Is Continuous Low-Dose Prophylaxis Superior to On-Demand Treatment for Patients with Hemophilia?

2016 ◽  
Vol 42 (05) ◽  
pp. 533-540 ◽  
Author(s):  
Jerzy Windyga
Keyword(s):  
Low Dose ◽  
Randomized Clinical Trials ◽  
Venous Access ◽  
Convincing Evidence ◽  
Clotting Factor ◽  
High Dose ◽  
Optimal Dosage ◽  
On Demand ◽  
Related Quality

Long-term (or continuous) prophylaxis is generally accepted as the best form of treatment for patients with severe hemophilia A and B. Results of recent prospective, randomized clinical trials, as well as observational studies performed in the last decades, have provided strong and convincing evidence that continuous prophylaxis leads to reduction in the number of bleeding episodes, better joint status and improved health-related quality of life as compared with on-demand (or episodic) treatment. Nevertheless, many questions regarding long-term prophylaxis still remain open, for instance: when should prophylaxis be started (before or after the first joint bleeding), what is the optimal dosage to replace the missing factor, when should discontinuation of long-term prophylaxis be considered, what is the best way to measure the outcome of prophylaxis, etc. Moreover, there are numerous obstacles to widespread use of prophylactic therapy. The most challenging seem to be adequate venous access (particularly in younger patients) and patients' adherence. The crucial barrier to long-term prophylaxis is, however, the remarkably high cost of clotting factor concentrates. For most countries high-dose or intermediate-dose prophylaxis regimens are not affordable due to lack of economic resources. So, is continuous prophylaxis reserved exclusively for wealthy societies? Fortunately, there is an increasing body of evidence to suggest that low-dose prophylaxis offers significant benefits over on-demand treatment with comparable amounts of factor concentrate (and much lower amounts if compared with intermediate or high-dose prophylaxis regimens). The aim of this article is to discuss the clinical and economical aspects of continuous prophylaxis in hemophilia with emphasis on the low-dose regimens.

scholarly journals The Effect of Long-Term Low-Dose Atropine on Refractive Progression in Myopic Australian School Children

2021 ◽  
Vol 10 (7) ◽  
pp. 1444
Author(s):  
William Myles ◽  
Catherine Dunlop ◽  
Sally A. McFadden
Keyword(s):  
Low Dose ◽  
High Dose ◽  
Eye Drops ◽  
Myopia Progression ◽  
At Risk Children ◽  
Slow Group ◽  
Blue Eyes ◽  
Global Population ◽  
Axial Growth

Myopia will affect half the global population by 2050 and is a leading cause of vision impairment. High-dose atropine slows myopia progression but with undesirable side-effects. Low-dose atropine is an alternative. We report the effects of 0.01% or 0.005% atropine eye drops on myopia progression in 13 Australian children aged between 2 and 18 years and observed for 2 years without and up to 5 years (mean 2.8 years) with treatment. Prior to treatment, myopia progression was either ‘slow’ (more positive than −0.5D/year; mean −0.19D/year) or ‘fast’ (more negative than −0.5D/year; mean −1.01D/year). Atropine reduced myopic progression rates (slow: −0.07D/year, fast: −0.25D/year, combined: before: −0.74, during: −0.18D/year, p = 0.03). Rebound occurred in 3/4 eyes that ceased atropine. Atropine halved axial growth in the ‘Slow’ group relative to an age-matched model of untreated myopes (0.098 vs. 0.196mm/year, p < 0.001) but was double that in emmetropes (0.051mm/year, p < 0.01). Atropine did not slow axial growth in ‘fast’ progressors compared to the age-matched untreated myope model (0.265 vs. 0.245mm/year, p = 0.754, Power = 0.8). Adverse effects (69% of patients) included dilated pupils (6/13) more common in children with blue eyes (5/7, p = 0.04). Low-dose atropine could not remove initial myopia offsets suggesting treatment should commence in at-risk children as young as possible.

