Topically Applied Halofuginone, An Inhibitor of Collagen Type I Transcription, Reduces Peritendinous Fibrous Adhesions Following Surgery

Nyska, Meir; Nyska, Abraham; Rivlin, Eyal; Porat, Shay; Pines, Mark; Shoshan, S.; Nagler, Arnon

doi:10.3109/03008209609021495

Cited by 36 publications

(20 citation statements)

References 13 publications

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“…Recently, halofuginone has been identified as a specific inhibitor of collagen type I gene expression (5,25). The rediscovery of halofuginone has led to intensive preclinical studies and rapid development of the drug for the control of many diseases involved in excessive collagen synthesis, such as pulmonary fibrosis (21), liver cirrhosis (24), peritendinous fibrous adhesions after surgery (22), wound repair (1), and injury-induced arterial intimal hyperplasia (18). A phase I clinical trial of halofuginone for the treatment of scleroderma is under way, and a phase II clinical trial of Tempostatin (halofuginone hydrobromide) for the treatment of recurring bladder carcinoma has just started in the United Kingdom.…”

Section: Discussionmentioning

confidence: 99%

Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs

Jiang

Zeng

Gettayacamin

et al. 2005

Antimicrob Agents Chemother

126

102

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Febrifugine is the active principal isolated 50 years ago from the Chinese herb chang shan (Dichroa febrifuga Lour), which has been used as an antimalarial in Chinese traditional medicine for more than 2,000 years. However, intensive study of the properties of febrifugine has been hindered for decades due to its side effects. We report new findings on the effects of febrifugine analogs compared with those of febrifugine extracted from the dry roots of D. febrifuga. The properties of the extracted febrifugine were comparable to those obtained from the standard febrifugine provided by our collaborators. A febrifugine structure-based computer search of the Walter Reed Chemical Information System identified 10 analogs that inhibited parasite growth in vitro, with 50% inhibitory concentrations ranging from 0.141 to 290 ng/ml. The host macrophages (J744 cells) were 50 to 100 times less sensitive to the febrifugine analogs than the parasites. Neuronal (NG108) cells were even more insensitive to these drugs (selectivity indices, >1,000), indicating that a feasible therapeutic index for humans could be established. The analogs, particularly halofuginone, notably reduced parasitemias to undetectable levels and displayed curative effects in Plasmodium berghei-infected mice. Recrudescence of the parasites after treatment with the febrifugine analogs was the key factor that caused the death of most of the mice in groups receiving an effective dose. Subcutaneous treatments with the analogs did not cause irritation of the gastrointestinal tract when the animals were treated with doses within the antimalarial dose range. In summary, these analogs appear to be promising lead antimalarial compounds that require intensive study for optimization for further down-selection and development.

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Section: Discussionmentioning

confidence: 99%

Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs

Jiang

Zeng

Gettayacamin

et al. 2005

Antimicrob Agents Chemother

126

102

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“…28 In animal models in which fibrosis was induced, halofuginone prevented the increase in collagen synthesis and collagen ␣1(I) gene expression. These models included mice afflicted with cGvHD, 29 rats with pulmonary fibrosis after bleomycin treatment, 30 and rats developing adhesions after surgery in tendons, 31 the abdomen, 32 and uterine horns. 33 In liver, halofuginone prevented collagen type I gene expression in dimethylnitrosamine-induced cirrhosis in rats.…”

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confidence: 99%

Halofuginone to Prevent and Treat Thioacetamide–Induced Liver Fibrosis in Rats

2001

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Hepatic fibrosis is associated with activation of hepatic stellate cells (HSC), the major source of the extracellular matrix (ECM) proteins. The predominant ECM protein synthesized by the HSC is collagen type I. We evaluated the effect of halofuginone-an inhibitor of collagen synthesis-on thioacetamide (TAA)-induced liver fibrosis in rats. In the control rats the HSC did not express smooth muscle actin, collagen type I gene, or tissue inhibitor of metalloproteinases-2 (TIMP-2), suggesting that they were in their quiescent state. When treated with TAA, the livers displayed large fibrous septa, which were populated by smooth muscle actin-positive cells expressing high levels of the collagen ␣1 (

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“…HF has been reported to reduce Wbrosis after bleomycininduced pulmonary Wbrosis [9], to improve Wbrosis after dimethylnitrosamine-induced liver cirrhosis in rats [7], to reduce postoperative Wbrous tendinous adhesions in chickens [10], to prevent postoperative intra-abdominal adhesions [11]. Our recent study showed that HF decreases Wbrosis/scar tissue formation secondary to experimentally induced subglottic trauma in the rat model [12].…”

Section: Discussionmentioning

confidence: 94%

Efficacy of topical halofuginone in myringotomy patency

Özdemir

Cincik

Doğru

et al. 2010

Eur Arch Otorhinolaryngol

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The objective of the study is to determine whether topical halofuginone (HF) application has an impact on prolonging the time for healing of myringotomy incision, and to investigate histopathologic effects of HF on tympanic membrane (TM) in rat model. Forty rats with normal eardrums were involved in this study. The study group and control group consisted of 30 and 10 rats, respectively. A posterior incision 1 mm in diameter was made on healthy eardrums of the rats. Following incision, gelfoam soaked with HF hydrobromide of 30 mg/dl was applied on the perforation in study group, whereas gelfoam soaked with isotonic saline was applied on the perforation in control group. On days 1, 3, 7, 10, 14, 18, 21, 24, 27, and 30, otoendoscopic evaluation of eardrums under general anesthesia was conducted and perforations were screened. A rat of each group was killed in control days and TMs were dissected to evaluate histopathological changes. The average times for patency of perforation in study and control groups were 21.43 and 7.50 days, respectively. The difference was found to be statistically significant (p < 0.05). Histopathological evaluation revealed that HF reduces hyalinisation and fibrosis in eardrum, when compared with the control group. In conclusion, HF significantly delays closure time of myringotomies in rat model. However, this delay may not be enough for recovery of otitis media with effusion.

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Topically Applied Halofuginone, An Inhibitor of Collagen Type I Transcription, Reduces Peritendinous Fibrous Adhesions Following Surgery

Cited by 36 publications

References 13 publications

Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs

Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs

Halofuginone to Prevent and Treat Thioacetamide–Induced Liver Fibrosis in Rats

Efficacy of topical halofuginone in myringotomy patency

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