Case Report : Efficacy of dobesilate in insertional Achilles tendinopathy

Achilles tendinopathy is an overuse syndrome, common among runners, with sometimes considerable negative impact on their performance, overall health, and well-being. Our report shows that local injection of an aqueous solution of the diethylammonium salt of dobesilate, an inhibitor of fibroblast growth factor with significant anti-angiogenic and anti-inflammatory effects, is effective in reducing vascular density and pain in insertional Achilles tendinopathy.

A 37-year-old healthy Caucasian male runner presented with a 3 month history of chronic pain and swelling on top of his left heel.There was no history of direct trauma to his left heel.He experienced a constant dull pain when walking.He had to discontinue sport because of the severity of his pain.At the beginning of symptomatology, the patient initiated sporadic treatments with over-the-counter analgesic and anti-inflammatory drugs.One week before presentation, following recommendations of his physician, the patient initiated, unsuccessfully, a treatment with paracetamol (1g twice a day) and ibuprofen (400mg three times per day).At presentation heel pain was rated as 6 out of 10 on the visual analogue scale (VAS).Colour doppler ultrasound examination at the insertional site of the left Achilles tendon revealed significant neovascularity, mainly at intratendinous mass (Figure 1).After discussing the various treatment options, the patient opted to try a dobesilate injection to the Achilles tendon and gave informed consent.Lidocaine was infiltrated into the skin overlying the Achilles tendon insertional junction.Dobesilate (2 ml of diethylammonium salt formulation; etamsylate, Dicynone ® , Sanofi, France) was peritendinously injected under ultrasound guidance into the Achilles tendon.The procedure was uneventful.The patient was advised to perform some gentile range of motion exercises the following day.He was back to his regular life the day after injection.At the 1 month follow-up visit, the patient reported a marked reduction of his pain, and the VAS was rated as 1.Colour doppler ultrasound scans revealed a significant reduction of tendon hypervascularity at the time (Figure 1).The patient was able to return to running and his previous level of sport without any restrictions.No adverse events were observed during treatment and the 2 month follow-up period.

Discussion
Tendinopathy is a common health problem affecting nearly 8% of middle and long distance runners under the age of 45.The consequences of this medical condition include pain, disability, early retirement from sport and work, mental distress and health care cost 1 .The treatment of tendinopathies is a significant challenge for sport medicine physicians wishing to avoid surgery, since there is no obvious non-surgical options as efficacious therapeutic treatments 2 .Inflammation and angiogenesis are two cardinal biological processes which cause tendinopathies 3 .Consequently, control of inflammation and neovascularization seem two obvious targets to develop new treatments for management of tendinopathies.
The anti-inflammatory treatments, by themselves, do not seem to achieve a significant success in the case of Achilles tendinopathies, in addition they seem less effective in patients with Achilles insertional tendinopathies than in those with mid-portion tendinopathies 4 .
Hypervascularity has been reported in human and animal Achilles tendinopathies, as well as in patellar disease, long head biceps tendons and in the rotator cuff 5,6 .Furthermore, the tendon area of hypervascularization coincides with the most common localisation for tears 5,6 .Healthy tendons are not painful, and have no detectable blood vessels, as assessed by ultrasonography 9 .However, pain is a common symptom which accompanies neovascularization in chronic Achilles tendinopathies.Furthermore, tendon neovascularization is accompanied with nerve in-growth facilitating pain transmission in Achilles tendinopathy 10 .Consequently, strategies to destroy neovessels (i.e local application of sclerosing agents as polidocanol) cause pain amelioration 11,12 , despite the associated side effects 13,14 .Inhibiting angiogenesis in addition to inflammation seems, thus, a reasonable strategy for development of new therapies against Achilles tendinopathies 4,7,8,15 .
Fibroblast growth factor (FGF) is nowadays considered a proinflammatory and pro-angiogenic protein [16][17][18] .FGF can be inhibited with dobesilate 19 .This old drug, with a high safety profile 20 but with considerably vague pharmacological and therapeutic targets until its anti-FGF activities were described, has been shown, since this precise point in time, to relieve inflammation and prevents undesirable neovessel formation in many different pathological scenarios [21][22][23][24][25] .
The data presented in this case report show that local administration of dobesilate seems also effective in reducing neovessel formation and inflammation in the case of insertional Achilles tendinopathies.Recently, it has been reported that FGF is a nociceptive modulator 26 .Since target inhibition of FGF in tissues undergoing pathological angiogenesis is safe without significant off-target effects on nondiseased tissues 27 , dobesilate seems an attractive drug for treating tendinopathies.
Large-scale therapeutic trials are obviously needed for more solidly establishing the efficacy of dobesilate in the treatment of Achilles tendinopathy.The results presented in this report seem a reasonable support for undertaking these trials.