Enlargement of cerebrospinal fluid spaces in long-term benzodiazepine abusers

1987 ◽  
Vol 17 (4) ◽  
pp. 869-873 ◽  
Author(s):  
C. Schmauss ◽  
J.-C. Krieg
Keyword(s):  
Low Dose ◽  
Matched Control ◽  
Control Group ◽  
High Dose ◽  
Withdrawal Therapy ◽  
The Mean ◽  
Dose Dependent ◽  
Dose Dependent Effect ◽  
Age And Sex

SynopsisIn 17 benzodiazepine (BDZ) dependent in-patients a CT scan was performed before initiation of withdrawal therapy. The evaluation of the ventricular to brain ratio (VBR) by standardized and computerized measurements revealed significantly higher mean VBRs for both high-and low-dose BDZ-dependent patients compared to the mean VBR of an age- and sex-matched control group. In addition, the mean VBR of high-dose BDZ-dependent patients (N = 8) was significantly higher than the mean VBR of low-dose BDZ-dependent patients (N = 9). This difference could not be accounted for by the age of the patients or duration of BDZ-dependency and, therefore, suggests a dose-dependent effect of BDZs on the enlargement of internal CSF-spaces. On the other hand, higher values for the width of external CSF-spaces were found to be related to increasing age of the patients and duration of BDZ-dependency.

scholarly journals Effects of replacement therapies with clotting factors in patients with hemophilia: A systematic review and meta-analysis

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262273
Author(s):  
Carolina J. Delgado-Flores ◽  
David García-Gomero ◽  
Stefany Salvador-Salvador ◽  
José Montes-Alvis ◽  
Celina Herrera-Cunti ◽  
...  
Keyword(s):  
Low Dose ◽  
Prophylactic Treatment ◽  
Hemophilia A ◽  
Clotting Factor ◽  
High Dose ◽  
Bleeding Rate ◽  
Episodic Treatment ◽  
Grade Methodology ◽  
Inform Decision Making ◽  
Intermediate Dose

Background Different prophylactic and episodic clotting factor treatments are used in the management of hemophilia. A summarize of the evidence is needed inform decision-making. Objective To compare the effects of factor replacement therapies in patients with hemophilia. Methods We performed a systematic search in PubMed, Central Cochrane Library, and Scopus. We included randomized controlled trials (RCTs) published up to December 2020, which compared different factor replacement therapies in patients with hemophilia. Random-effects meta-analyses were performed whenever possible. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The study protocol was registered in PROSPERO (CRD42021225857). Results Nine RCTs were included in this review, of which six compared episodic with prophylactic treatment, all of them performed in patients with hemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means [RM]: 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups (p = 0.003, I2 = 82.9%). In addition, compared to the episodic treatment group, the annualized joint bleeding rate was lower in the low-dose prophylactic group (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic group (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic group (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates (CFCs), assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration. Conclusions Our results suggest that prophylactic treatment (at either low, intermediate, or high doses) is superior to episodic treatment for bleeding prevention. In patients with hemophilia A, the bleeding rate seems to have a dose-response effect. However, no study compared different doses of prophylactic treatment, and all results had a very low certainty of the evidence. Thus, future studies are needed to confirm these results and inform decision making.

Case Report: Rapid Response to Low-Dose Thalidomide in a Case of Severe Steroid Recalcitrant Erythema Nodosum Leprosum

2021 ◽  
Author(s):  
B. Savitha ◽  
Kabir Sardana ◽  
Ritu Kumari ◽  
Ananta Khurana ◽  
Surabhi Sinha ◽  
...  
Keyword(s):  
Low Dose ◽  
Erythema Nodosum ◽  
Lepromatous Leprosy ◽  
High Dose ◽  
Effective Treatment Option ◽  
Steroid Dependence ◽  
Erythema Nodosum Leprosum ◽  
Organ Specific ◽  
Inflammatory Drugs

Erythema nodosum leprosum (ENL), or type 2 lepra reaction, presents with crops of evanescent, tender erythematous nodules accompanied by fever, arthralgia, weight loss, malaise, and organ-specific manifestations, and is seen in borderline and lepromatous leprosy. The drugs approved for ENL include nonsteroidal anti-inflammatory drugs, systemic steroids, thalidomide, and clofazimine. The management of ENL is challenging because long-term steroid use leads to steroid dependence. Our patient had severe steroid recalcitrant ENL with vesicular and pustular lesions mimicking Sweet’s syndrome, and was treated effectively with a low-dose thalidomide regimen (100 mg/d) as opposed to the high dose (400 mg/d) recommended in the literature. We discuss the patho-mechanics and clinical utility of a low-dose thalidomide regimen as an effective treatment option for ENL.

