The Preventive and Therapeutic Effects of Acute and Severe Inflammatory Disorders with Heparin and Heparinoid.

Systematic inflammatory response syndrome (SIRS) and the accompanying sepsis pose a huge threat to human health worldwide. Heparin is a part of the standard supportive care for the disease. However, the molecular mechanism is not fully understood yet, and the potential signaling pathways that play key roles have not yet been elucidated. In this paper, the main findings regarding the molecular mechanisms associated with the beneficial effects of heparin, including inhibiting HMGB-1-driven inflammation reactions, histone-induced toxicity, thrombo-inflammatory response control and the new emerging mechanisms are concluded. To set up the link between the preclinical research and the clinical effects, the outcomes of the clinical trials are summarized. Then, the structure and function relationship of heparin is discussed. By providing an updated analysis of the above results, the paper highlights the feasibility of heparin as a possible alternative for sepsis prophylaxis and therapy.

Prurigo nodularis as a sweat gland/duct-related disorder: resolution associated with restoration of sweating disturbance.

Little attention has been given to the involvement of sweat glands/ducts in the pathogenesis of prurigo nodularis (PN). According to recent studies, PN is likely to develop under conditions characterized by dry skin, such as atopic dermatitis (AD), suggesting a strong impact of skin dryness on PN development. No therapeutic modalities produced complete resolution of PN without exacerbations. We previously reported that increases in skin dryness by sweating disturbance could initiate the development of AD. We investigated whether sweating responses were impaired in refractory PN lesions; and, if so, we asked whether the PN lesions could resolve by restoring sweating disturbance. Using the impression mold technique, which allows an accurate quantification of individual sweat gland/duct activity, we examined basal sweating under quiescent conditions and inducible sweating responses to thermal stimulus in PN lesions and normal-appearing skin in the same patients before and after treatment with a moisturizer or topical corticosteroids. Sweating disturbance, either basal or inducible, was most profoundly detected in the "hub" structure corresponding to the center of PN papule before the treatment. This sweating disturbance was immunohistochemically associated with the leakage of sweat into the dermis. This disturbance was restored by treatment with a moisturizer. Our limitations include a relatively small patient cohort and lack of blinding. Sweating disturbance could be one of the aggravating factors of PN development. Refractory PN with low skin hydration may resolve by restoring sweating disturbance.

Heparinoids Danaparoid and Sulodexide as clinically used drugs.

Heparin is the first glycosaminoglycan ever identified. All the heparin-like glycosaminoglycans that are also isolated from animal tissues or any polysaccharides that mimic the biological activities of heparin are called heparinoids. Heparin is the mostly sulfated glycosaminoglycan made by mast cells and an essential anticoagulant drug in modern medicine. Heparin inhibits both thrombin generation and thrombin activity, releases tissue factor pathway inhibitor, and possesses anti-inflammatory, anti-viral, anti-angiogenesis, anti-neoplastic, and anti-metastatic properties though high affinity interactions with a variety of proteins in the blood circulation. The multi-pharmacological effects of heparin are both sequence- and sulfation degree dependent. Less sulfated heparinoids have been indicated to have more physiological functions than heparin. Since the anticoagulant heparin is associated with severe side effects, such as bleeding and heparin-induced thrombocytopenia and thrombosis, it is expected that the less sulfated heparinoids might serve as alternative drugs for patients who cannot use heparin. The crude heparin isolated from animal tissues contains ~50% heparin and ~50% less sulfated heparinoids. Indeed, the less sulfated waste heparinoids 1 during heparin production is chemically degraded and developed into the clinical drug Danaparoid and the more sulfated waste heparinoids 2 during heparin production is chemically degraded and developed into the clinical drug Sulodexide. Moreover, clinical studies indicate that Danaparoid and Sulodexide have the expected pharmacological activities. We will provide an update on the chemical characteristics and clinical use of the heparinoids Danaparoid and Sulodexide. In addition, the potential clinical applications of Danaparoid and Sulodexide in other therapeutic area will also be discussed.

Efficacy of heparinoid PSS in treating cardiovascular diseases and beyond-A review of 31 years clinical experiences in China.