3.
There is little modern evidence that neovascularity is the primum movens of tendinopathy, and that it should be a therapeutic target.
The enrollment of the patient after such a short period of symptoms is questionable.
The follow up is much too short to be able to make recommendations.References 1. Tol J, Spiezia F, Maffulli N: Neovascularization in Achilles tendinopathy: have we been chasing a red herring?.

Pedro Cuevas
In summary, our report has been considered by the not to be of an acceptable scientific standard reviewer Nicola Maffulli.This blunt disqualifier statement is surprising.The report submited to F1000 has been elaborated according the same scientific standards employed in the rest of our scientific papers, quoted thousands of times (according the statistics of the WOK), sometimes published in journals of the widest international diffusion.Keystone for the scientific disqualification seems an article published by the reviewer in 2012, in the journal "Knee Surg Sports Traumatol Arthrosc" (20:1891-1894), which has been quoted eleven times along these last four years, that defends that detecting neovessels has no additional value for the diagnosis, no firmly confirmed in Achilles tendinopathy, a statement that prognostic value, and no proven relation with symptoms seems contradictory with some studies quoted in the same article: In (a series of) Swedish studies, the investigators were able to detect neovessels in 100 % of the symptomatic tendons [1, 26, 37,  38]..... other researchers, ... reported a percentage varying from 47 to 88 % [13, 41, 42, 54].
Our report does not aim to engage in any sort of controversy about the relevance of neovascularization of the Achilles tendinopathy and whether it is a or not in such primum movens diseases, a discussion that still seem widely open, according to the results of bibliographical searches of recent publications.Accordingly, the report should not be judged from such a point of view.We, exclusively, intend to report the case of a tendinopathy the vascularization of which healed very efficiently, accompanied of a considerable relief of pain, after local treatment with an inhibitor of fibroblast growth factor (FGF), a main angiogenic and inflammatory protein.The treatment was applied after three months of unsuccessfully treated chronic pain and swelling on top of his left heel that made the patient had to discontinue sport practices.This does not seem a questionable short period of symptoms, before the enrolment in the alternative treatment (point 2 of the reviewer considerations), taking into account the quite undesiderable consequences of a prolonged inflammation and abnormal vascularization [Carmeliet, Nature 438 (2005) 932].We did not try to report a long term healing process, but the fast disappearance of neovascularization and pain relief by inhibiting FGF, a treatment supported by a solid rationale.To this purpose a two-month follow up seems reasonable.A different question is if we had intended to report on a long-term cure.But this is the objective of a different-aimed observational study that we are carrying out at this moment (point 3 of the reviewer comments).The treatment was carried out, as carrying out at this moment (point 3 of the reviewer comments).The treatment was carried out, as detailedly described in the report, according to the requirements of a proper science, which, surprisingly, was straight on globally disqualified without pointing out at any major mistake in the followed procedure.
We disclose any competing interests.

Competing Interests:
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Figure 1 .
Figure 1.Effect of dobesilate injection in insertional Achilles tendinopathy.Long-axis colour doppler ultrasound scans taken at three different planes before and after one month of treatment.Note the reduction of hypervascularity after treatment.The large vessels were persistently observed in real time ultrasonography examination.Achilles tendon mass was delimited by discontinuous line.