Effects of long-term continuous GnRH administration on the pituitary–gonadal axis in Eld's deer stags (Cervus eldi thamin)

1995 ◽  
Vol 73 (9) ◽  
pp. 1609-1619 ◽  
Author(s):  
S. L. Monfort ◽  
J. L. Brown ◽  
T. C. Wood ◽  
M. Bush ◽  
L. R. Williamson ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
High Dose ◽  
Fertile Period ◽  
Nonbreeding Season ◽  
Testosterone Secretion ◽  
High Doses ◽  
Seasonal Decline ◽  
Seasonally Breeding

Eld's deer stags (Cervus eldi thamin) (in groups of three) were continuously administered gonadotropin-releasing hormone (GnRH) in control, low, medium, or high doses (0, 20.1 ± 0.7, 83.3 ± 2.6, and 292.9 ± 4.9 ng∙kg−1∙d−1, respectively) via osmotic minipumps for ~80 d to investigate the potential for precociously reactivating the pituitary–testicular axis during the nonbreeding season. Secretory patterns of LH, FSH, and testosterone concentrations were qualitatively similar among treatments. However, in the low-dose group, basal LH and FSH concentrations were both increased (p < 0.05) and pituitary responsiveness to a superimposed GnRH challenge was augmented (p < 0.05) after 12 weeks of treatment compared with all other groups. Despite these endocrine changes, continuous low-dose GnRH administration was not effective for precociously inducing testicular activity in this seasonally breeding species. High-dose GnRH administration initially induced a transient increase in LH, FSH, and testosterone secretion and delayed, but did not prevent, the seasonal decline in spermatogenesis. After 6–12 weeks of high-dose GnRH administration, however, attenuated pituitary responsiveness appeared to delay the normal seasonal reactivation of the pituitary–gonadal axis. In conclusion, prolonged, continuous low-dose GnRH administration did not effectively translate into a precocious onset of testicular activity; therefore, this specific approach is unlikely to be useful for prolonging the fertile period in this seasonally breeding species.

scholarly journals MANAGEMENT OF ENDOCRINE DISEASE: Critical review of the evidence underlying management of glucocorticoid-induced hyperglycaemia

2018 ◽  
Vol 179 (4) ◽  
pp. R207-R218 ◽  
Author(s):  
Anjana Radhakutty ◽  
Morton G Burt
Keyword(s):  
Low Dose ◽  
Randomized Clinical Trials ◽  
Chronic Inflammatory Disease ◽  
Hospitalized Patients ◽  
Isophane Insulin ◽  
Wide Range ◽  
Clinical Benefits ◽  
High Doses ◽  
Bolus Insulin

Glucocorticoids are frequently prescribed to patients with a wide range of inflammatory and autoimmune diseases. The semi-synthetic glucocorticoid prednisolone is most commonly prescribed and in two main patterns. Prednisolone is prescribed short term at medium-high doses to treat an acute inflammatory illness or long term at lower doses to attenuate chronic inflammatory disease progression. In hospitalized patients with acute prednisolone-induced hyperglycaemia, there is a distinct circadian pattern of glucose elevation, which occurs predominantly in the afternoon and evening. As a morning dose of isophane insulin has a pharmacokinetic pattern that matches this pattern of glucose elevation, treatment comprising a basal dose of morning isophane insulin in combination with short-acting insulin boluses is generally recommended. However, evidence is lacking that isophane-based basal bolus insulin is more efficacious than other insulin regimens. In outpatients, low-dose prednisolone causes a small increase in post glucose-load glucose concentration but no change in overall glycaemic control as measured by glycosylated haemoglobin. If treatment is indicated, metformin has been shown to be effective and may attenuate other adverse effects of long-term prednisolone therapy. Further studies are necessary in order to identify factors underlying the variability in response to insulin therapy and clinical benefits of treatment in hospitalized patients with prednisolone-induced hyperglycaemia. In outpatients prescribed low-dose prednisolone, the cardiovascular risk associated with postprandial hyperglycaemia and efficacy of hypoglycaemic therapies should be evaluated in future randomized clinical trials.

Successful Long Term Therapeutic Expression of Factor VIII in Hemophilia A Dogs After Administration of AAV-cFVIII Using a Two-Chain or Single Chain Delivery Approach.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 546-546
Author(s):  
Denise E. Sabatino ◽  
Ekaterina Altynova ◽  
Amy M. Lange ◽  
Shangzhen Zhou ◽  
Elizabeth P. Merricks ◽  
...  
Keyword(s):  
Low Dose ◽  
Hemophilia A ◽  
High Dose ◽  
Dependent Manner ◽  
Igg Antibodies ◽  
Single Chain ◽  
Spontaneous Bleeding ◽  
Aav Vector ◽  
Bleeding Episodes

