://www.fda.gov/ohrms/dockets/AC/08/briefing/2008-4345b1-01-FDA.pdf
31.
. Broudy VC. & Lin NL. AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl. Cytokine 2004 ;25:52–60.

JCDR is now Monthly and more widely Indexed .
  • Emerging Sources Citation Index (Web of Science, thomsonreuters)
  • Index Copernicus ICV 2017: 134.54
  • Academic Search Complete Database
  • Directory of Open Access Journals (DOAJ)
  • EBSCOhost
  • Google Scholar
  • HINARI Access to Research in Health Programme
  • Indian Science Abstracts (ISA)
  • Journal seek Database
  • Google
  • Popline (reproductive health literature)
  • www.omnimedicalsearch.com