Products

Recombinant Human Erythropoietin

Native human erythropoietin was originally prepared from urine of patients with aplastic anemia. The amount of human erythropoietin obtained from the patient's urine is rare, and a traditional process for purifying the human erythropoietin is laborious and time-consuming. Therefore, there is a demand to develop a process for producing and purifying a large amount of human erythropoietin in a simple and economical way.
 Genetic engineering techniques using an mammalian cell line as a host for producing a high level of recombinant human erythropoietin (rhEPO) has been developed. A cDNA fragment encoding human erythropoietin was cloned and sequenced by Jacob et al. (Nature, 313: 806-809, 1985). we use the gene recombinant technology to extract the recombinant EPO, thus making it possible for mass and cost effective production. In addition, its in vivo and in vitro biological activity makes no difference from the natural EPO.
SEPO® recombinant human erythropoietin injection, which stimulates red blood cell production, is a 165 amino acid glycoprotein manufactured by recombinant DNA technology. It is produced by CHO (Chinese Hamster Ovary) cell into which the human erythropoietin gene has been introduced. The product contains the identical amino acid sequence of isolated natural erythropoietin and has the same biological effects as endogenous erythropoietin.

Description: Clear colorless and transparent. pH 6.9±0.3

Composition: rhEPO, citric acid buffer solution and human serum albumin as stabilizer

Indications
Treatment of anemia of chronic renal failure patients, including patients on dialysis and patients not on dialysis
Treatment of anemia in cancer patients on chemotherapy
Reduction of allogeneic blood transfusion in surgery patients

Usage and Dosage (for treatment of renal anemia)

SEPO® should be used under instruction of physicians. It may be administrated subcutaneously or intravenously, 2-3 times per week. The dosage should be adjusted according to the severity of anemia, age and other related factors. The following dosage is for reference:
Treatment period: The initial dose is 100-150IU/kg per week for patients on hemodialysis and 75-100 IU/kg for patients not on hemodialysis. If hematocrit increases less than 0.5vol% weekly the dose can be increased by 15-30IU/kg 4 weeks after the initial dose, but the increased maximum dose is not more than 30IU/kg /week. The hematocrit should be increased within the range of 30-33vol%, but not higher than 34vol%.
Maintenance period: When hematocrit has reached to 30-33vol% or hemoglobin has reached to 100-110g/l, maintenance period starts. The dosage in this period shall be adjusted to the 2/3 of the recommended dosage in the treatment period. The hematocrit shall be monitored once every 2-4 weeks to adjust the dosage so as to maintain the hematocrit and hemoglobin at the proper level, at the same time to avoid erythropoiesis too quickly.
Intravenous administration is recommended for patients on hemodialysis and subcutaneous administration for patients on peritoneal dialysis and not on dialysis.

Contraindications
SEPO® is contraindicated in patients with:
Uncontrolled hypertention
Known hypersensitivity to mammalian cell-derived products
Known hypersensitivity to human albumin

Specifications
Single-dose, preservative-free vial. Each 1 ml of solution contains 2000IU, 2500IU, 3000IU, 4000IU, 5000IU or 10,000IU per vial.

Storage
Stored at 2-8℃ and protected from light. Do not freeze and shake

Shelf Life: Two years

Confirmed, Marked Clinical Effectiveness

Phase II clinical trial sites:
Beijing Friendship Hospital of Capital Medical University
PLA 301 Hospital, Nanjing Military General Hospital, Xinqiao Hospital of Third Military Medical University, Union Hospital of Tongji Medical University, Affiliated Hospital of Kunming Medical College, Affiliated Hospital of Jiangxi Medical College

Phase II clinical trial results:
The total effective rate of SEPO® for treatment of renal anemia is 96.8%
Pairs-matching comparative study indicated that SEPO® has similar effectiveness to imported rhEPO (ESPO®, Kirin Pharmaceutical, Japan) (see figure below)

Clinical study conducted in India for the purpose of registration

Study sites:
K.E.M. Hospital & Research Centre, Pune
Muljibhai Patel Kidney Hospital, Nadiad
Sir H.N. Hospital & Research Centre, Mumbai
Bombay Hospital, Mumbai

Conclusion:

Newly developed drugs

LMWH-Ca (Low-molecular-weight heparin calcium)

Brand name: Sparin®

The project has been awarded with new drug license issued by State Food and Drug Administration. And is now in the process of large-scale manufacturing.It is keen to be launched on September,2004.
LMWH-Ca is a new drug for Treatment of Deep Vein Thrombosis. Prophylaxis of Deep Vein Thrombosis in General Surgery and Orthopedic Surgery (Hip, Knee)
LMWH-Ca is derived from depolymerization of standard heparin, Whereas standard heparin has a molecular weight of 5,000 to 30,000 daltons,LMWH-Ca ranges from 1,000 to 10,000 daltons, resulting in properties that are distinct from those of traditional heparin.LMWH-Cabinds less strongly to protein, has enhanced bioavailability, interacts less with platelets and yields a very predictable dose response, eliminating the need to monitor the aPPT. LMWH-Ca, like standard heparin, binds to antithrombin III; however,LMWH-Ca inhibits thrombin to a lesser degree (and Factor Xa to a greater degree) than standard heparin.
Advantages ofLMWH-Caover standard heparin include predictable blood levels, lower likelihood of bleeding and no reports of thrombocytopenia or osteoporosis.