Heparin is a life-saving drug with multiple molecular targets and mostly well known for its anticoagulant and antithrombotic pharmacological effects in treating cardiovascular diseases. All the heparin-like polysaccharides that mimic the biological activities of heparin are called heparinoids. However, heparin has no pharmacological effect if taken orally and has to be used by injection in hospital settings. Thus, heparinoids that can be taken orally are critically needed. Propylene glycol alginate sodium sulfate (PSS) is the world's first oral heparinoid used in treating cardiovascular diseases approved by Chinese Food and Drug Administration in 1987. PSS is produced by modifying partially hydrolyzed alginate, one of the most abundant marine polysaccharides isolated from brown algae, by epoxypropane esterification and by chemical sulfation. It is used for treating and preventing cardiovascular-related diseases. The low cost (US$1.29/100 tablets, ~4 tablets/day), remarkable clinical effects, and convenient oral administration make PSS an ideal long-term cardiovascular disease-prevention drug. PSS is also clinically trialed for treating diabetes and diabetes-associated complications, hepatitis, kidney, skin, and many other diseases in China. PSS is available in most drug stores in China, and millions of patients take PSS routinely during the past 31 years. The 24,089 reported clinical cases as well as the structure, preparation, clinical efficacy, adverse reactions, pharmacokinetics, pharmacodynamics, and future perspectives of PSS based on the results of peer-reviewed publications will be discussed. This review should bring the knowledge of PSS gained in China to the world to stimulate in depth academic and clinical studies of PSS and other heparinoids.

Efficacy of heparinoid moisturizer as a prophylactic agent for radiation dermatitis following radiotherapy after breast-conserving surgery: a randomized controlled trial.

BACKGROUND: The application of heparinoid moisturizer for 2 weeks following whole-breast radiotherapy (WBRT) was previously reported to significantly increase skin water content (WC) and help improve skin dryness and desquamation. The prospective open-label, randomized trial included an exploratory arm to investigate the preventive efficacy of heparinoid moisturizer for acute radiation dermatitis (ARD). METHODS: Between April 2011 and April 2013, patients receiving WBRT were assigned (1:2:2) to receive either: moisturizer for prophylaxis (group P), moisturizer starting 2 weeks after WBRT for treatment (group M), and no moisturizer (group C). This paper presents the results of comparison between the exploratory arm and no moisturizer group. Skin WC was measured prior to WBRT, on the last day of WBRT, and 2 weeks, 4 weeks and 3 months following WBRT. Signs and symptoms were also assessed. RESULTS: Comparing two groups, WC values were significantly higher in group P until 4 weeks following WBRT. At 2 weeks following WBRT, mean WC values in group P and C were 38.5 ± 6.1 arbitrary units (a.u.) and 30.2 ± 7.8 a.u., respectively (P < 0.001). In group C, dryness was more severe at 2 and 4 weeks following WBRT and desquamation more severe until 3 months following WBRT. However, the erythema score showed no difference between the two groups. Regarding symptoms, group C pain scores on the last day of WBRT were significantly higher than in group P (P < 0.030). CONCLUSIONS: The preventive application of heparinoid moisturizer has the potential of reducing skin desquamation and dryness in patients receiving WBRT.

Low-Molecular-Weight Heparin or Heparinoids vs. Unfractionated Heparin in Acute Ischemic Stroke.

Editor's note: This is a summary of a nursing care-related systematic review from the Cochrane Library. For more information, see http://nursingcare.cochrane.org.

Early chemoprophylaxis is associated with decreased venous thromboembolism risk without concomitant increase in intraspinal hematoma expansion after traumatic spinal cord injury.

BACKGROUND: After traumatic spinal cord injury (SCI), there is increased risk of venous thromboembolism (VTE), but chemoprophylaxis (PPX) may cause expansion of intraspinal hematoma (ISH). METHODS: Single-center retrospective study of adult trauma patients from 2012 to 2015 with SCI. EXCLUSION CRITERIA: VTE diagnosis, death, or discharge within 48 hours. Patients were dichotomized based on early (≤48 hours) heparinoid and/or aspirin PPX. Intraspinal hematoma expansion was diagnosed intraoperatively or by follow-up radiology. We used multivariable Cox proportional hazards to estimate the effect of PPX on risk of VTE and ISH expansion controlling for age, injury severity score (ISS), complete SCI, and mechanism as static covariates and operative spine procedure as a time-varying covariate. RESULTS: Five hundred one patients with SCI were dichotomized into early PPX (n = 260 [52%]) and no early PPX (n = 241 [48%]). Early PPX patients were less likely blunt injured (91% vs 97%) and had fewer operative spine interventions (65% vs 80%), but age (median, 43 vs 49 years), ISS (median 24 vs 21), admission ISH (47% vs 44%), and VTE (5% vs 9%) were similar. Cox analysis found that early heparinoids was associated with reduced VTE (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.16-0.84) and reduced pulmonary embolism (PE) (HR, 0.20; 95% CI, 0.06-0.69). The estimated number needed to treat with heparinoids was 10 to prevent one VTE and 13 to prevent one PE at 30 days. Early aspirin was not associated with reduced VTE or PE. Seven patients (1%) had ISH expansion, of which four were on PPX at the time of expansion. Using heparinoid and aspirin as time-varying covariates, neither heparinoids (HR, 1.90; 95% CI, 0.32-11.41) nor aspirin (HR, 3.67; 95% CI, 0.64-20.88) was associated with ISH expansion. CONCLUSION: Early heparinoid therapy was associated with decreased VTE and PE risk in SCI patients without concomitant increase in ISH expansion. LEVEL OF EVIDENCE: Therapeutic, level IV.