Abstract Abstract 546 While adeno-associated virus (AAV) is a promising gene delivery vector, it has been challenging to deliver FVIII due to the large size of the FVIII cDNA and the high frequency of FVIII antibody formation in hemophilia A (HA) patients. We used two approaches to overcome the size limitation of AAV for FVIII: (1) two-chain delivery in which the canine FVIII (cFVIII) heavy chain (HC) is delivered in one AAV vector and the cFVIII light chain (LC) is delivered in a second AAV vector and (2) single chain delivery in which the B-domain deleted cFVIII cDNA with minimal regulatory elements is within one AAV vector. In the two-chain approach AAV-HC (4.0 Kb) and AAV-LC (3.9 Kb) with a liver specific promoter was co-injected at a dose of 6×1012 vector genomes/vector/kg or 1.25×1013vg/vector/kg using AAV8 or AAV9 via hepatic infusion. Five hemophilia A dogs treated with AAV-HC and AAV-LC expressed 0.5-11% cFVIII in a dose-dependent manner. The mean cFVIII activity based on Coatest assay for the low dose was 1.3% (>1220d)(Linus)(AAV8) and 0.6% (>1770d)(H19)(AAV9), while for the high dose it was 5.2% (800d)(F24)(AAV8) and 2.4% (>1270d)(Woodstock)(AAV9). One dog (J60) had a splenectomy due to a complication at the time of surgery and has maintained high levels of expression (mean 11.0%; >820d). The WBCT consistently remained at a mean of 17.6 min for low dose dogs and 13.7 min for high dose dogs compared to 8-12 min in normal dogs. Using novel reagents that we generated specific to cFVIII, we developed assays to detect cFVIII antigen levels and IgG antibodies. Despite receiving equal doses of each vector, at day 85 the cFVIII-LC antigen levels (71.7 ± 19.2 ng/ml) were >10-fold higher than would be predicted based on activity while the cFVIII-HC antigen levels (14.6 ± 9.2 ng/ml) were >3-fold higher than activity. Since functional FVIII synthesis relies on the co-transduction of AAV-HC and AAV-LC in the same cell, this suggests that only a portion of the vector co-transduces and expresses cFVIII in the same cell and that the light chain is secreted more efficiently than the HC. No IgG antibodies to cFVIII were detected at any time point in these dogs. Three dogs have maintained FVIII expression for >3.5 years and two dogs for >2 years with ongoing observation. No spontaneous bleeding episodes have been observed in these dogs for a cumulative observation of >16 years while >80 bleeding episodes would be expected during this time period. The second approach, the single chain delivery, overcomes the co-transduction requirement of the two-chain approach by ensuring that each transduced cell expresses functional FVIII. However, it is difficult to efficiently package the large 5.2 Kb single chain construct into an AAV vector. Since no significant differences were observed between AAV8 and AAV9 using the two-chain approach, we used AAV8 to deliver the single chain cFVIII by peripheral vein infusion at 2×1013vg/kg or 4×1013vg/kg. The mean cFVIII activity was 0.7% (>430d) for the low dose dog (L51) and 6.8% (>290d) and 2.2% (>110d) for the high dose dogs (M06, M50). cFVIII HC and LC ELISA showed that cFVIII antigen levels correlated with activity. WBCT was a mean of 19.1 min for L51, 15.3 min for M06 and 11.6 min for M50. No spontaneous bleeding episodes have been observed in these dogs. The high dose dogs had no IgG antibodies to FVIII. L51 had transient IgG antibodies to FVIII until d52 in the absence of a Bethesda titer. A rise in FVIII expression in L51 coincided with the disappearance of anti-cFVIII antibodies. Comparison of single chain and two-chain delivery of FVIII reveals that (1) long term therapeutic levels of cFVIII in a dose-dependent manner can be obtained with both delivery approaches; (2) circulating cFVIII antigen levels are >10-fold higher than activity in the two-chain delivery in contrast to single chain delivery in which antigen correlates with activity; and (3) high antigen levels may facilitate tolerance to FVIII in the setting of liver-directed gene transfer, since a transient non-inhibitory antibody was observed in only one dog with very low FVIII levels. Notably, no cellular toxicity due to continuous expression of various forms of FVIII was found in these animals based on long-term sustained FVIII expression levels and normal liver enzymes in all eight HA dogs. Further studies to characterize the immune responses to the transgene will define the optimal vector approach. These data will form the basis for clinical studies in humans with severe HA. Disclosures: No relevant conflicts of interest to declare.

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