Properties of pharmacological action
Like standard heparin, Sparin also is antithrombase III (AT III) dependent antithrombotic and anticoagulative agent. The main difference between them is: standard heparin has the same strength of anti-Factor IIa activity to anti-Factor Xa activity, so it more likely leads to bleeding while as anticoagulant; Only with 25%~50% anti-Factor IIa activity of standard heparin, Sparin is characterized by a higher ratio of anti-Factor Xa activity to anti-Factor IIa activity (2~4:1), therefore Sparin has significantly decreased hemorrhagic side effect thanks to the dissociation of antithrombotic from hemorrhagic effect.

Advantages over standard heparin
Significantly decreased bleeding tendency
Excellent and prolonged antithrombotic and anticoagulative effect
Longer half-life and higher bioavailability
Simpler to use without the need of laboratory monitoring
For antithrombotic and anticoagulant
Sparin preferred

Indications:
Prevention and treatment of deep vein thrombosis and pulmonary embolism
Prevention of clotting during hemodialysis
Treatment of unstable angina or certain types of heart attacks
Treatment of ischemic cerebrovascular disease
Treatment of dropsical nephritis, diabetic nephropathy and glomerular nephritis
Thromboprophylaxis in pregnant women with thrombophilic disorders and treatment in pregnant women with venous thromboembolism
Treatment of disseminated intravascular coagulation (DIC)

Clinical Application

1.   Deep vein thrombosis (DVT)

DVT is frequently encountered disease in orthopedic and general surgery. Without prophylaxis, deep vein thrombosis occurs in 50 to 70 percent of patients undergoing total hip replacement, total knee replacement, or surgery for hip fractures.
As compared with placebo in randomized clinical trials1, low-molecular-weight heparins significantly reduced the risk of deep vein thrombosis (range of risk reduction, 31 percent to 79 percent) without increasing bleeding.
Low-molecular-weight heparins were more effective than low-dose standard heparin2 and equal or superior3 to adjusted-dose standard heparin.
LMWH are marginally more effective in the prevention of thromboembolism4 and cause fewer wound haematomas5
Reference
1. Turpie AGG, Levine MN, Hirsh J, et al. A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. N Engl J Med 1986;315:925-9.
2. Nurmohamed MT, Rosendaal FR, Buller HR, et al. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992;340:152-6.
3. Dechavanne M, Ville D, Berruyer M, et al. Randomized trial of a low-molecular-weight heparin (Kabi 2165) versus adjusted-dose subcutaneous standard heparin in the prophylaxis of deep-vein thrombosis after elective hip surgery. Haemostasis 1989;19:5-12.
4. Nurmohamed MT, Rosendaal FR, Buller HR, et al. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992;340:152-6.
5. Kakkar W, Cohen AT, Edmonson RA, et al. Low molecular weight versus standard heparin for prevention of venous thromboembolism after major abdominal surgery. Lancet 1993;341:259-65.

2.   Hemodialysis
LMWH seems to be as safe as UFH in terms of bleeding complications and as effective as UFH in preventing extracorporeal circuit thrombosis.
Reference
Wendy Lim*, Deborah J. Cook*, and Mark A. Crowther*. Safety and Efficacy of Low Molecular Weight Heparins for Hemodialysis in Patients with End-Stage Renal Failure: A Meta-analysis of Randomized Trials. J Am Soc Nephrol.2004; 15: 3192-3206.

LMWH is safe and effective in hemodialysis patients who have a risk of bleeding with standard heparin.
Reference
Jyh-Gang Leua,c,d, Shou-Shan Chianga, Shu-May Linb, Jung-Kuei Paia, Wey-Wen Jiangd. Low Molecular Weight Heparin in Hemodialysis Patients with a Bleeding Tendency. Nephron 2000;86:499-501

3.   Acute coronary syndrome
The limitations of conventional treatment with unfractionated heparin in unstable angina and non-Q wave myocardial infarction patients are demonstrated by the 7 to 9% rate of serious complications (infarction and/or death) at 30 days. The benefit of LMWHs in acute coronary syndromes has been validated in several clinical trials. TIMI1 study showed that combination antithrombotic therapy with enoxaparin plus aspirin is more effective than unfractionated heparin plus aspirin in decreasing ischemic outcomes in patients with unstable angina or non-Q-wave myocardial infarction in the early (30 days) phase, and that the lower recurrent ischemic event rate seen with the LMWH is achieved without an increase in major bleeding. The subcutaneous administration, the lack of a need for laboratory tests, better predictability of the anticoagulant effect and better tolerance are powerful arguments favoring LMWH for use in unstable angina and infarction without Q wave.

Reference
Turpie AG. Management of acute coronary syndromes with low molecular weight heparin: TIMI 11A and 11B. Can J Cardiol. 1998;14 Suppl E:20E-23E.

4.    Ischemic cerebrovascular disease
Low-molecular-weight heparin for the treatment of acute ischemic stroke.
N Engl J Med. 1995 Dec 14;333(24):1588-93
Method: 312 patients with ischemic stroke were randomly assigned within 48 hours of the onset of symptoms to receive high-dose nadroparin, low-dose nadroparin, or placebo subcutaneously for 10 days.
Results: see table below

Conclusions: For patients with ischemic stroke treated within 48 hours of the onset of symptoms, low-molecular-weight heparin was effective in improving outcomes at six months.