Low-molecular-weight heparins or heparinoids versus standard unfractionated heparin for acute ischaemic stroke.

BACKGROUND: Low-molecular-weight heparins (LMWHs) and heparinoids are anticoagulants that may have more powerful antithrombotic effects than standard unfractionated heparin (UFH) but a lower risk of bleeding complications. This is an update of the original Cochrane Review of these agents, first published in 2001 and last updated in 2008. OBJECTIVES: To determine whether antithrombotic therapy with LMWHs or heparinoids is associated with a reduction in the proportion of people who are dead or dependent for activities in daily living compared with UFH. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched February 2017), the Cochrane Central Register of Controlled Trials (CENTRAL: the Cochrane Library Issue 1, 2017), MEDLINE (1966 to February 2017), and Embase (1980 to February 2017). We also searched trials registers to February 2017: ClinicalTrials.gov, EU Clinical Trials Register, Stroke Trials Registry, ISRCTN Registry and the World Health Organization (WHO) International Clinical Trials Registry Platform. SELECTION CRITERIA: Unconfounded randomised trials comparing LMWH or heparinoids with standard UFH in people with acute ischaemic stroke, in which participants were recruited within 14 days of stroke onset. DATA COLLECTION AND ANALYSIS: Two review authors independently chose studies for inclusion, assessed risk of bias and trial quality, extracted and analysed the data. Differences were resolved by discussion. MAIN RESULTS: We included nine trials involving 3137 participants. We did not identify any new trials for inclusion in this updated review. None of the studies reported data on the primary outcome in sufficient detail to enable analysis for the review. Overall, there was a moderate risk of bias in the included studies. Compared with UFH, there was no evidence of an effect of LMWH or heparinoids on death from all causes during the treatment period (96/1616 allocated LMWH/heparinoid versus 78/1486 allocated UFH; odds ratio (OR) 1.06, 95% CI 0.78 to 1.47; 8 trials, 3102 participants, low quality evidence). LMWH or heparinoid were associated with a significant reduction in deep vein thrombosis (DVT) compared with UFH (OR 0.55, 95% CI 0.44 to 0.70, 7 trials, 2585 participants, low quality evidence). However, the number of the major clinical events such as pulmonary embolism (PE) and intracranial haemorrhage was too small to provide a reliable estimate of the effects. AUTHORS' CONCLUSIONS: Treatment with a LMWH or heparinoid after acute ischaemic stroke appears to decrease the occurrence of DVT compared with standard UFH, but there are too few data to provide reliable information on their effects on other important outcomes, including functional outcome, death and intracranial haemorrhage.

Anticoagulation for renal replacement therapy for patients with acute kidney injury.

Patients with acute kidney injury are generally prothrombotic, and as such prone to increased risk of clotting in extracorporeal renal replacement therapy (RRT) circuits. Although some patients may be adequately treated by intermittent RRT, however due to cardiovascular instability many patients are treated by continuous renal replacement therapy (CCRT) or prolonged intermittent renal replacement therapy (PIRRT). Clotting in the RRT circuit not only reduces the efficiency of solute clearances, affects fluid balance, but also has economic health care costs. The longer duration RRT modes, CRRT and PIRRT are more prone to clotting, and more dependent on adequate anticoagulation. This review will compare the currently available systemic and regional anticoagulation options for CRRT and PIRRT for the patient with acute kidney injury.

Efficacy of Heparinoid PSS in Treating Cardiovascular Diseases and Beyond-A Review of 27 Years Clinical Experiences in China.

Propylene glycol alginate sodium sulfate (PSS) is the world's first oral heparinoid approved by Chinese Food and Drug Administration in 1987. Propylene glycol alginate sodium sulfate is produced by modifying partially hydrolyzed alginate, one of the most abundant marine polysaccharides isolated from brown algae, by epoxypropane esterification and by chemical sulfation. It is used for treating and preventing cardiovascular-related diseases. The low cost (US$1.29/100 tablets, ∼4 tablets/day), remarkable clinical effects, and convenient oral administration make PSS an ideal long-term prevention drug. Propylene glycol alginate sodium sulfate is available in most drug stores in China, and millions of patients take PSS routinely during the past 27 years. The 22 784 reported clinical cases as well as the structure, preparation, clinical efficacy, adverse reactions, pharmacokinetics, pharmacodynamics, and future perspectives of PSS based on the results of peer-reviewed publications will be discussed. This review should bring the knowledge of PSS gained in China to the world to stimulate in depth academic and clinical studies of PSS.

Randomized, prospective assessment of moisturizer efficacy for the treatment of radiation dermatitis following radiotherapy after breast-conserving surgery.

OBJECTIVE: The effect of heparinoid moisturizer use after acute skin damage for patients receiving whole-breast radiotherapy after lumpectomy is understudied. METHODS: A total of 30 patients were randomly assigned to receive heparinoid moisturizer (Group M), and 32 patients comprised the control group (Group C). Patients in Group M were instructed to apply heparinoid moisturizer from 2 weeks following whole-breast radiotherapy, and to continue to use the moisturizer until 3 months after completion of whole-breast radiotherapy. Group C patients were instructed to not apply any topical moisturizer during the study period. The relative ratio of skin water content ratio (RWCR(t) = (It /Nt)/(I0/N0)) between irradiated and non-irradiated field was calculated. Signs and symptoms were also assessed. The primary endpoint was the difference in relative ratio of skin water content ratio between 2 and 4 weeks following whole-breast radiotherapy. RESULTS: In Group C, relative ratio of skin water content ratio dropped to 0.80 ± 0.15 at 2 weeks and maintained the low level at 4 weeks following whole-breast radiotherapy. Similarly, in Group M, relative ratio of skin water content ratio dropped to 0.81 ± 0.19 at 2 weeks (prior to application), however, it returned to baseline level (1.05 ± 0.23) at 4 weeks (2 weeks after application). The arithmetic difference of relative ratio of skin water content ratio in Group M was 0.24 ± 0.23 and was significantly larger than in Group C (0.06 ± 0.15; P < 0.01). Skin dryness and desquamation were less severe in Group M. CONCLUSIONS: The application of heparinoid moisturizer for 2 weeks following whole-breast radiotherapy significantly increased water content and helped improve skin dryness and desquamation compared with no use of moisturizer.

Effectiveness of a heparinoid-containing moisturiser to treat senile xerosis.

BACKGROUND AND OBJECTIVES: With the increasing elderly population in Japan, skin problems have become a greater concern. A heparinoid-containing moisturiser is frequently used in Japan, but there is a lack of evidence for its efficacy in treating senile xerosis. To determine whether there is a correlation between age and the hydration state of the stratum corneum (SC) assessed by skin capacitance, and to evaluate the efficiency of a heparinoid-containing moisturiser and a bed bath to treat senile xerosis. METHODS: We recruited 73 individuals to assess the hydration state of the SC on their flexor forearm by measuring their skin capacitance. To evaluate the efficacy of a heparinoid-containing moisturiser on senile xerosis, we recruited seven inpatients with an inactive daily life (IDL) who had senile xerosis. They were treated with the moisturiser in addition to a bed bath in two different protocols, and we measured the skin capacitance on their flexor forearms on days 0, 7 and 14. RESULTS: There was a weak negative correlation (-0.3854, P < 0.01) between skin capacitance and age. Following the moisturiser treatments, the seven inpatients had increased hydration of both arms on days 7 and 14. The skin capacitance of the right forearm slightly decreased on day 14, even though it was significantly different from day 0 (P < 0.05). CONCLUSIONS: These findings indicate that treatment with a heparinoid-containing moisturiser together with a bed bath is an effective method for treating patients who have senile xerosis and IDL.

[Anticoagulation]. / Antikoagulation.

Anticoagulant drugs belong to the group of antithrombotic agents and are successfully used in the prophylaxis and treatment of thromboembolic disorders. The use of anticoagulants in the prevention of deep venous thrombosis has significantly lowered the risk of venous thrombosis and fatal pulmonary embolisms even in high-risk situations such as orthopedic surgery. Anticoagulants play a central role in the treatment of acute venous thrombosis and in the prevention of recurrent events. Long-term anticoagulation therapy with orally active anticoagulants significantly reduces the risk of thromboembolic complications in patients showing cardiac arrhythmias. Whereas a few years ago heparins and vitamin K antagonists were the dominant anticoagulants, today a wide range of anticoagulants with improved pharmacological profiles are available. It remains an open question whether these new anticoagulants will improve the efficacy, safety, and acceptance of anticoagulant treatment approaches.

Dabigatran etexilate: a possible replacement for heparinoids and vitamin K antagonists?

Dabigatran etexilate is the first oral anticoagulant to be approved in the United States in decades. It works directly by inhibiting clot-bound and free factor IIa (ie, thrombin) and indirectly by inhibiting platelet aggregation induced by thrombin. It is approved in the United States for stroke prophylaxis in nonvalvular atrial fibrillation. There is evidence to suggest that it is also effective for the treatment of acute venous thromboembolism and venous thromboembolism prophylaxis after knee and hip replacement surgery. Dabigatran etexilate therapy does not require laboratory monitoring, an advantage over warfarin. Unlike the earlier direct thrombin inhibitor, ximelagatran, it has demonstrated no potential for serious hepatotoxicity. It is also subject to a much lower degree of interpatient variability in dose response, has no diet-drug interactions, and has fewer clinically significant drug-drug interactions compared with warfarin. Dabigatran etexilate appears to be a valuable addition to our anticoagulant armamentarium.

Questionnaire survey of the efficacy of emollients for adult patients with atopic dermatitis.

Emollients are useful and important treatment adjuncts for patients with atopic dermatitis (AD). Heparinoid mucopolysaccharide creams or lotions are emulsion ointments for moisturizing the skin. The objective of this study was to investigate the view among adult AD patients regarding the effectiveness of emollients. We developed a questionnaire at our University Hospital to characterize how patients with AD viewed the efficacy of emollients. Patients were asked to participate prior to treatment and the questionnaire was given within 1 month of treatment. The severity of AD was graded as mild, moderate, severe or very severe. The severity scoring was performed only when the participants answered the questionnaire. Of the 110 enrolled AD patients, 103 returned the completed questionnaires. Ninety-eight patients (95.1%) used heparinoid mucopolysaccharide creams or lotions. There was a strong correlation between their view of the efficacy of the emollient and the condition of dry skin, pruritus and eczematous skin. There was a significant correlation between AD severity and the perceived efficacy of the emollient for dry skin, pruritus and eczematous skin. There was a greater sense of efficacy among patients with milder AD than in more severe AD cases. Patients who felt sufficient efficacy of the emollient for pruritus were significantly older than those who felt there was no efficacy. In addition, the age of onset of AD was significantly higher among those who felt sufficient efficacy for pruritus compared to those who felt little efficacy. We speculate that the efficacy of emollients could be demonstrated in the treatment of milder AD, but may only have partial efficacy in more severe cases. Emollient therapy might have lower efficacy for pruritus among younger or earlier onset AD patients.

Should anticoagulation be resumed after intracerebral hemorrhage?

Intracerebral hemorrhage (ICH) is the most feared and the most deadly complication of oral anticoagulant therapy, eg, with warfarin (Coumadin). After such an event, clinicians wonder whether their patients should resume anticoagulant therapy. The authors review the management of anticoagulation during and after anticoagulation-associated ICH.

[Efficacy of local heparinoids on preventing edema and ecchymosis after rhinoplasty]. / Lokal heparinoidlerin rinoplasti sonrasi ödem ve ekimozun önlenmesindeki etkinligi.

OBJECTIVES: In this study, the effect of local heparinoids on prevention of periorbital edema and ecchymosis due to rhinoplasty was investigated. PATIENTS AND METHODS: Twenty patients (12 males, 8 females, mean age 23.3 years; range 19 to 34 years) who had bilateral osteotomy were randomly administered postoperative local heparinoid on one periorbital region, without performing any care in the other one. One and a half centimeter of heparinoid was applied once a day for nine days. The other periorbital region was used as control group. The heparinoid was applied additionally, 8 mg dexamethasone i.v was administered to all patients 30 minutes before the surgery and 24 hours after the surgery. Photographs of each patient which were taken on postoperative days 1, 3, 5 and 9 were evaluated as double-blind by two observers. Scoring was performed according to edema and ecchymosis scales. RESULTS: There was no statistical difference with respect to edema and ecchymosis between local heparinoid treated and control eyes. CONCLUSION: No hypersensitivity to drugs occurred in any patients. After analysing the scores, we observed that heparanoids administered locally was not effective in preventing periorbital edema and ecchymosis after rhinoplasty (p>0.05).